全文获取类型
收费全文 | 6268篇 |
免费 | 534篇 |
国内免费 | 5篇 |
出版年
2023年 | 39篇 |
2022年 | 95篇 |
2021年 | 174篇 |
2020年 | 90篇 |
2019年 | 96篇 |
2018年 | 140篇 |
2017年 | 129篇 |
2016年 | 221篇 |
2015年 | 400篇 |
2014年 | 440篇 |
2013年 | 428篇 |
2012年 | 624篇 |
2011年 | 570篇 |
2010年 | 335篇 |
2009年 | 290篇 |
2008年 | 400篇 |
2007年 | 401篇 |
2006年 | 388篇 |
2005年 | 291篇 |
2004年 | 311篇 |
2003年 | 211篇 |
2002年 | 220篇 |
2001年 | 44篇 |
2000年 | 29篇 |
1999年 | 46篇 |
1998年 | 42篇 |
1997年 | 45篇 |
1996年 | 29篇 |
1995年 | 20篇 |
1994年 | 35篇 |
1993年 | 19篇 |
1992年 | 22篇 |
1991年 | 19篇 |
1990年 | 13篇 |
1989年 | 15篇 |
1988年 | 6篇 |
1987年 | 7篇 |
1986年 | 8篇 |
1985年 | 7篇 |
1984年 | 10篇 |
1983年 | 12篇 |
1982年 | 7篇 |
1981年 | 6篇 |
1980年 | 11篇 |
1978年 | 6篇 |
1977年 | 14篇 |
1974年 | 4篇 |
1973年 | 5篇 |
1970年 | 4篇 |
1960年 | 3篇 |
排序方式: 共有6807条查询结果,搜索用时 15 毫秒
141.
Irene Pichler Fabiola Del Greco M. Martin G?gele Christina M. Lill Lars Bertram Chuong B. Do Nicholas Eriksson Tatiana Foroud Richard H. Myers PD GWAS Consortium Michael Nalls Margaux F. Keller International Parkinson's Disease Genomics Consortium Wellcome Trust Case Control Consortium Beben Benyamin John B. Whitfield Genetics of Iron Status Consortium Peter P. Pramstaller Andrew A. Hicks John R. Thompson Cosetta Minelli 《PLoS medicine》2013,10(6)
Background
Although levels of iron are known to be increased in the brains of patients with Parkinson disease (PD), epidemiological evidence on a possible effect of iron blood levels on PD risk is inconclusive, with effects reported in opposite directions. Epidemiological studies suffer from problems of confounding and reverse causation, and mendelian randomization (MR) represents an alternative approach to provide unconfounded estimates of the effects of biomarkers on disease. We performed a MR study where genes known to modify iron levels were used as instruments to estimate the effect of iron on PD risk, based on estimates of the genetic effects on both iron and PD obtained from the largest sample meta-analyzed to date.Methods and Findings
We used as instrumental variables three genetic variants influencing iron levels, HFE rs1800562, HFE rs1799945, and TMPRSS6 rs855791. Estimates of their effect on serum iron were based on a recent genome-wide meta-analysis of 21,567 individuals, while estimates of their effect on PD risk were obtained through meta-analysis of genome-wide and candidate gene studies with 20,809 PD cases and 88,892 controls. Separate MR estimates of the effect of iron on PD were obtained for each variant and pooled by meta-analysis. We investigated heterogeneity across the three estimates as an indication of possible pleiotropy and found no evidence of it. The combined MR estimate showed a statistically significant protective effect of iron, with a relative risk reduction for PD of 3% (95% CI 1%–6%; p = 0.001) per 10 µg/dl increase in serum iron.Conclusions
Our study suggests that increased iron levels are causally associated with a decreased risk of developing PD. Further studies are needed to understand the pathophysiological mechanism of action of serum iron on PD risk before recommendations can be made. Please see later in the article for the Editors'' Summary 相似文献142.
