全文获取类型
收费全文 | 1448篇 |
免费 | 162篇 |
国内免费 | 2篇 |
出版年
2022年 | 10篇 |
2021年 | 22篇 |
2020年 | 11篇 |
2019年 | 12篇 |
2018年 | 15篇 |
2017年 | 14篇 |
2016年 | 33篇 |
2015年 | 35篇 |
2014年 | 56篇 |
2013年 | 58篇 |
2012年 | 66篇 |
2011年 | 72篇 |
2010年 | 51篇 |
2009年 | 41篇 |
2008年 | 71篇 |
2007年 | 67篇 |
2006年 | 50篇 |
2005年 | 60篇 |
2004年 | 58篇 |
2003年 | 47篇 |
2002年 | 49篇 |
2001年 | 39篇 |
2000年 | 51篇 |
1999年 | 40篇 |
1998年 | 20篇 |
1997年 | 15篇 |
1996年 | 10篇 |
1995年 | 11篇 |
1994年 | 16篇 |
1992年 | 37篇 |
1991年 | 39篇 |
1990年 | 38篇 |
1989年 | 28篇 |
1988年 | 31篇 |
1987年 | 24篇 |
1986年 | 25篇 |
1985年 | 21篇 |
1984年 | 17篇 |
1983年 | 16篇 |
1981年 | 16篇 |
1980年 | 12篇 |
1979年 | 17篇 |
1978年 | 22篇 |
1976年 | 12篇 |
1975年 | 13篇 |
1974年 | 13篇 |
1973年 | 17篇 |
1971年 | 20篇 |
1969年 | 10篇 |
1968年 | 10篇 |
排序方式: 共有1612条查询结果,搜索用时 31 毫秒
101.
Kirk Broders Gloria IriarteBroders Gary C. Bergstrom Emmanuel Byamukama Martin Chilvers Christian Cruz Felipe DallaLana Zachary Duray Dean Malvick Daren Mueller Pierce Paul Diane Plewa Richard Raid Alison E. Robertson Catalina SalgadoSalazar Damon Smith Darcy Telenko Katherine VanEtten Nathan M. Kleczewski 《Ecology and evolution》2022,12(4)
The genus Phyllachora contains numerous obligate fungal parasites that produce raised, melanized structures called stromata on their plant hosts referred to as tar spot. Members of this genus are known to infect many grass species but generally do not cause significant damage or defoliation, with the exception of P. maydis which has emerged as an important pathogen of maize throughout the Americas, but the origin of this pathogen remains unknown. To date, species designations for Phyllachora have been based on host associations and morphology, and most species are assumed to be host specific. We assessed the sequence diversity of 186 single stroma isolates collected from 16 hosts representing 15 countries. Samples included both herbarium and contemporary strains that covered a temporal range from 1905 to 2019. These 186 isolates were grouped into five distinct species with strong bootstrap support. We found three closely related, but genetically distinct groups of Phyllachora are capable of infecting maize in the United States, we refer to these as the P. maydis species complex. Based on herbarium specimens, we hypothesize that these three groups in the P. maydis species complex originated from Central America, Mexico, and the Caribbean. Although two of these groups were only found on maize, the third and largest group contained contemporary strains found on maize and other grass hosts, as well as herbarium specimens from maize and other grasses that include 10 species of Phyllachora. The herbarium specimens were previously identified based on morphology and host association. This work represents the first attempt at molecular characterization of Phyllachora species infecting grass hosts and indicates some Phyllachora species can infect a broad range of host species and there may be significant synonymy in the Phyllachora genus. 相似文献
102.
Daichao Wu Ragul Gowathaman Brian G. Pierce Roy A. Mariuzza 《The Journal of biological chemistry》2022,298(3)
Adoptive cell therapy with tumor-specific T cells can mediate durable cancer regression. The prime target of tumor-specific T cells are neoantigens arising from mutations in self-proteins during malignant transformation. To understand T cell recognition of cancer neoantigens at the atomic level, we studied oligoclonal T cell receptors (TCRs) that recognize a neoepitope arising from a driver mutation in the p53 oncogene (p53R175H) presented by the major histocompatibility complex class I molecule HLA-A2. We previously reported the structures of three p53R175H-specific TCRs (38-10, 12-6, and 1a2) bound to p53R175H and HLA-A2. The structures showed that these TCRs discriminate between WT and mutant p53 by forming extensive interactions with the R175H mutation. Here, we report the structure of a fourth p53R175H-specific TCR (6-11) in complex with p53R175H and HLA-A2. In contrast to 38-10, 12-6, and 1a2, TCR 6-11 makes no direct contacts with the R175H mutation, yet is still able to distinguish mutant from WT p53. Structure-based in silico mutagenesis revealed that the 60-fold loss in 6-11 binding affinity for WT p53 compared to p53R175H is mainly due to the higher energetic cost of desolvating R175 in the WT p53 peptide during complex formation than H175 in the mutant. This indirect strategy for preferential neoantigen recognition by 6-11 is fundamentally different from the direct strategies employed by other TCRs and highlights the multiplicity of solutions to recognizing p53R175H with sufficient selectivity to mediate T cell killing of tumor but not normal cells. 相似文献
103.
