全文获取类型
收费全文 | 3044篇 |
免费 | 285篇 |
出版年
2022年 | 36篇 |
2021年 | 70篇 |
2020年 | 33篇 |
2019年 | 41篇 |
2018年 | 51篇 |
2017年 | 41篇 |
2016年 | 72篇 |
2015年 | 120篇 |
2014年 | 131篇 |
2013年 | 180篇 |
2012年 | 172篇 |
2011年 | 205篇 |
2010年 | 79篇 |
2009年 | 87篇 |
2008年 | 123篇 |
2007年 | 125篇 |
2006年 | 99篇 |
2005年 | 106篇 |
2004年 | 106篇 |
2003年 | 117篇 |
2002年 | 110篇 |
2001年 | 57篇 |
2000年 | 73篇 |
1999年 | 58篇 |
1998年 | 32篇 |
1996年 | 20篇 |
1995年 | 22篇 |
1994年 | 19篇 |
1993年 | 21篇 |
1992年 | 34篇 |
1991年 | 37篇 |
1990年 | 28篇 |
1989年 | 34篇 |
1988年 | 31篇 |
1987年 | 38篇 |
1986年 | 44篇 |
1985年 | 34篇 |
1984年 | 34篇 |
1983年 | 48篇 |
1982年 | 28篇 |
1981年 | 30篇 |
1980年 | 24篇 |
1979年 | 32篇 |
1978年 | 38篇 |
1977年 | 26篇 |
1976年 | 23篇 |
1975年 | 21篇 |
1974年 | 27篇 |
1972年 | 19篇 |
1971年 | 26篇 |
排序方式: 共有3329条查询结果,搜索用时 15 毫秒
201.
Breakdown of CTL tolerance to self HLA-B*2705 induced by exposure to Chlamydia trachomatis 总被引:1,自引:0,他引:1
Popov I Dela Cruz CS Barber BH Chiu B Inman RD 《Journal of immunology (Baltimore, Md. : 1950)》2002,169(7):4033-4038
There is a strong association between seronegative arthritis and HLA B27, but it is still unresolved whether the contribution of B27 to disease pathogenesis is solely as a restriction element for an arthritogenic peptide, or whether B27 itself serves as an autoantigen. This study uses transgenic rats to address the question as to whether exposure to an arthritogenic pathogen can alter tolerance to B27. Unlike their nontransgenic counterparts, B27-transgenic rats are tolerant of B27 immunization using either B27(+) splenocytes or plasmid DNA and do not develop anti-B27 CTL. However, if splenocytes from such immunized animals are exposed to Chlamydia in vitro, CTL are generated that lyse B27(+) targets. No killing was seen with targets transfected with control B7, B14, B40, or B44. This phenomenon was not observed with immunization by nontransgenic splenocytes, or HLA-A2 DNA alone. Using targets expressing mutated B27, we show that the epitope for autoreactive CTL recognition of B27 involves the Lys(70) amino acid residue in the alpha(1) domain of the MHC class I molecule. The generation of CTL with specificity for B27 under these conditions demonstrates that tolerance to B27 can be subverted by CHLAMYDIA: This indicates a dynamic interrelationship between the pathogen and B27, which may have important implications for B27-related spondyloarthropathies triggered by intracellular bacteria. 相似文献
202.
En route to maturing as T cell receptor (TCR) alphabeta-expressing cells, the development of thymocytes is contingent on expression of a pre-TCR complex comprising a TCRbeta chain paired with a surrogate TCRalpha chain, pre-Talpha (pTalpha). The pre-TCR has been proposed to promote cell survival, proliferation, differentiation, and lineage commitment. However, the precise molecular mechanisms governing this variety of effects remain elusive. Here, we present a cellular system designed to biochemically dissect signals elicited upon pre-TCR expression. Using the T cell line 4G4 stably transfected with one of the two known pTalpha isoforms or selective pTalpha deletion mutants and TCRbeta, we were able to observe that expression of a functional pre-TCR complex is sufficient to control the levels of surface Fas protein, the stimulation of mitogen-activated and stress-regulated kinases, and the activation status of the p53 antioncogene. We demonstrate that this regulation has a major impact on the expression of important regulators of apoptosis, such as Bcl-2 family members, and the cell cycle, such as p21(WAF). Furthermore, we show here that cells expressing a functional pre-TCR are more resistant to different types of DNA damage-induced apoptosis and that these effects are contingent on an intact cytoplasmic tail of pTalpha. We finally propose that the presence of a functional pre-TCR complex triggers many intracellular pathways capable of driving and ensuring thymocyte survival in the presence of DNA damage. 相似文献
203.