Nathan Donley Eric P. Stoffregen Leslie Smith Christina Montagna Mathew J. Thayer 《PLoS genetics》2013,9(4)
Mammalian chromosomes initiate DNA replication at multiple sites along their length during each S phase following a temporal replication program. The majority of genes on homologous chromosomes replicate synchronously. However, mono-allelically expressed genes such as imprinted genes, allelically excluded genes, and genes on female X chromosomes replicate asynchronously. We have identified a cis-acting locus on human chromosome 6 that controls this replication-timing program. This locus encodes a large intergenic non-coding RNA gene named Asynchronous replication and Autosomal RNA on chromosome 6, or ASAR6. Disruption of ASAR6 results in delayed replication, delayed mitotic chromosome condensation, and activation of the previously silent alleles of mono-allelic genes on chromosome 6. The ASAR6 gene resides within an ∼1.2 megabase domain of asynchronously replicating DNA that is coordinated with other random asynchronously replicating loci along chromosome 6. In contrast to other nearby mono-allelic genes, ASAR6 RNA is expressed from the later-replicating allele. ASAR6 RNA is synthesized by RNA Polymerase II, is not polyadenlyated, is restricted to the nucleus, and is subject to random mono-allelic expression. Disruption of ASAR6 leads to the formation of bridged chromosomes, micronuclei, and structural instability of chromosome 6. Finally, ectopic integration of cloned genomic DNA containing ASAR6 causes delayed replication of entire mouse chromosomes. 相似文献
143.
Lionel Guy Bj?rn Nystedt Christina Toft Katarzyna Zaremba-Niedzwiedzka Eva C. Berglund Fredrik Granberg Kristina N?slund Ann-Sofie Eriksson Siv G. E. Andersson 《PLoS genetics》2013,9(3)
Gene transfer agents (GTAs) randomly transfer short fragments of a bacterial genome. A novel putative GTA was recently discovered in the mouse-infecting bacterium Bartonella grahamii. Although GTAs are widespread in phylogenetically diverse bacteria, their role in evolution is largely unknown. Here, we present a comparative analysis of 16 Bartonella genomes ranging from 1.4 to 2.6 Mb in size, including six novel genomes from Bartonella isolated from a cow, two moose, two dogs, and a kangaroo. A phylogenetic tree inferred from 428 orthologous core genes indicates that the deadly human pathogen B. bacilliformis is related to the ruminant-adapted clade, rather than being the earliest diverging species in the genus as previously thought. A gene flux analysis identified 12 genes for a GTA and a phage-derived origin of replication as the most conserved innovations. These are located in a region of a few hundred kb that also contains 8 insertions of gene clusters for type III, IV, and V secretion systems, and genes for putatively secreted molecules such as cholera-like toxins. The phylogenies indicate a recent transfer of seven genes in the virB gene cluster for a type IV secretion system from a cat-adapted B. henselae to a dog-adapted B. vinsonii strain. We show that the B. henselae GTA is functional and can transfer genes in vitro. We suggest that the maintenance of the GTA is driven by selection to increase the likelihood of horizontal gene transfer and argue that this process is beneficial at the population level, by facilitating adaptive evolution of the host-adaptation systems and thereby expansion of the host range size. The process counters gene loss and forces all cells to contribute to the production of the GTA and the secreted molecules. The results advance our understanding of the role that GTAs play for the evolution of bacterial genomes. 相似文献
144.
Cecilia Alsmark Åke Strese Christina Wedén Anders Backlund 《Phytochemistry Reviews》2013,12(3):531-542
Marine multi-cellular organisms are described as sources of many newly discovered bioactive compounds. Meanwhile, it has been demonstrated repeatedly for several natural products of reputed multicellular origin that they are, in fact, produced by endophytic unicellular organisms—such as microbial fungi or bacteria. Consequently, while studying compounds isolated from a living organism, it is essential to ensure that the sample integrity is not compromised. To test the diversity of the endobiome from Alcyonium digitatum, a cold water coral found along the Atlantic coasts of the northern hemisphere, we performed a culture dependent surveyed using a phylogenetic approach. A 1 cm3 cube from the interior tissue of A. digitatum was excised under aseptic conditions, homogenized, spread onto agar-based growth medium plates and incubated in 22 °C to promote microbial growth. Colonies were transferred to secondary medium plates, incubated, and after harvesting lysed using sterile water to release DNA. 16S and 23S rDNA regions were amplified using PCR, and sequenced for systematic evaluation using phylogenetic analysis. From this survey we identified a broad selection of bacteria, predominantly of the α-proteobacterial, bacteriodete, actinobacterial and firmicute lineages, demonstrating a significant biodiversity of the coral bacterial endobiome. 相似文献
145.
