全文获取类型
收费全文 | 4489篇 |
免费 | 383篇 |
国内免费 | 2篇 |
专业分类
4874篇 |
出版年
2024年 | 6篇 |
2023年 | 47篇 |
2022年 | 98篇 |
2021年 | 166篇 |
2020年 | 97篇 |
2019年 | 140篇 |
2018年 | 150篇 |
2017年 | 101篇 |
2016年 | 205篇 |
2015年 | 313篇 |
2014年 | 337篇 |
2013年 | 338篇 |
2012年 | 436篇 |
2011年 | 454篇 |
2010年 | 239篇 |
2009年 | 205篇 |
2008年 | 276篇 |
2007年 | 287篇 |
2006年 | 214篇 |
2005年 | 188篇 |
2004年 | 145篇 |
2003年 | 123篇 |
2002年 | 115篇 |
2001年 | 21篇 |
2000年 | 16篇 |
1999年 | 21篇 |
1998年 | 16篇 |
1997年 | 8篇 |
1996年 | 5篇 |
1995年 | 10篇 |
1994年 | 5篇 |
1993年 | 5篇 |
1992年 | 6篇 |
1991年 | 3篇 |
1990年 | 3篇 |
1989年 | 5篇 |
1987年 | 3篇 |
1986年 | 4篇 |
1985年 | 5篇 |
1983年 | 4篇 |
1982年 | 7篇 |
1981年 | 3篇 |
1980年 | 3篇 |
1962年 | 2篇 |
1961年 | 3篇 |
1960年 | 3篇 |
1959年 | 2篇 |
1958年 | 2篇 |
1955年 | 4篇 |
1911年 | 2篇 |
排序方式: 共有4874条查询结果,搜索用时 11 毫秒
11.
Joseph T. Hicks Kimberly Edwards Xueting Qiu Do-Kyun Kim James E. Hixson Scott Krauss Richard J. Webby Robert G. Webster Justin Bahl 《PLoS pathogens》2022,18(4)
Wild birds can carry avian influenza viruses (AIV), including those with pandemic or panzootic potential, long distances. Even though AIV has a broad host range, few studies account for host diversity when estimating AIV spread. We analyzed AIV genomic sequences from North American wild birds, including 303 newly sequenced isolates, to estimate interspecies and geographic viral transition patterns among multiple co-circulating subtypes. Our results show high transition rates within Anseriformes and Charadriiformes, but limited transitions between these orders. Patterns of transition between species were positively associated with breeding habitat range overlap, and negatively associated with host genetic distance. Distance between regions (negative correlation) and summer temperature at origin (positive correlation) were strong predictors of transition between locations. Taken together, this study demonstrates that host diversity and ecology can determine evolutionary processes that underlie AIV natural history and spread. Understanding these processes can provide important insights for effective control of AIV. 相似文献
12.
William R. Hardin Germain C. M. Alas Nikita Taparia Elizabeth B. Thomas Melissa C. Steele-Ogus Kelli L. Hvorecny Aaron R. Halpern Pavla Tmov Justin M. Kollman Joshua C. Vaughan Nathan J. Sniadecki Alexander R. Paredez 《PLoS pathogens》2022,18(4)
Attachment to the intestinal epithelium is critical to the lifestyle of the ubiquitous parasite Giardia lamblia. The ventrolateral flange is a sheet-like membrane protrusion at the interface between parasites and attached surfaces. This structure has been implicated in attachment, but its role has been poorly defined. Here, we identified a novel actin associated protein with putative WH2-like actin binding domains we named Flangin. Flangin complexes with Giardia actin (GlActin) and is enriched in the ventrolateral flange making it a valuable marker for studying the flanges’ role in Giardia biology. Live imaging revealed that the flange grows to around 1 μm in width after cytokinesis, then remains uniform in size during interphase, grows in mitosis, and is resorbed during cytokinesis. A flangin truncation mutant stabilizes the flange and blocks cytokinesis, indicating that flange disassembly is necessary for rapid myosin-independent cytokinesis in Giardia. Rho family GTPases are important regulators of membrane protrusions and GlRac, the sole Rho family GTPase in Giardia, was localized to the flange. Knockdown of Flangin, GlActin, and GlRac result in flange formation defects. This indicates a conserved role for GlRac and GlActin in forming membrane protrusions, despite the absence of canonical actin binding proteins that link Rho GTPase signaling to lamellipodia formation. Flangin-depleted parasites had reduced surface contact and when challenged with fluid shear force in flow chambers they had a reduced ability to remain attached, confirming a role for the flange in attachment. This secondary attachment mechanism complements the microtubule based adhesive ventral disc, a feature that may be particularly important during mitosis when the parental ventral disc disassembles in preparation for cytokinesis. This work supports the emerging view that Giardia’s unconventional actin cytoskeleton has an important role in supporting parasite attachment. 相似文献
13.