Julien S Soulas P Garaud JC Martin T Pasquali JL 《Journal of immunology (Baltimore, Md. : 1950)》2002,169(8):4198-4204
It is well established that autoreactive B cells undergo negative selection. This stands in paradox with the high frequency of so-called natural autoreactive B cells producing low affinity polyreactive autoantibodies with recurrent specificities, suggesting that these B cells are selected on the basis of their autoreactivity. We previously described two transgenic mouse lines (with and without IgD) producing a human natural autoantibody (nAAb) that binds ssDNA and human Fcgamma. In the absence of human IgG, nAAb-transgenic B cells develop normally. By crossing these mice with animals expressing knockin chimeric IgG with the human Fcgamma, we now show that the constitutive expression of chimeric IgG promotes the increase of nAAb-expressing B cells. This positive selection is critically dependent on the presence of IgD, occurs in the spleen, and concerns all mature B cell subsets, with a relative preferential enrichment of marginal zone B cells. These data support the view that soluble self-Ags can result in positive clonal selection. 相似文献
204.
Altering the expression kinetics of VP5 results in altered virulence and pathogenesis of herpes simplex virus type 1 in mice
下载免费PDF全文
![点击此处可从《Journal of virology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
While many herpes simplex virus (HSV) structural proteins are expressed with strict-late kinetics, the HSV virion protein 5 (VP5) is expressed as a "leaky-late" protein, such that appreciable amounts of VP5 are made prior to DNA replication. Our goal has been to determine if leaky-late expression of VP5 is a requirement for a normal HSV infection. It had been shown previously that recombinant viruses in which the VP5 promoter was replaced with promoters of other kinetic classes (including a strict late promoter) exhibited no alterations in replication kinetics or virus yields in vitro. In contrast, here we report that alterations in pathogenesis were observed when these recombinants were analyzed by experimental infection of mice. Following intracranial inoculation, a recombinant expressing VP5 from a strict-late promoter (U(L)38) exhibited an increased 50% lethal dose and a 10-fold decrease in virus yields in the central nervous system, while a recombinant expressing VP5 from an early (dUTPase) or another leaky-late (VP16) promoter exhibited wild-type neurovirulence. Moreover, following infection of the footpad, changing the expression kinetics of VP5 from leaky-late to strict-late resulted in 100-fold-less virus in the spinal ganglia during the acute infection than produced by either the parent virus or the rescued virus. These data indicate that the precise timing of appearance of the major capsid protein plays a role in the pathogenesis of HSV infections and that changing the expression kinetics has different effects in different cell types and tissues. 相似文献
205.
The determination of the structure of PSII at high resolution is required in order to fully understand its reaction mechanisms. Two-dimensional crystals of purified highly active Synechococcus elongatus PSII dimers were obtained by in vitro reconstitution. Images of these crystals were recorded by electron cryo-microscopy, and their analysis revealed they belong to the two-sided plane group p22(1)2(1), with unit cell parameters a = 121 A, b = 333 A, and alpha = 90 degrees. From these crystals, a projection map was calculated to a resolution of approximately 16 A. The reliability of this projection map is confirmed by its close agreement with the recently presented three-dimensional model of the same complex obtained by X-ray crystallography. Comparison of the projection map of the Synechococcus elongatus PSII complex with data obtained by electron crystallography of the spinach PSII core dimer reveals a similar organization of the main transmembrane subunits. However, some differences in density distribution between the cyanobacterial and higher plant PSII complexes exist, especially in the outer region of the complex between CP43 and cytochrome b(559) and adjacent to the B-helix of the D1 protein. These differences are discussed in terms of the number and organization of some of the PSII low molecular weight subunits. 相似文献
206.