Werner Kremer Michael Weyand Andreas Winklmeier Christina Schreier Hans Robert Kalbitzer 《The protein journal》2013,32(7):533-542
Here we present the structure of the T1 domain derived from the voltage-dependent potassium channel Kv1.3 of Homo sapiens sapiens at 1.2 Å resolution crystallized under near-physiological conditions. The crystals were grown without precipitant in 150 mM KPi, pH 6.25. The crystals show I4 symmetry typical of the natural occurring tetrameric assembly of the single subunits. The obtained structural model is based on the highest resolution currently achieved for tetramerization domains of voltage-gated potassium channels. We identified an identical fold of the monomer but inside the tetramer the single monomers show a significant rotation which leads to a different orientation of the tetramer compared to other known structures. Such a rotational movement inside the tetrameric assembly might influence the gating properties of the channel. In addition we see two distinct side chain configurations for amino acids located in the top layer proximal to the membrane (Tyr109, Arg116, Ser129, Glu140, Met142, Arg146), and amino acids in the bottom layer of the T1-domain distal from the membrane (Val55, Ile56, Leu77, Arg86). The relative populations of these two states are ranging from 50:50 for Val55, Tyr109, Arg116, Ser129, Glu140, 60:40 for Met142, 65:35 for Arg86, 70:30 for Arg146, and 80:20 for Ile56 and Leu77. The data suggest that in solution these amino acids are involved in an equilibrium of conformational states that may be coupled to the functional states of the whole potassium channel. 相似文献
146.
Emotion recognition in children and adolescents with attention-deficit/hyperactivity disorder (ADHD)
Christina Schwenck Thekla Schneider Jutta Schreckenbach Yvonne Zenglein Angelika Gensthaler Regina Taurines Christine M. Freitag Wolfgang Schneider Marcel Romanos 《Attention deficit and hyperactivity disorders》2013,5(3):295-302
Children with attention-deficit/hyperactivity disorder (ADHD) are impaired in social adaptation and display deficits in social competence. Deficient emotion recognition has been discussed to underlie these social problems. However, comorbid conduct problems have not been considered in the majority of studies conducted so far, and the influence of medication on emotion recognition has rarely been studied. Here, emotion recognition performance was assessed in children with ADHD without medication compared with children with ADHD under stimulant medication and a matched control group. In order to rule out confounding by externalizing symptoms, children with comorbid conduct problems were excluded. Video clips with neutral faces developing a basic emotion (happiness, sadness, disgust, fear and anger) were presented in order to assess emotion recognition. Results indicated between-group differences neither concerning the number of correctly identified emotions nor concerning reaction times and their standard deviations. Thus, we suggest that ADHD per se is not associated with deficits in emotion recognition. 相似文献
147.
Kathleen Hennecke Joern Redeker Joern W. Kuhbier Sarah Strauss Christina Allmeling Cornelia Kasper Kerstin Reimers Peter M. Vogt 《PloS one》2013,8(4)
Repair success for injuries to the flexor tendon in the hand is often limited by the in vivo behaviour of the suture used for repair. Common problems associated with the choice of suture material include increased risk of infection, foreign body reactions, and inappropriate mechanical responses, particularly decreases in mechanical properties over time. Improved suture materials are therefore needed. As high-performance materials with excellent tensile strength, spider silk fibres are an extremely promising candidate for use in surgical sutures. However, the mechanical behaviour of sutures comprised of individual silk fibres braided together has not been thoroughly investigated. In the present study, we characterise the maximum tensile strength, stress, strain, elastic modulus, and fatigue response of silk sutures produced using different braiding methods to investigate the influence of braiding on the tensile properties of the sutures. The mechanical properties of conventional surgical sutures are also characterised to assess whether silk offers any advantages over conventional suture materials. The results demonstrate that braiding single spider silk fibres together produces strong sutures with excellent fatigue behaviour; the braided silk sutures exhibited tensile strengths comparable to those of conventional sutures and no loss of strength over 1000 fatigue cycles. In addition, the braiding technique had a significant influence on the tensile properties of the braided silk sutures. These results suggest that braided spider silk could be suitable for use as sutures in flexor tendon repair, providing similar tensile behaviour and improved fatigue properties compared with conventional suture materials. 相似文献
148.
