全文获取类型
收费全文 | 2572篇 |
免费 | 344篇 |
专业分类
2916篇 |
出版年
2021年 | 21篇 |
2016年 | 34篇 |
2015年 | 67篇 |
2014年 | 62篇 |
2013年 | 82篇 |
2012年 | 100篇 |
2011年 | 140篇 |
2010年 | 70篇 |
2009年 | 72篇 |
2008年 | 100篇 |
2007年 | 87篇 |
2006年 | 86篇 |
2005年 | 98篇 |
2004年 | 113篇 |
2003年 | 75篇 |
2002年 | 84篇 |
2001年 | 74篇 |
2000年 | 77篇 |
1999年 | 51篇 |
1998年 | 34篇 |
1997年 | 31篇 |
1996年 | 29篇 |
1995年 | 29篇 |
1994年 | 27篇 |
1993年 | 21篇 |
1992年 | 72篇 |
1991年 | 61篇 |
1990年 | 54篇 |
1989年 | 57篇 |
1988年 | 55篇 |
1987年 | 45篇 |
1986年 | 59篇 |
1985年 | 54篇 |
1984年 | 59篇 |
1983年 | 37篇 |
1982年 | 35篇 |
1981年 | 27篇 |
1980年 | 32篇 |
1979年 | 41篇 |
1978年 | 40篇 |
1977年 | 45篇 |
1975年 | 31篇 |
1974年 | 41篇 |
1973年 | 26篇 |
1972年 | 42篇 |
1971年 | 39篇 |
1970年 | 34篇 |
1969年 | 37篇 |
1968年 | 33篇 |
1967年 | 22篇 |
排序方式: 共有2916条查询结果,搜索用时 0 毫秒
991.
Shira Weisthal Nurit Keinan Danya Ben-Hail Tasleem Arif Varda Shoshan-Barmatz 《Biochimica et Biophysica Acta (BBA)/Molecular Cell Research》2014
VDAC1, an outer mitochondrial membrane (OMM) protein, is crucial for regulating mitochondrial metabolic and energetic functions and acts as a convergence point for various cell survival and death signals. VDAC1 is also a key player in apoptosis, involved in cytochrome c (Cyto c) release and interactions with anti-apoptotic proteins. Recently, we demonstrated that various pro-apoptotic agents induce VDAC1 oligomerization and proposed that a channel formed by VDAC1 oligomers mediates cytochrome c release. As VDAC1 transports Ca2 + across the OMM and because Ca2 + has been implicated in apoptosis induction, we addressed the relationship between cytosolic Ca2 + levels ([Ca2 +]i), VDAC1 oligomerization and apoptosis induction. We demonstrate that different apoptosis inducers elevate cytosolic Ca2 + and induce VDAC1 over-expression. Direct elevation of [Ca2 +]i by the Ca2 +-mobilizing agents A23187, ionomycin and thapsigargin also resulted in VDAC1 over-expression, VDAC1 oligomerization and apoptosis. In contrast, decreasing [Ca2 +]i using the cell-permeable Ca2 +-chelating reagent BAPTA-AM inhibited VDAC1 over-expression, VDAC1 oligomerization and apoptosis. Correlation between the increase in VDAC1 levels and oligomerization, [Ca2 +]i levels and apoptosis induction, as induced by H2O2 or As2O3, was also obtained. On the other hand, cells transfected to overexpress VDAC1 presented Ca2 +-independent VDAC1 oligomerization, cytochrome c release and apoptosis, suggesting that [Ca2 +]i elevation is not a pre-requisite for apoptosis induction when VDAC1 is over-expressed. The results suggest that Ca2 + promotes VDAC1 over-expression by an as yet unknown signaling pathway, leading to VDAC1 oligomerization, ultimately resulting in apoptosis. These findings provide a new insight into the mechanism of action of existing anti-cancer drugs involving induction of VDAC1 over-expression as a mechanism for inducing apoptosis. This article is part of a Special Issue entitled: Calcium Signaling in Health and Disease. Guest Editors: Geert Bultynck, Jacques Haiech, Claus W. Heizmann, Joachim Krebs, and Marc Moreau 相似文献
992.
