首页 | 本学科首页   官方微博 | 高级检索  
文章检索
  按 检索   检索词:      
出版年份:   被引次数:   他引次数: 提示:输入*表示无穷大
  收费全文   1645篇
  免费   136篇
  国内免费   1篇
  2023年   5篇
  2021年   25篇
  2020年   20篇
  2019年   40篇
  2018年   47篇
  2017年   35篇
  2016年   49篇
  2015年   91篇
  2014年   91篇
  2013年   105篇
  2012年   150篇
  2011年   120篇
  2010年   82篇
  2009年   74篇
  2008年   100篇
  2007年   77篇
  2006年   94篇
  2005年   73篇
  2004年   82篇
  2003年   61篇
  2002年   65篇
  2001年   15篇
  2000年   16篇
  1999年   18篇
  1998年   17篇
  1997年   18篇
  1996年   9篇
  1995年   8篇
  1994年   11篇
  1993年   14篇
  1992年   11篇
  1991年   11篇
  1990年   6篇
  1989年   8篇
  1988年   9篇
  1987年   6篇
  1986年   15篇
  1985年   13篇
  1984年   5篇
  1983年   5篇
  1982年   8篇
  1981年   5篇
  1980年   8篇
  1979年   11篇
  1978年   5篇
  1977年   5篇
  1975年   6篇
  1974年   7篇
  1973年   4篇
  1972年   5篇
排序方式: 共有1782条查询结果,搜索用时 15 毫秒
1.
Abstract The purpose of this study was to investigate complement resistance in Branhamella (Moraxella) catarrhalis isolated from healthy schoolchildren or sputum-producing adult patients. Two techniques were used: a serum bactericidal assay as the gold standard and an easier ‘culture and spot’ test. Children (age 4–13; n = 303) and patients ( n = 1047) showed high colonization/infection rates with B. catarrhalis (31% and 19%, respectively). Complement resistance or intermediate sensitivity occurred frequently in patient isolates (62% and 27%, respectively) and less often in children (33% and 8.5%, respectively; P ⪡ 0.0001). In young children (age 4–5 years), the proportion of complement-resistant strains was around 50%. Complement resistance in B. catarrhalis is associated with illness and may hence be considered a virulence factor.  相似文献   
2.
3.
Retinoids have a dominant role in topical acne therapy and to date, only RARβ and RARγ dual agonists have reached the market. Given the tissue distribution of RAR isoforms, it was hypothesized that developing RARγ -selective agonists could yield a new generation of topical acne treatments that would increase safety margins while maintaining the robust efficacy of previous drugs. Structural knowledge derived from the X-ray structure of known γ-selective CD437, suggested the design of a novel triaryl series of agonists which was optimized and ultimately led to the discovery of Trifarotene/CD5789.  相似文献   
4.
Dispersal is thought to be an important process determining range size, especially for species in highly spatially structured habitats, such as tropical reef fishes. Despite intensive research efforts, there is conflicting evidence about the role of dispersal in determining range size. We hypothesize that traits related to dispersal drive range sizes, but that complete and comprehensive datasets are essential for detecting relationships between species’ dispersal ability and range size. We investigate the roles of six traits affecting several stages of dispersal (adult mobility, spawning mode, pelagic larval duration (PLD), body size, aggregation behavior, and circadian activity), in explaining range size variation of reef fishes in the Tropical Eastern Pacific (TEP). All traits, except for PLD (148 species), had data for all 497 species in the region. Using a series of statistical models, we investigated which traits were associated with large range sizes, when analyzing all TEP species or only species with PLD data. Furthermore, using null models, we analyzed whether the PLD‐subset is representative of the regional species pool. Several traits affecting dispersal ability were strongly associated with range size, although these relationships could not be detected when using the PLD‐subset. Pelagic spawners (allowing for passive egg dispersal) had on average 56% larger range sizes than nonpelagic spawners. Species with medium or high adult mobility had on average a 25% or 33% larger range, respectively, than species with low mobility. Null models showed that the PLD‐subset was nonrepresentative of the regional species pool, explaining why model outcomes using the PLD‐subset differed from the ones based on the complete dataset. Our results show that in the TEP, traits affecting dispersal ability are important in explaining range size variation. Using a regionally complete dataset was crucial for detecting the theoretically expected, but so far empirically unresolved, relationship between dispersal and range size.  相似文献   
5.
Introduction: The availability of big data sets (‘OMICS’) has greatly impacted fundamental and translational science. High-throughput analysis of HLA class I and II associated peptidomes by mass spectrometry (MS) has generated large datasets, with the last decade witnessing tremendous growth in the breadth and number of studies.