Pierce KL Tohgo A Ahn S Field ME Luttrell LM Lefkowitz RJ 《The Journal of biological chemistry》2001,276(25):23155-23160
"Transactivation" of epidermal growth factor receptors (EGFRs) in response to activation of many G protein-coupled receptors (GPCRs) involves autocrine/paracrine shedding of heparin-binding EGF (HB-EGF). HB-EGF shedding involves proteolytic cleavage of a membrane-anchored precursor by incompletely characterized matrix metalloproteases. In COS-7 cells, alpha(2A)-adrenergic receptors (ARs) stimulate ERK phosphorylation via two distinct pathways, a transactivation pathway that involves the release of HB-EGF and the EGFR and an alternate pathway that is independent of both HB-EGF and the EGFR. We have developed a mixed culture system to study the mechanism of GPCR-mediated HB-EGF shedding in COS-7 cells. In this system, alpha(2A)AR expressing "donor" cells are co-cultured with "acceptor" cells lacking the alpha(2A)AR. Each population expresses a uniquely epitope-tagged ERK2 protein, allowing the selective measurement of ERK activation in the donor and acceptor cells. Stimulation with the alpha(2)AR selective agonist UK14304 rapidly increases ERK2 phosphorylation in both the donor and the acceptor cells. The acceptor cell response is sensitive to inhibitors of both the EGFR and HB-EGF, indicating that it results from the release of HB-EGF from the alpha(2A)AR-expressing donor cells. Experiments with various chemical inhibitors and dominant inhibitory mutants demonstrate that EGFR-dependent activation of the ERK cascade after alpha(2A)AR stimulation requires Gbetagamma subunits upstream and dynamin-dependent endocytosis downstream of HB-EGF shedding and EGFR activation, whereas Src kinase activity is required both for the release of HB-EGF and for HB-EGF-mediated ERK2 phosphorylation. 相似文献
104.
The chloroplast symbiosis between the ascoglossan (=Sacoglossa) sea slug Elysia chlorotica and plastids from the chromophytic alga Vaucheria litorea is the longest-lived relationship of its kind known, lasting up to 9 months. During this time, the plastids continue to photosynthesize in the absence of the algal nucleus at rates sufficient to meet the nutritional needs of the slugs. We have previously demonstrated that the synthesis of photosynthetic proteins occurs while the plastids reside within the diverticular cells of the slug. Here, we have identified several of these synthesized proteins as belonging to the nuclear-encoded family of polypeptides known as light-harvesting complex I (LHCI). The synthesis of LHCI is blocked by the cytosolic ribosomal inhibitor cycloheximide and proceeds in the presence of chloramphenicol, a plastid ribosome inhibitor, indicating that the gene encoding LHCI resides in the nuclear DNA of the slug. These results suggest that a horizontal transfer of the LHCI gene from the alga to the slug has taken place. 相似文献
105.
The TASTY locus on chromosome 1 of Arabidopsis affects feeding of the insect herbivore Trichoplusia ni 总被引:3,自引:0,他引:3
The generalist insect herbivore Trichoplusia ni (cabbage looper) readily consumes Arabidopsis and can complete its entire life cycle on this plant. Natural isolates (ecotypes) of Arabidopsis are not equally susceptible to T. ni feeding. While some are hardly touched by T. ni, others are eaten completely to the ground. Comparison of two commonly studied Arabidopsis ecotypes in choice experiments showed that Columbia is considerably more resistant than Landsberg erecta. In no-choice experiments, where larvae were confined on one or the other ecotype, weight gain was more rapid on Landsberg erecta than on Columbia. Genetic mapping of this difference in insect susceptibility using recombinant inbred lines resulted in the discovery of the TASTY locus near 85 cM on chromosome 1 of Arabidopsis. The resistant allele of this locus is in the Columbia ecotype, and an F(1) hybrid has a sensitive phenotype that is similar to that of Landsberg erecta. The TASTY locus is distinct from known genetic differences between Columbia and Landsberg erecta that affect glucosinolate content, trichome density, disease resistance, and flowering time. 相似文献
106.