April T. Davenport Kathleen A. Grant Kendall T. Szeliga David P. Friedman James B. Daunais 《Cell and tissue banking》2014,15(1):99-110
Appropriate animal models are critical to conduct translational studies of human disorders without variables that can confound clinical studies. Such analytic methods as patch-clamp electrophysiological and voltammetric recordings of neurons in brain slices require living brain tissue. In order to obtain viable tissue from nonhuman primate brains, tissue collection methods must be designed to preserve cardiovascular and respiratory functions for as long as possible. This paper describes a method of necropsy that has been used in three species of monkeys that satisfies this requirement. At necropsy, animals were maintained under a deep surgical plane of anesthesia while a craniotomy was conducted to expose the brain. Following the craniotomy, animals were perfused with ice-cold, oxygenated artificial cerebrospinal fluid to displace blood and to reduce the temperature of the entire brain. The brain was removed within minutes of death and specific brain regions were immediately dissected for subsequent in vitro electrophysiology or voltammetry experiments. This necropsy method also provided for the collection of tissue blocks containing all brain regions that were immediately frozen and stored for subsequent genomic, proteomic, autoradiographic and histological studies. An added benefit from the design of this necropsy method is that all major peripheral tissues were also collected and are now being utilized in a wide range of genomic, biochemical and histological assays. This necropsy method has resulted in the establishment and growth of a nonhuman primate alcohol tissue bank designed to distribute central nervous system and peripheral tissues to the larger scientific community. 相似文献
993.
994.
Duan Chen Andrey A. Bobko Amy C. Gross Randall Evans Clay B. Marsh Valery V. Khramtsov Timothy D. Eubank Avner Friedman 《PloS one》2014,9(10)
The four variables, hypoxia, acidity, high glutathione (GSH) concentration and fast reducing rate (redox) are distinct and varied characteristics of solid tumors compared to normal tissue. These parameters are among the most significant factors underlying the metabolism and physiology of solid tumors, regardless of their type or origin. Low oxygen tension contributes to both inhibition of cancer cell proliferation and therapeutic resistance of tumors; low extracellular pH, the reverse of normal cells, mainly enhances tumor invasion; and dysregulated GSH and redox potential within cancer cells favor their proliferation. In fact, cancer cells under these microenvironmental conditions appreciably alter tumor response to cytotoxic anti-cancer treatments. Recent experiments measured the in vivo longitudinal data of these four parameters with tumor development and the corresponding presence and absence of tumor macrophage HIF-1α or HIF-2α in a mouse model of breast cancer. In the current paper, we present a mathematical model-based system of (ordinary and partial) differential equations to monitor tumor growth and susceptibility to standard chemotherapy with oxygen level, pH, and intracellular GSH concentration. We first show that our model simulations agree with the corresponding experiments, and then we use our model to suggest treatments of tumors by altering these four parameters in tumor microenvironment. For example, the model qualitatively predicts that GSH depletion can raise the level of reactive oxygen species (ROS) above a toxic threshold and result in inhibition of tumor growth. 相似文献
995.
996.
Pasqualini JR Caubel P Friedman AJ Philippe JC Chetrite GS 《The Journal of steroid biochemistry and molecular biology》2003,84(2-3):193-198
Human breast cancer tissue contains enzymes (estrone sulfatase, 17beta-hydroxysteroid dehydrogenase, aromatase) involved in the last steps of estradiol (E(2)) formation. In this tissue, E(2) can be synthesized by two main pathways: (1) sulfatase-transforms estrogen sulfates into bioactive E(2), and the (2) aromatase-converts androgens into estrogens. Quantitative assessment of E(2) formation in human breast tumors indicates that metabolism of estrone sulfate (E(1)S) via the sulfatase pathway produces 100-500 times more E(2) than androgen aromatization.In the present study, we demonstrated in T-47D and MCF-7 human breast cancer cells that norelgestromin (NGMN) (a metabolite of norgestimate) is a potent inhibitory agent of the estrone sulfatase activity. After 24h incubation of physiological concentrations of E(1)S (5 x 10(-9)mol/l) the inhibitory effect of NGMN at concentrations of 5 x 10(-9), 5 x 10(-7) and 5 x 10(-5)mol/l was 43+/-7, 74+/-4 and 97+/-2%, respectively, in T-47D cells; 25+/-4, 57+/-5 and 96+/-2% respectively, in MCF-7 cells. Comparative studies using medroxyprogesterone acetate (MPA) showed that this progestin also has an inhibitory effect on sulfatase activity, but significantly less intense than that of NGMN. The inhibition for MPA at concentrations of 5 x 10(-9), 5 x 10(-7) and 5 x 10(-5)mol/l was 31+/-5, 47+/-3 and 61+/-3%, respectively, for T-47D cells; 6+/-3, 20+/-3 and 63+/-4%, respectively, for MCF-7 cells.In conclusion, the present data show that NGMN is a very potent inhibitory agent for sulfatase activity in the hormone-dependent breast cancer cells, resulting in decreased tissue concentration of E(2). The clinical significance of this finding remains to be elucidated. 相似文献
997.
