全文获取类型
收费全文 | 4495篇 |
免费 | 114篇 |
专业分类
4609篇 |
出版年
2024年 | 27篇 |
2023年 | 43篇 |
2022年 | 60篇 |
2021年 | 124篇 |
2020年 | 106篇 |
2019年 | 115篇 |
2018年 | 107篇 |
2017年 | 116篇 |
2016年 | 205篇 |
2015年 | 246篇 |
2014年 | 236篇 |
2013年 | 319篇 |
2012年 | 378篇 |
2011年 | 350篇 |
2010年 | 255篇 |
2009年 | 179篇 |
2008年 | 263篇 |
2007年 | 271篇 |
2006年 | 228篇 |
2005年 | 195篇 |
2004年 | 155篇 |
2003年 | 159篇 |
2002年 | 139篇 |
2001年 | 33篇 |
2000年 | 39篇 |
1999年 | 32篇 |
1998年 | 35篇 |
1997年 | 24篇 |
1996年 | 21篇 |
1995年 | 18篇 |
1994年 | 16篇 |
1993年 | 12篇 |
1992年 | 7篇 |
1991年 | 11篇 |
1990年 | 14篇 |
1989年 | 6篇 |
1988年 | 6篇 |
1987年 | 5篇 |
1986年 | 3篇 |
1985年 | 2篇 |
1984年 | 6篇 |
1983年 | 7篇 |
1982年 | 3篇 |
1981年 | 7篇 |
1980年 | 5篇 |
1979年 | 5篇 |
1977年 | 3篇 |
1975年 | 3篇 |
1971年 | 5篇 |
1970年 | 3篇 |
排序方式: 共有4609条查询结果,搜索用时 0 毫秒
1.
Marcelo V. Sousa Michael Richardson Wagner Fontes Lauro Morhy 《Journal of Protein Chemistry》1994,13(8):659-667
Enterolobin, a 55-kDa cytolytic, inflammatory, and insecticidal protein isolated from seeds of the Brazilian treeEnterolobium contortisiliquum (Leguminosae-Mimosoideae) has been further purified and partially sequenced by using both manual and automated methods. A computational search of enterolobin partial amino acid sequence against the PIR database revealed possible sequence similarities with aerolysins, cytolytic proteins fromAeromonas species. An alignment of enterolobin partial sequence to the amino acid sequences ofA. hydrophila andA. sobria aerolysins showed several similar regions with many residue identites. The seed protein enterolobin and the bacterial aerolysins may be homologous proteins despite the distant phylogenetic relationship. 相似文献
2.
Marcelo dos Santos Guerra Maria Tereza M. Nogueira 《Plant Systematics and Evolution》1990,170(3-4):229-236
Analysis of several populations in a large part of the distribution area of the genusEmilia in Brazil has revealed only two species: the diploidE. sonchifolia and the tetraploidE. fosbergii. The more widely reportedE. coccinea was not found. They show a karyotype constancy in morphology and chromosome number (2n = 10 and 2n = 20, respectively), C-banding pattern and number of secondary constrictions. Some indications were found thatE. fosbergii may be an allopolyploid and that its ancestors had different genome sizes. 相似文献
3.
4.
Câmara Paulo E. A. S. Convey Peter Rangel Sandro B. Konrath Marcelo Barreto Cristine Chaves Pinto Otavio H. B. Silva Micheline Carvalho Henriques Diego Knop de Oliveira Hermeson Cassiano Rosa Luiz H. 《Extremophiles : life under extreme conditions》2021,25(4):369-384
Extremophiles - As part of the reconstruction of the Brazilian Antarctic Station on King George Island, three areas of moss carpet were transplanted to minimize the impact of the new facilities on... 相似文献
5.