Areas covered: For this, we first analyzed naturally processed peptide (NP) data captured within the IEDB to survey and characterize the current state of NP data. We next asked to what extent the NP data overlap with existing T cell epitope and MHC binding data.

Expert commentary: The current collection of NP data represents a large and diverse set of class I/II peptides mostly derived from self-antigens. These data overlap only marginally with existing immunogenicity and binding data and it is thus difficult to ascertain the correspondence between the different assay methodologies. This highlights a need for unbiased studies benchmarking in model antigen systems how well MHC binding and NP data predicts immunogenicity. Going forward, efforts at generating an integrated process for capturing all NP, curating associated metadata and accessing NP data from an immunological viewpoint will be important for development of novel methods for identifying optimal target antigens and for class I and II epitope prediction.  相似文献   

6.
Most theoretical research in sexual selection has focused on indirect selection. However, empirical studies have not strongly supported indirect selection. A well-established finding is that direct benefits and costs exert a strong influence on the evolution of mate choice. We present an analytical model in which unilateral mate choice evolves solely by direct sexual selection on choosiness. We show this is sufficient to generate the evolution of all possible levels of choosiness, because of the fundamental trade-off between mating rate and mating benefits. We further identify the relative searching time (RST, i.e. the proportion of lifetime devoted to searching for mates) as a predictor of the effect of any variable affecting the mating rate on the evolution of choosiness. We show that the RST: (i) allows one to make predictions about the evolution of choosiness across a wide variety of mating systems; (ii) encompasses all alternative variables proposed thus far to explain the evolution of choosiness by direct sexual selection; and (iii) can be empirically used to infer qualitative differences in choosiness.  相似文献   
7.
The RNA-synthesizing machinery of the severe acute respiratory syndrome Coronavirus (SARS-CoV) is composed of 16 non-structural proteins (nsp1–16) encoded by ORF1a/1b. The 148-amino acid nsp10 subunit contains two zinc fingers and is known to interact with both nsp14 and nsp16, stimulating their respective 3′-5′ exoribonuclease and 2′-O-methyltransferase activities. Using alanine-scanning mutagenesis, in cellulo bioluminescence resonance energy transfer experiments, and in vitro pulldown assays, we have now identified the key residues on the nsp10 surface that interact with nsp14. The functional consequences of mutations introduced at these positions were first evaluated biochemically by monitoring nsp14 exoribonuclease activity. Disruption of the nsp10-nsp14 interaction abrogated the nsp10-driven activation of the nsp14 exoribonuclease. We further showed that the nsp10 surface interacting with nsp14 overlaps with the surface involved in the nsp10-mediated activation of nsp16 2′-O-methyltransferase activity, suggesting that nsp10 is a major regulator of SARS-CoV replicase function. In line with this notion, reverse genetics experiments supported an essential role of the nsp10 surface that interacts with nsp14 in SARS-CoV replication, as several mutations that abolished the interaction in vitro yielded a replication-negative viral phenotype. In contrast, mutants in which the nsp10-nsp16 interaction was disturbed proved to be crippled but viable. These experiments imply that the nsp10 surface that interacts with nsp14 and nsp16 and possibly other subunits of the viral replication complex may be a target for the development of antiviral compounds against pathogenic coronaviruses.  相似文献   
8.

Background

2013 WHO guidelines recommend starting ART at CD4+ T-cell counts ≤500 cells/μL. We present the T-cell counts from adult Africans with HIV shortly following transmission to their sexual partners.

Methods

HIV-discordant couples in Zambia, Uganda and Rwanda were followed prospectively and received couples counseling and condoms. HIV uninfected partners were tested for HIV at least quarterly and HIV-infected partners received HIV care and referral for ART per national guidelines. Upon diagnosis of incident HIV infection in the previously HIV-uninfected partner, a blood sample was collected from both partners to measure CD4+ T-cells and perform viral linkage. The estimated date of infection (EDI) of the incident case was calculated based on testing history. EDI was unknown for suspected transmitting partners.