149.
Michelle R. Gaither Greta Aeby Matthias Vignon Yu-ichiro Meguro Mark Rigby Christina Runyon Robert J. Toonen Chelsea L. Wood Brian W. Bowen 《PloS one》2013,8(2)
Efforts to limit the impact of invasive species are frustrated by the cryptogenic status of a large proportion of those species. Half a century ago, the state of Hawai''i introduced the Bluestripe Snapper, Lutjanus kasmira, to O''ahu for fisheries enhancement. Today, this species shares an intestinal nematode parasite, Spirocamallanus istiblenni, with native Hawaiian fishes, raising the possibility that the introduced fish carried a parasite that has since spread to naïve local hosts. Here, we employ a multidisciplinary approach, combining molecular, historical, and ecological data to confirm the alien status of S. istiblenni in Hawai''i. Using molecular sequence data we show that S. istiblenni from Hawai''i are genetically affiliated with source populations in French Polynesia, and not parasites at a geographically intermediate location in the Line Islands. S. istiblenni from Hawai''i are a genetic subset of the more diverse source populations, indicating a bottleneck at introduction. Ecological surveys indicate that the parasite has found suitable intermediate hosts in Hawai''i, which are required for the completion of its life cycle, and that the parasite is twice as prevalent in Hawaiian Bluestripe Snappers as in source populations. While the introduced snapper has spread across the entire 2600 km archipelago to Kure Atoll, the introduced parasite has spread only half that distance. However, the parasite faces no apparent impediments to invading the entire archipelago, with unknown implications for naïve indigenous Hawaiian fishes and the protected Papahānaumokuākea Marine National Monument. 相似文献
150.
Marta Rodriguez-Garcia Nabanita Biswas Mickey V. Patel Fiona D. Barr Sarah G. Crist Christina Ochsenbauer John V. Fahey Charles R. Wira 《PloS one》2013,8(4)
The magnitude of the HIV epidemic in women requires urgent efforts to find effective preventive methods. Even though sex hormones have been described to influence HIV infection in epidemiological studies and regulate different immune responses that may affect HIV infection, the direct role that female sex hormones play in altering the susceptibility of target cells to HIV-infection is largely unknown. Here we evaluated the direct effect of 17-β-estradiol (E2) and ethinyl estradiol (EE) in HIV-infection of CD4+ T-cells and macrophages. Purified CD4+ T-cells and monocyte-derived macrophages were generated in vitro from peripheral blood and infected with R5 and X4 viruses. Treatment of CD4+ T-cells and macrophages with E2 prior to viral challenge reduced their susceptibility to HIV infection in a dose-dependent manner. Addition of E2 2 h after viral challenge however did not result in reduced infection. In contrast, EE reduced infection in macrophages to a lesser extent than E2 and had no effect on CD4+ T-cell infection. Reduction of HIV-infection induced by E2 in CD4+ T-cells was not due to CCR5 down-regulation, but was an entry-mediated mechanism since infection with VSV-G pseudotyped HIV was not modified by E2. In macrophages, despite the lack of an effect of E2 on CCR5 expression, E2–treatment reduced viral entry 2 h after challenge and increased MIP-1β secretion. These results demonstrate the direct effect of E2 on susceptibility of HIV-target cells to infection and indicate that inhibition of target cell infection involves cell-entry related mechanisms. 相似文献