Mardones M Valenzuela R Romanque P Covarrubias N Anghileri F Fernández V Videla LA Tapia G 《The Journal of nutritional biochemistry》2012,23(9):1113-1120
Several preconditioning strategies are used to prevent ischemia–reperfusion (IR) liver injury, a deleterious condition associated with tissue resection, transplantation or trauma. Although thyroid hormone (T3) administration exerts significant protection against liver IR injury in the rat, its clinical application is controversial due to possible adverse effects. Considering that prevention of liver IR injury has also been achieved by n-3 polyunsaturated fatty acid (n-3 PUFA) supplementation to rats, we studied the effect of n-3 PUFA dietary supplementation plus a lower dose of T3 against IR injury. Male Sprague-Dawley rats receiving fish oil (300 mg/kg) for 3 days followed by a single intraperitoneal dose of 0.05 mg T3/kg were subjected to 1 h of ischemia followed by 20 h of reperfusion. Parameters of liver injury (serum transaminases, histology) and oxidative stress (liver contents of GSH and oxidized proteins) were correlated with fatty acid composition, NF-κB activity, and tumor necrosis factor-α (TNF-α) and haptoglobin expression. IR significantly modified liver histology; enhanced serum transaminases, TNF-α response or liver oxidative stress; and decreased liver NF-κB activity and haptoglobin expression. Although IR injury was not prevented by either n-3 PUFA supplementation or T3 administration, substantial decrease in liver injury and oxidative stress was achieved by the combined protocol, which also led to increased liver n-3 PUFA content and decreased n-6/n-3 PUFA ratios, with recovery of NF-κB activity and TNF-α and haptoglobin expression. Prevention of liver IR injury achieved by a combined protocol of T3 and n-3 PUFA supplementation may represent a novel noninvasive preconditioning strategy with potential clinical application. 相似文献
6.
Leandro R. Monteiro Marcelo R. Nogueira 《Evolution; international journal of organic evolution》2010,64(3):724-744
The evolutionary integration of complex morphological structures is a macroevolutionary pattern in which morphogenetic components evolve in a coordinated fashion, which can result from the interplay among processes of developmental, genetic integration, and different types of selection. We tested hypotheses of ecological versus developmental factors underlying patterns of within‐species and evolutionary integration in the mandible of phyllostomid bats, during the most impressive ecological and morphological radiation among mammals. Shape variation of mandibular morphogenetic components was associated with diet, and the transition of integration patterns from developmental to within‐species to evolutionary was examined. Within‐species (as a proxy to genetic) integration in different lineages resembled developmental integration regardless of diet specialization, however, evolutionary integration patterns reflected selection in different mandibular components. For dietary specializations requiring extensive functional changes in mastication patterns or biting, such as frugivores and sanguivores, the evolutionary integration pattern was not associated with expected within‐species or developmental integration. On the other hand, specializations with lower mastication demands or without major functional reorganization (such as nectarivores and carnivores), presented evolutionary integration patterns similar to the expected developmental pattern. These results show that evolutionary integration patterns are largely a result of independent selection on specific components regardless of developmental modules. 相似文献
7.
Patricia R Facciotti Rose EG Rici Durvanei A Maria Marcelo Bertolini Carlos E Ambrósio Maria A Miglino 《Reproductive biology and endocrinology : RB&E》2009,7(1):25-7
Background
Placental and fetal growth requires high rates of cellular turnover and differentiation, which contributes to conceptus development. The trophoblast has unique properties and a wide range of metabolic, endocrine and angiogenic functions, but the proliferative profile of the bovine placenta characterized by flow cytometry analysis and its role in fetal development are currently uncharacterized. Complete understanding of placental apoptotic and proliferative rates may be relevant to development, especially if related to the pathogenesis of pregnancy losses and placental abnormalities. 相似文献8.