Jinming Guan Leanne Barnard Jeanne Cresson Annabelle Hoegl Justin H. Chang Erick Strauss Karine Auclair 《Bioorganic & medicinal chemistry》2018,26(22):5896-5902
Pantothenate kinase (PanK) catalyzes the transformation of pantothenate to 4′-phosphopantothenate, the first committed step in coenzyme A biosynthesis. While numerous pantothenate antimetabolites and PanK inhibitors have been reported for bacterial type I and type II PanKs, only a few weak inhibitors are known for bacterial type III PanK enzymes. Here, a series of pantothenate analogues were synthesized using convenient synthetic methodology. The compounds were exploited as small organic probes to compare the ligand preferences of the three different types of bacterial PanK. Overall, several new inhibitors and substrates were identified for each type of PanK. 相似文献
14.
15.
Eliza F. Chakravarty Viktor Martyanov David Fiorentino Tammara A. Wood David James Haddon Justin Ansel Jarrell Paul J. Utz Mark C. Genovese Michael L. Whitfield Lorinda Chung 《Arthritis research & therapy》2015,17(1)
IntroductionSystemic sclerosis is an autoimmune disease characterized by inflammation and fibrosis of the skin and internal organs. We sought to assess the clinical and molecular effects associated with response to intravenous abatacept in patients with diffuse cutaneous systemic.MethodsAdult diffuse cutaneous systemic sclerosis patients were randomized in a 2:1 double-blinded fashion to receive abatacept or placebo over 24 weeks. Primary outcomes were safety and the change in modified Rodnan Skin Score (mRSS) at week 24 compared with baseline. Improvers were defined as patients with a decrease in mRSS of ≥30 % post-treatment compared to baseline. Skin biopsies were obtained for differential gene expression and pathway enrichment analyses and intrinsic gene expression subset assignment.ResultsTen subjects were randomized to abatacept (n = 7) or placebo (n = 3). Disease duration from first non-Raynaud’s symptom was significantly longer (8.8 ± 3.8 years vs. 2.4 ± 1.6 years, p = 0.004) and median mRSS was higher (30 vs. 22, p = 0.05) in the placebo compared to abatacept group. Adverse events were similar in the two groups. Five out of seven patients (71 %) randomized to abatacept and one out of three patients (33 %) randomized to placebo experienced ≥30 % improvement in skin score. Subjects receiving abatacept showed a trend toward improvement in mRSS at week 24 (−8.6 ± 7.5, p = 0.0625) while those in the placebo group did not (−2.3 ± 15, p = 0.75). After adjusting for disease duration, mRSS significantly improved in the abatacept compared with the placebo group (abatacept vs. placebo mRSS decrease estimate −9.8, 95 % confidence interval −16.7 to −3.0, p = 0.0114). In the abatacept group, the patients in the inflammatory intrinsic subset showed a trend toward greater improvement in skin score at 24 weeks compared with the patients in the normal-like intrinsic subset (−13.5 ± 3.1 vs. −4.5 ± 6.4, p = 0.067). Abatacept resulted in decreased CD28 co-stimulatory gene expression in improvers consistent with its mechanism of action. Improvers mapped to the inflammatory intrinsic subset and showed decreased gene expression in inflammatory pathways, while non-improver and placebos showed stable or reverse gene expression over 24 weeks.ConclusionsClinical improvement following abatacept therapy was associated with modulation of inflammatory pathways in skin.
Trial registration
ClinicalTrials.gov . Registered 1 March 2007. NCT00442611Electronic supplementary material
The online version of this article (doi:10.1186/s13075-015-0669-3) contains supplementary material, which is available to authorized users. 相似文献16.
Justin Y. Lee Mark P. Styczynski 《Metabolomics : Official journal of the Metabolomic Society》2018,14(12):153
Introduction
A common problem in metabolomics data analysis is the existence of a substantial number of missing values, which can complicate, bias, or even prevent certain downstream analyses. One of the most widely-used solutions to this problem is imputation of missing values using a k-nearest neighbors (kNN) algorithm to estimate missing metabolite abundances. kNN implicitly assumes that missing values are uniformly distributed at random in the dataset, but this is typically not true in metabolomics, where many values are missing because they are below the limit of detection of the analytical instrumentation.Objectives
Here, we explore the impact of nonuniformly distributed missing values (missing not at random, or MNAR) on imputation performance. We present a new model for generating synthetic missing data and a new algorithm, No-Skip kNN (NS-kNN), that accounts for MNAR values to provide more accurate imputations.Methods
We compare the imputation errors of the original kNN algorithm using two distance metrics, NS-kNN, and a recently developed algorithm KNN-TN, when applied to multiple experimental datasets with different types and levels of missing data.Results
Our results show that NS-kNN typically outperforms kNN when at least 20–30% of missing values in a dataset are MNAR. NS-kNN also has lower imputation errors than KNN-TN on realistic datasets when at least 50% of missing values are MNAR.Conclusion
Accounting for the nonuniform distribution of missing values in metabolomics data can significantly improve the results of imputation algorithms. The NS-kNN method imputes missing metabolomics data more accurately than existing kNN-based approaches when used on realistic datasets.17.
18.
19.
20.
Juan Ignacio Ruiz Kaamel Nuhu Justin Tyler McDaniel Federico Popoff Ariel Izcovich Juan Martin Criniti 《PloS one》2015,10(10)