Heterozygous submicroscopic inversions involving olfactory receptor-gene clusters mediate the recurrent t(4;8)(p16;p23) translocation
下载免费PDF全文
![点击此处可从《American journal of human genetics》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Giglio S Calvari V Gregato G Gimelli G Camanini S Giorda R Ragusa A Guerneri S Selicorni A Stumm M Tonnies H Ventura M Zollino M Neri G Barber J Wieczorek D Rocchi M Zuffardi O 《American journal of human genetics》2002,71(2):276-285
The t(4;8)(p16;p23) translocation, in either the balanced form or the unbalanced form, has been reported several times. Taking into consideration the fact that this translocation may be undetected in routine cytogenetics, we find that it may be the most frequent translocation after t(11q;22q), which is the most common reciprocal translocation in humans. Case subjects with der(4) have the Wolf-Hirschhorn syndrome, whereas case subjects with der(8) show a milder spectrum of dysmorphic features. Two pairs of the many olfactory receptor (OR)-gene clusters are located close to each other, on both 4p16 and 8p23. Previously, we demonstrated that an inversion polymorphism of the OR region at 8p23 plays a crucial role in the generation of chromosomal imbalances through unusual meiotic exchanges. These findings prompted us to investigate whether OR-related inversion polymorphisms at 4p16 and 8p23 might also be involved in the origin of the t(4;8)(p16;p23) translocation. In seven case subjects (five of whom both represented de novo cases and were of maternal origin), including individuals with unbalanced and balanced translocations, we demonstrated that the breakpoints fell within the 4p and 8p OR-gene clusters. FISH experiments with appropriate bacterial-artificial-chromosome probes detected heterozygous submicroscopic inversions of both 4p and 8p regions in all the five mothers of the de novo case subjects. Heterozygous inversions on 4p16 and 8p23 were detected in 12.5% and 26% of control subjects, respectively, whereas 2.5% of them were scored as doubly heterozygous. These novel data emphasize the importance of segmental duplications and large-scale genomic polymorphisms in the evolution and pathology of the human genome. 相似文献
207.
CD44 and sulfation have both been implicated in leukocyte adhesion. In monocytes, the inflammatory cytokine tumor necrosis factor alpha (TNF-alpha) stimulates CD44 sulfation, and this correlates with the induction of CD44-mediated adhesion events. However, little is known about the sulfation of CD44 or its induction by inflammatory cytokines. We determined that TNF-alpha induces the carbohydrate sulfation of CD44. CD44 was established as a major sulfated cell surface protein on myeloid cells. In the SR91 myeloid cell line, the majority of CD44 sulfation was attributed to the glycosaminoglycan chondroitin sulfate. However, TNF-alpha stimulation increased CD44 sulfation two- to threefold, largely attributed to the increased sulfation of N- and O-linked glycans on CD44. Therefore, TNF-alpha induced a decrease in the percentage of CD44 sulfation due to chondroitin sulfate and an increase due to N- and O-linked sulfation. Furthermore, TNF-alpha induced the expression of 6-sulfo N-acetyl lactosamine (LacNAc)/Lewis x on these cells, which was detected by a monoclonal antibody after neuraminidase treatment. This 6-sulfo LacNAc/Lewis x epitope was induced on N-linked and (to a lesser extent) on O-linked glycans present on CD44. This demonstrates that CD44 is modified by sulfated carbohydrates in myeloid cells and that TNF-alpha modifies both the type and amount of carbohydrate sulfation occurring on CD44. In addition, it demonstrates that TNF-alpha can induce the expression of 6-sulfo N-acetyl glucosamine on both N- and O-linked glycans of CD44 in myeloid cells. 相似文献
208.
209.
Autotetraploid tangor plant regeneration from in vitro Citrus somatic embryogenic callus treated with colchicine 总被引:2,自引:0,他引:2
In vitro chromosome doubling of embryogenic callus lines of the Citrus cultivars Umatilla and Dweet tangors (Citrus reticulata Blanco×C. sinensis [L.] Osb.), Caffin clementine (C. clementina Hort. ex Tan.) and Wheeny grapefruit (C. paradisi Macf) was carried out in the presence of either 0.05 or 0.1% colchicine, or 0.01, 0.05 or 0.1% oryzalin. Embryogenic callus development was partly suppressed in the presence of colchicine, and completely suppressed by oryzalin at all concentrations tested. No plants were regenerated from any of the oryzalin treatments. Ploidy level of plants regenerated from the colchicine treatments was determined using flow cytometry and chromosome squashes. Three desirable non-chimeric, autotetraploid plants of the mono-embryonic cultivar Umatilla were produced using 0.05% colchicine and one from 0.1% colchicine. One mixoploid Dweet plant was produced using 0.1% colchicine. 相似文献
210.
There is a continuing need for monitoring the health of the environment due to the presence of pollutants. Here, we review the development and attributes of biosensors by which bacteria have been genetically modified to express the luminescence genes, i.e. to glow, in a quantified manner, in response to pollutants. We have concentrated on the detection of organic hydrocarbon pollutants and discussed the molecular mechanisms by which some of these chemicals act as effector molecules on the respective regulatory systems. The future of environmental biosensors is predictably bright. As more knowledge is gathered on the sensing regulatory component, the possibility of developing targeted or pollutant-specific biosensors is promising. Moreover, the repertoire of biosensors for culprit organic pollutants is expected to be enlarged through advances in genomics technology and identification of new sensory or receptor molecules. The need for pollutant detection at concentrations in the parts per trillion range or biosensors configured in a nanoscale is anticipated. 相似文献