Burchat AF Calderwood DJ Friedman MM Hirst GC Li B Rafferty P Ritter K Skinner BS 《Bioorganic & medicinal chemistry letters》2002,12(12):1687-1690
A series of para-substituted 3-phenyl pyrazolopyrimidines was synthesized and evaluated as inhibitors of lck. The nature of the substitution affected enzyme selectivity and potency for lck, src, kdr, and tie-2. The para-phenoxyphenyl analogue 2 is an orally active lck inhibitor with a bioavailability of 69% and exhibits an extended duration of action in animal models of T cell inhibition. 相似文献
998.
We have screened a human adult iris cDNA library to identify genes that are highly expressed and conserved between humans and pigs. We identified human iris cDNAs that hybridized at high stringency to a porcine choroidal ring cDNA probe. Of 1568 human iris cDNAs examined, 176 were found to have high expression in porcine choroidal rings. One of the 176 clones was identified as a previously uncharacterized cDNA that we have named the Ubiquitin-like 5 gene (UBL5). The UBL5 gene is located on chromosome 19p13.2, and its genomic structure has been examined. There is a UBL5 pseudogene on chromosome 17p11.2. We have also found homologues to the UBL5 gene in Arabidopsis thaliana, Caenorhabditis elegans, Schizosaccharomyces pombe, and Saccharomyces cerevisiae. Northern blot analysis of the Ubiquitin-like gene 5 revealed expression in every tissue tested, with the highest levels of RNA expression in heart, skeletal muscle, kidney, liver, iris, and lymphoblasts. Intracellular localization experiments in COS-7 cells showed that the recombinant UBL5 protein is cytoplasmic. Western analysis demonstrated that the recombinant UBL5 protein is approximately 9 kDa, as predicted from the cDNA. A comparison between UBL5 and its homologues with other Ubiquitin-like proteins and Ubiquitin, using the PROTDIST program, suggests that the UBL5 genes are a separate class of Ubiquitin-like genes. Further characterization of the UBL5 gene will determine the function of the encoded protein and whether it is a candidate for ocular disease. 相似文献
999.
Artashes Vardanyan Hovhannes Haroyan Arsen Babajanyan Khachatur Nerkararyan Barry Friedman 《Plasmonics (Norwell, Mass.)》2012,7(1):1-5
We consider the formation of the surface plasmon polariton (SPP) mode in the structure with a metallic torus and a metallic
flat surface separated by a dielectric medium. The energy of the wave field is mainly concentrated in the dielectric medium
at the vicinity of the minimum thickness of the gap between the metallic surfaces. The dependence of the resonant frequency
on parameters of the structure was determined. The strongly localized SPP mode in the transverse direction contributes to
the increase in the Purcell factor that is crucial for enhancement of the spontaneous emission rate. 相似文献
1000.
Brooke M. Steenhard Roberto Vanacore David Friedman Adrian Zelenchuk Larysa Stroganova Kathryn Isom Patricia L. St. John Billy G. Hudson Dale R. Abrahamson 《PloS one》2012,7(12)
Alport disease in humans, which usually results in proteinuria and kidney failure, is caused by mutations to the COL4A3, COL4A4, or COL4A5 genes, and absence of collagen α3α4α5(IV) networks found in mature kidney glomerular basement membrane (GBM). The Alport mouse harbors a deletion of the Col4a3 gene, which also results in the lack of GBM collagen α3α4α5(IV). This animal model shares many features with human Alport patients, including the retention of collagen α1α2α1(IV) in GBMs, effacement of podocyte foot processes, gradual loss of glomerular barrier properties, and progression to renal failure. To learn more about the pathogenesis of Alport disease, we undertook a discovery proteomics approach to identify proteins that were differentially expressed in glomeruli purified from Alport and wild-type mouse kidneys. Pairs of cy3- and cy5-labeled extracts from 5-week old Alport and wild-type glomeruli, respectively, underwent 2-dimensional difference gel electrophoresis. Differentially expressed proteins were digested with trypsin and prepared for mass spectrometry, peptide ion mapping/fingerprinting, and protein identification through database searching. The intermediate filament protein, vimentin, was upregulated ∼2.5 fold in Alport glomeruli compared to wild-type. Upregulation was confirmed by quantitative real time RT-PCR of isolated Alport glomeruli (5.4 fold over wild-type), and quantitative confocal immunofluorescence microscopy localized over-expressed vimentin specifically to Alport podocytes. We next hypothesized that increases in vimentin abundance might affect the basement membrane protein receptors, integrins, and screened Alport and wild-type glomeruli for expression of integrins likely to be the main receptors for GBM type IV collagen and laminin. Quantitative immunofluorescence showed an increase in integrin α1 expression in Alport mesangial cells and an increase in integrin α3 in Alport podocytes. We conclude that overexpression of mesangial integrin α1 and podocyte vimentin and integrin α3 may be important features of glomerular Alport disease, possibly affecting cell-signaling, cell shape and cellular adhesion to the GBM. 相似文献