Weksler M 《Molecular phylogenetics and evolution》2003,29(2):331-349
Sigmodontine rodents are the most diverse family-level mammalian clade in the Neotropical region, with about 70 genera and 320 recognized species. Partial sequences (1266 bp) from the first exon of the nuclear gene encoding the Interphotoreceptor Retinoid Binding Protein (IRBP) were used to infer the phylogenetic relationships among 44 species representing all 16 currently recognized genera of the largest sigmodontine tribe, the Oryzomyini. Monophyly of the tribe was assessed relative to 15 non-oryzomyine sigmodontine taxa representing all major sigmodontine lineages. Twelve taxa from seven muroid subfamilies were used as outgroups. The resulting matrix included 71 taxa and 386 parsimony-informative characters. Phylogenetic analysis of this matrix resulted in 16 equally parsimonious cladograms, which contained the following well-supported groups: (i). a monophyletic Oryzomyini, (ii). a clade containing all oryzomyines except Scolomys and Zygodontomys, (iii). a clade containing Oecomys, Handleyomys, and several species of forest-dwelling Oryzomys, and (iv). a clade containing the remaining oryzomyine taxa. The last clade is composed of two large subclades, each with lower nodal support, containing the following taxa: (i). Microryzomys, Oligoryzomys, Neacomys, and Oryzomys balneator; (ii). Holochilus, Lundomys, Pseudoryzomys, Nectomys, Amphinectomys, Sigmodontomys, and several species of open-vegetation or semiaquatic Oryzomys. Regarding relationships among non-oryzomyine taxa, sigmodontines, neotomines, and tylomyines do not form a monophyletic group; a clade containing Rheomys and Sigmodon is basal relative to all other sigmodontines; and the remaining sigmodontines are grouped in three clades: the first containing Thomasomyini, Akodontini, and Reithrodon; the second containing Abrothrichini, and Phyllotini, plus Wiedomys, Juliomys, Irenomys, and Delomys; and the third containing the oryzomyines. No conflict is observed between IRBP results and previous robust hypotheses from mitochondrial data, while a single case of incongruence is present between the IRBP topology and robust hypothesis from morphological studies. 相似文献
9.
Emrah Altindis Roberta Cozzi Benedetta Di Palo Francesca Necchi Ravi P. Mishra Maria Rita Fontana Marco Soriani Fabio Bagnoli Domenico Maione Guido Grandi Sabrina Liberatori 《Molecular & cellular proteomics : MCP》2015,14(2):418-429
New generation vaccines are in demand to include only the key antigens sufficient to confer protective immunity among the plethora of pathogen molecules. In the last decade, large-scale genomics-based technologies have emerged. Among them, the Reverse Vaccinology approach was successfully applied to the development of an innovative vaccine against Neisseria meningitidis serogroup B, now available on the market with the commercial name BEXSERO® (Novartis Vaccines). The limiting step of such approaches is the number of antigens to be tested in in vivo models. Several laboratories have been trying to refine the original approach in order to get to the identification of the relevant antigens straight from the genome. Here we report a new bioinformatics tool that moves a first step in this direction. The tool has been developed by identifying structural/functional features recurring in known bacterial protective antigens, the so called “Protectome space,” and using such “protective signatures” for protective antigen discovery. In particular, we applied this new approach to Staphylococcus aureus and Group B Streptococcus and we show that not only already known protective antigens were re-discovered, but also two new protective antigens were identified.Although vaccines based on attenuated pathogens as pioneered by Luis Pasteur have been shown to be extremely effective, safety and technical reasons recommend that new generation vaccines include few selected pathogen components which, in combination with immunostimulatory molecules, can induce long lasting protective responses. Such approach implies that the key antigens sufficient to confer protective immunity are singled out among the plethora of pathogen molecules. As it turns out, the search for such protective antigens can be extremely complicated.Genomic technologies have opened the way to new strategies in vaccine antigen discovery (1, 2, 3). Among them, Reverse Vaccinology (RV)1 has proved to be highly effective, as demonstrated by the fact that a new Serogroup B Neisseria meningitidis (MenB) vaccine, incorporating antigens selected by RV, is now available to defeat meningococcal meningitis (4, 5). In essence, RV is based on the simple assumption that cloning all annotated proteins/genes and screening them against a robust and reliable surrogate-of-protection assay must lead to the identification of all protective antigens. Because most of the assays available for protective antigen selection involve animal immunization and challenge, the number of antigens to be tested represents a severe bottleneck of the entire process. For this reason, despite the fact that RV is a brute force, inclusive approach (“test-all-to-lose-nothing” type of approach) in their pioneered work of MenB vaccine discovery, Pizza and co-workers did not test the entire collection of MenB proteins but rather restricted their analysis to the ones predicted to be surface-localized. This was based on the evidence that for an anti-MenB vaccine to be protective bactericidal antibodies must be induced, a property that only surface-exposed antigens have. For the selection of surface