全文获取类型
收费全文 | 2154篇 |
免费 | 180篇 |
国内免费 | 1篇 |
专业分类
2335篇 |
出版年
2023年 | 7篇 |
2022年 | 27篇 |
2021年 | 39篇 |
2020年 | 14篇 |
2019年 | 35篇 |
2018年 | 45篇 |
2017年 | 35篇 |
2016年 | 74篇 |
2015年 | 111篇 |
2014年 | 126篇 |
2013年 | 125篇 |
2012年 | 194篇 |
2011年 | 143篇 |
2010年 | 105篇 |
2009年 | 107篇 |
2008年 | 138篇 |
2007年 | 128篇 |
2006年 | 99篇 |
2005年 | 92篇 |
2004年 | 104篇 |
2003年 | 101篇 |
2002年 | 90篇 |
2001年 | 27篇 |
2000年 | 29篇 |
1999年 | 25篇 |
1998年 | 28篇 |
1997年 | 22篇 |
1996年 | 22篇 |
1995年 | 10篇 |
1994年 | 12篇 |
1993年 | 10篇 |
1992年 | 15篇 |
1991年 | 8篇 |
1990年 | 12篇 |
1989年 | 12篇 |
1988年 | 8篇 |
1987年 | 13篇 |
1986年 | 7篇 |
1983年 | 8篇 |
1981年 | 6篇 |
1980年 | 8篇 |
1979年 | 13篇 |
1978年 | 10篇 |
1976年 | 6篇 |
1975年 | 6篇 |
1974年 | 8篇 |
1973年 | 7篇 |
1971年 | 8篇 |
1970年 | 6篇 |
1968年 | 10篇 |
排序方式: 共有2335条查询结果,搜索用时 15 毫秒
71.
Raciti D Reggiani L Geffers L Jiang Q Bacchion F Subrizi AE Clements D Tindal C Davidson DR Kaissling B Brändli AW 《Genome biology》2008,9(5):R84-21
Background
The pronephros, the simplest form of a vertebrate excretory organ, has recently become an important model of vertebrate kidney organogenesis. Here, we elucidated the nephron organization of the Xenopus pronephros and determined the similarities in segmentation with the metanephros, the adult kidney of mammals.Results
We performed large-scale gene expression mapping of terminal differentiation markers to identify gene expression patterns that define distinct domains of the pronephric kidney. We analyzed the expression of over 240 genes, which included members of the solute carrier, claudin, and aquaporin gene families, as well as selected ion channels. The obtained expression patterns were deposited in the searchable European Renal Genome Project Xenopus Gene Expression Database. We found that 112 genes exhibited highly regionalized expression patterns that were adequate to define the segmental organization of the pronephric nephron. Eight functionally distinct domains were discovered that shared significant analogies in gene expression with the mammalian metanephric nephron. We therefore propose a new nomenclature, which is in line with the mammalian one. The Xenopus pronephric nephron is composed of four basic domains: proximal tubule, intermediate tubule, distal tubule, and connecting tubule. Each tubule may be further subdivided into distinct segments. Finally, we also provide compelling evidence that the expression of key genes underlying inherited renal diseases in humans has been evolutionarily conserved down to the level of the pronephric kidney.Conclusion
The present study validates the Xenopus pronephros as a genuine model that may be used to elucidate the molecular basis of nephron segmentation and human renal disease. 相似文献72.
Background
Chronic persistent asthma is characterized by ongoing airway inflammation and airway remodeling. The processes leading to airway remodeling are poorly understood, and there is increasing evidence that even aggressive anti-inflammatory therapy does not completely prevent this process. We sought to investigate whether TGFβ1 stimulates bronchial epithelial cells to undergo transition to a mesenchymal phenotype, and whether this transition can be abrogated by corticosteroid treatment or enhanced by the pro-inflammatory cytokine IL-1β.Methods
BEAS-2B and primary normal human bronchial epithelial cells were stimulated with TGFβ1 and expression of epithelial and mesenchymal markers assessed by quantitative real-time PCR, immunoblotting, immunofluorescence microscopy and zymography. In some cases the epithelial cells were also incubated with corticosteroids or IL-1β. Results were analyzed using non-parametric statistical tests.Results
Treatment of BEAS-2B or primary human bronchial epithelial cells with TGFβ1 significantly reduced the expression level of the epithelial adherence junction protein E-cadherin. TGFβ1 then markedly induced mesenchymal marker proteins such as collagen I, tenascin C, fibronectin and α-smooth muscle actin mRNA in a dose dependant manner. The process of mesenchymal transition was accompanied by a morphological change towards a more spindle shaped fibroblast cell type with a more motile and invasive phenotype. Corticosteroid pre-treatment did not significantly alter the TGFβ1 induced transition but IL-1β enhanced the transition.Conclusion
Our results indicate, that TGFβ1 can induce mesenchymal transition in the bronchial epithelial cell line and primary cells. Since asthma has been strongly associated with increased expression of TGFβ1 in the airway, epithelial to mesenchymal transition may contribute to the contractile and fibrotic remodeling process that accompanies chronic asthma. 相似文献73.