Repair of chromosomal breaks is essential for cellular viability, but misrepair generates mutations and gross chromosomal rearrangements. We investigated the interrelationship between two homologous-repair pathways, i.e., mutagenic single-strand annealing (SSA) and precise homology-directed repair (HDR). For this, we analyzed the efficiency of repair in mammalian cells in which double-strand break (DSB) repair components were disrupted. We observed an inverse relationship between HDR and SSA when RAD51 or BRCA2 was impaired, i.e., HDR was reduced but SSA was increased. In particular, expression of an ATP-binding mutant of RAD51 led to a >90-fold shift to mutagenic SSA repair. Additionally, we found that expression of an ATP hydrolysis mutant of RAD51 resulted in more extensive gene conversion, which increases genetic loss during HDR. Disruption of two other DSB repair components affected both SSA and HDR, but in opposite directions: SSA and HDR were reduced by mutation of Brca1, which, like Brca2, predisposes to breast cancer, whereas SSA and HDR were increased by Ku70 mutation, which affects nonhomologous end joining. Disruption of the BRCA1-associated protein BARD1 had effects similar to those of mutation of BRCA1. Thus, BRCA1/BARD1 has a role in homologous repair before the branch point of HDR and SSA. Interestingly, we found that Ku70 mutation partially suppresses the homologous-repair defects of BARD1 disruption. We also examined the role of RAD52 in homologous repair. In contrast to yeast, Rad52(-)(/)(-) mouse cells had no detectable HDR defect, although SSA was decreased. These results imply that the proper genetic interplay of repair factors is essential to limit the mutagenic potential of DSB repair. 相似文献
107.
We have previously shown that infection with Chlamydia pneumoniae can significantly exacerbate atherosclerotic lesions in LDLR-/- mice concurrently fed a high cholesterol diet in 6 or 9 months. We now report that a period of 4 month was sufficient for demonstrating the C. pneumoniae atherogenicity. However, heat inactivation of C. pneumoniae organisms completely abolished the ability of C. pneumoniae to exacerbate the atherosclerotic lesions, suggesting that viable organism infection may be required for the C. pneumoniae atherogenicity. 相似文献
108.
109.
Botta D Franklin CC White CC Krejsa CM Dabrowski MJ Pierce RH Fausto N Kavanagh TJ 《Free radical biology & medicine》2004,37(5):632-642
Glutathione (GSH) is important in free radical scavenging, maintaining cellular redox status, and regulating cell survival in response to a wide variety of toxicants. The rate-limiting enzyme in GSH synthesis is glutamate-cysteine ligase (GCL), which is composed of catalytic (GCLC) and modifier (GCLM) subunits. To determine whether increased GSH biosynthetic capacity enhances cellular resistance to tumor necrosis factor-alpha- (TNF-alpha-) induced apoptotic cell death, we have established several mouse liver hepatoma (Hepa-1) cell lines overexpressing GCLC and/or GCLM. Cells overexpressing GCLC alone exhibit modest increases in GCL activity, while cells overexpressing both subunits have large increases in GCL activity. Importantly, cells overexpressing both GCL subunits exhibit increased resistance to TNF-induced apoptosis as judged by a loss of redox potential; mitochondrial membrane potential; translocation of cytochrome c to the cytoplasm; and activation of caspase-3, caspase-8, and caspase-9. Analysis of the effects of TNF on these parameters indicates that maintaining mitochondrial integrity mediates this protective effect in GCL-overexpressing cells. 相似文献
110.
Recently, it has been shown that PKA-mediated phosphorylation of the β2-adrenergic receptor (β2-AR) by the cyclic AMP-dependent protein kinase (PKA) reduces its affinity for Gs and increases its affinity for Gi. Here we demonstrate that, like the β2-AR, the β1-AR is also capable of “switching” its coupling from Gs to Gi in a PKA-dependent manner. The β1-AR is capable of activating adenylate cyclase via Gs, and can also activate the extracellular-regulated kinases, p44 and p42 (ERK1/2). In transfected CHO cells, the observed β1-AR-mediated activation of ERK is both sensitive to pertussis toxin (PTX), indicating involvement of Gi/Go, and to the PKA inhibitor, H-89. β1-ARs with PKA phosphorylation sites mutated to alanines are unable to activate ERK. Mutating these same residues to aspartic acid, mimicking PKA phosphorylation, leads to a decrease in Gs-stimulated cAMP accumulation and an increase in PTX-sensitive ERK activation. These results strongly support the hypothesis that the β1-AR, like the β2-AR, can undergo PKA-dependent “Gs/Gi switching”. 相似文献