antigens Pizza and co-workers mainly used PSORT and other available tools like MOTIFS and FINDPATTERNS to find proteins carrying localization-associated features such as transmembrane domains, leader peptides, and lipobox and outer membrane anchoring motifs. At the end, 570 proteins were selected and entered the still very labor intensive screening phase. Over the last few years, our laboratories have been trying to move to more selective strategies. Our ultimate goal, we like to refer to as the “Holy Grail of Vaccinology,” is to identify protective antigens by “simply” scanning the genome sequence of any given pathogen, thus avoiding time consuming “wet science” and “move straight from genome to the clinic” (6).With this objective in mind, we have developed a series of proteomics-based protocols that, in combination with bioinformatics tools, have substantially reduced the number of antigens to be tested in the surrogate-of-protection assays (7, 8). In particular, we have recently described a three-technology strategy that allows to narrow the number of antigens to be tested in the animal models down to less than ten (9). However, this strategy still requires high throughput experimental activities. Therefore, the availability of in silico tools that selectively and accurately single out relevant categories of antigens among the complexity of pathogen components would greatly facilitate the vaccine discovery process.In the present work, we describe a new bioinformatics approach that brings an additional contribution to our “from genome to clinic” goal. The approach has been developed on the basis of the assumption that protective antigens are protective in that they have specific structural/functional features (“protective signatures”) that distinguish them from immunologically irrelevant pathogen components. These features have been identified by using existing databases and prediction tools, such as PFam and SMART. Our approach focuses on protein biological role rather than its localization: it is completely protein localization unbiased, and lead to the identification of both surface-exposed and secreted antigens (which are the majority in extracellular bacteria) as well as cytoplasmic protective antigens (for instance, antigens that elicit interferon γ producing CD4+ T cells, thus potentiating the killing activity of phagocytic cells toward intracellular pathogens). Should these assumptions be valid, PS could be identified if: (1) all known protective antigens are compiled to create what we refer to as “the Protectome space,” and (2) Protectome is subjected to computer-assisted scrutiny using selected tools. Once signatures are identified, novel protective antigens of a pathogen of interest should be identifiable by scanning its genome sequence in search for proteins that carry one or more protective signatures. A similar attempt has been reported (10), where the discrimination of protective antigens versus nonprotective antigens was tried using statistical methods based on amino acid compositional analysis and auto cross-covariance. This model was implemented in a server for the prediction of vaccine candidates, that is, Vaxijen (www.darrenflower.info/Vaxijen); however, the selection criteria applied are still too general leading to a list of candidates that include ca. 30% of the total genome ORFs very similarly to the number of antigens predicted by classical RV based on the presence of localization signals.Here we show that Protectome analysis unravels specific signatures embedded in protective antigens, most of them related to the biological role/function of the proteins. These signatures narrow down the candidate list to ca. 3% of the total ORFs content and can be exploited for protective antigen discovery. Indeed, the strategy was validated by demonstrating that well characterized vaccine components could be identified by scanning the genome sequence of the corresponding pathogens for the presence of the PS. Furthermore, when the approach was applied to Staphylococcus aureus and Streptococcus agalactiae (Group B Streptococcus, GBS) not only already known protective antigens were rediscovered, but also two new protective antigens were identified. 相似文献
10.
Wang H Yang C Leskow FC Sun J Canagarajah B Hurley JH Kazanietz MG 《The EMBO journal》2006,25(10):2062-2074
Although receptor-mediated regulation of small G-proteins and the cytoskeleton is intensively studied, the mechanisms for attenuation of these signals are poorly understood. In this study, we have identified the Rac-GAP beta2-chimaerin as an effector of the epidermal growth factor receptor (EGFR) via coupling to phospholipase Cgamma (PLCgamma) and generation of the lipid second messenger diacylglycerol (DAG). EGF redistributes beta2-chimaerin to promote its association with the small GTPase Rac1 at the plasma membrane, as determined by FRET. This relocalization and association with Rac1 were impaired by disruption of the beta2-chimaerin C1 domain as well as by PLCgamma1 RNAi, thus defining beta2-chimaerin as a novel DAG effector. On the other hand, GAP-deficient beta2-chimaerin mutants show enhanced translocation and sustained Rac1 association in the FRET assays. Remarkably, RNAi depletion of beta2-chimaerin significantly extended the duration of Rac activation by EGF, suggesting that beta2-chimaerin serves as a mechanism that self-limits Rac activity in response to EGFR activation. Our results represent the first direct evidence of divergence in DAG signaling downstream of a tyrosine-kinase receptor via a PKC-independent mechanism. 相似文献