Results

From 2006–2011, 4,705 HIV-discordant couples were enrolled in this cohort, and 443 cases of incident HIV infection were documented. Virus linkage analysis was performed in 374 transmission pairs, and 273 (73%) transmissions were linked genetically. CD4 counts in the transmitting partner were measured a median of 56 days after EDI (mean:90.5, min:10, max:396). The median CD4 count was 339 cells/μl (mean:386.4, min:15, max:1,434), and the proportion of partners with a CD4+ T-cell count above 500/μl was 25% (95% CI:21, 31).

Conclusions

In our cohort of discordant couples, 73% of HIV transmissions occurred within the relationship, and the transmitter CD4+ T cell count shortly after the transmission event was frequently higher than the WHO 2013 ART-initiation guidelines.  相似文献   
9.
Scavenger receptor Class B type 1 (SR-B1) is a lipid transporter and sensor. In intestinal epithelial cells, SR-B1-dependent lipid sensing is associated with SR-B1 recruitment in raft-like/ detergent-resistant membrane domains and interaction of its C-terminal transmembrane domain with plasma membrane cholesterol. To clarify the initiating events occurring during lipid sensing by SR-B1, we analyzed cholesterol trafficking and raft-like domain composition in intestinal epithelial cells expressing wild-type SR-B1 or the mutated form SR-B1-Q445A, defective in membrane cholesterol binding and signal initiation. These features of SR-B1 were found to influence both apical cholesterol efflux and intracellular cholesterol trafficking from plasma membrane to lipid droplets, and the lipid composition of raft-like domains. Lipidomic analysis revealed likely participation of d18:0/16:0 sphingomyelin and 16:0/0:0 lysophosphatidylethanolamine in lipid sensing by SR-B1. Proteomic analysis identified proteins, whose abundance changed in raft-like domains during lipid sensing, and these included molecules linked to lipid raft dynamics and signal transduction. These findings provide new insights into the role of SR-B1 in cellular cholesterol homeostasis and suggest molecular links between SR-B1-dependent lipid sensing and cell cholesterol and lipid droplet dynamics.  相似文献   
10.

Background

Mycorrhizal strategies are very effective in enhancing plant acquisition of poorly-mobile nutrients, particularly phosphorus (P) from infertile soil. However, on very old and severely P-impoverished soils, a carboxylate-releasing and P-mobilising cluster-root strategy is more effective at acquiring this growth-limiting resource. Carboxylates are released during a period of only a few days from ephemeral cluster roots. Despite the cluster-root strategy being superior for P acquisition in such environments, these species coexist with a wide range of mycorrhizal species, raising questions about the mechanisms contributing to their coexistence.

Scope

We surmise that the coexistence of mycorrhizal and non-mycorrhizal strategies is primarily accounted for by a combination of belowground mechanisms, namely (i) facilitation of P acquisition by mycorrhizal plants from neighbouring cluster-rooted plants, and (ii) interactions between roots, pathogens and mycorrhizal fungi, which enhance the plants’ defence against pathogens. Facilitation of nutrient acquisition by cluster-rooted plants involves carboxylate exudation, making more P available for both themselves and their mycorrhizal neighbours. Belowground nutrient exchanges between carboxylate-exuding plants and mycorrhizal N2-fixing plants appear likely, but require further experimental testing to determine their nutritional and ecological relevance. Anatomical studies of roots of cluster-rooted Proteaceae species show that they do not form a complete suberised exodermis.

Conclusions

The absence of an exodermis may well be important to rapidly release carboxylates, but likely lowers root structural defences against pathogens, particularly oomycetes. Conversely, roots of mycorrhizal plants may not be as effective at acquiring P when P availability is very low, but they are better defended against pathogens, and this superior defence likely involves mycorrhizal fungi. Taken together, we are beginning to understand how an exceptionally large number of plant species and P-acquisition strategies coexist on the most severely P-impoverished soils.
  相似文献   
设为首页 | 免责声明 | 关于勤云 | 加入收藏

Copyright©北京勤云科技发展有限公司  京ICP备09084417号