Eco‐industrial networks (EINs, of which eco‐industrial parks are a subset) have gained support as a solution that simultaneously reduces environmental burdens and promotes economic interests. EINs operate under a mutualistic framework, where waste materials and energy are exchanged between industries to their mutual benefit, creating a diverse web of flows. Recent studies have focused on analogies between food webs (FWs) and EINs, measuring a network's success at ecological imitation as representative of its sustainability. Studies have focused heavily on the number of links and nodes in a network, but have neglected the economic reality that each investment comes at the opportunity cost of all alternatives. This analysis focuses on the nestedness metric as used by ecologists to address this pivotal facet to the FW‐EIN analogy. Nestedness describes an ecological strategy for the position of links between nodes in a network in a way that maximizes network cycling for a given number of connections. This metric presents many advantages for EIN design and analysis, including maturity independence, size normalization, and a strong statistical record in highly mutualistic ecological systems. Application of nestedness to EINs indicates a lower presence of nested structures and more randomness than what is typically seen in FWs. The industrial networks also display a correlation between high nestedness and internal cycles, suggesting that the reuse of materials and energy in EINs can be improved upon by increasing the nestedness of structures. 相似文献
74.
Diane Y Kim Peter D Countway Adriane C Jones Astrid Schnetzer Warren Yamashita Christine Tung David A Caron 《The ISME journal》2014,8(3):515-530
The monthly, seasonal and interannual variability of microbial eukaryote assemblages were
examined at 5 m, the deep chlorophyll maximum, 150 m and 500 m at the
San Pedro Ocean Time-series station (eastern North Pacific). The depths spanned
transitions in temperature, light, nutrients and oxygen, and included a persistently
hypoxic environment at 500 m. Terminal restriction fragment length polymorphism was
used for the analysis of 237 samples that were collected between September 2000 and
December 2010. Spatiotemporal variability patterns of microeukaryote assemblages indicated
the presence of distinct shallow and deep communities at the SPOT station, presumably
reflecting taxa that were specifically adapted for the conditions in those environments.
Community similarity values between assemblages collected 1 month apart at each depth
ranged between ∼20% and ∼84% (averages were
∼50–59%). The assemblage at 5 m was temporally more dynamic than
deeper assemblages and also displayed substantial interannual variability during the first
∼3 years of the study. Evidence of seasonality was detected for the microbial
eukaryote assemblage at 5 m between January 2008 and December 2010 and at
150 m between September 2000 and December 2003. Seasonality was not detected for
assemblages at the deep chlorophyll a maximum, which varied in depth seasonally,
or at 500 m. Microbial eukaryote assemblages exhibited cyclical patterns in at
least 1 year at each depth, implying an annual resetting of communities. Substantial
interannual variability was detected for assemblages at all depths and represented the
largest source of temporal variability in this temperate coastal ecosystem. 相似文献
75.
Lessard CJ Adrianto I Ice JA Wiley GB Kelly JA Glenn SB Adler AJ Li H Rasmussen A Williams AH Ziegler J Comeau ME Marion M Wakeland BE Liang C Ramos PS Grundahl KM Gallant CJ Alarcón-Riquelme ME Alarcón GS Anaya JM Bae SC Boackle SA Brown EE Chang DM Cho SK Criswell LA Edberg JC Freedman BI Gilkeson GS Jacob CO James JA Kamen DL Kimberly RP Kim JH Martin J Merrill JT Niewold TB Park SY Petri MA Pons-Estel BA Ramsey-Goldman R Reveille JD Scofield RH Song YW Stevens AM Tsao BP Vila LM Vyse TJ 《American journal of human genetics》2012,90(4):648-660
Systemic lupus erythematosus (SLE) is a chronic heterogeneous autoimmune disorder characterized by the loss of tolerance to self-antigens and dysregulated interferon responses. The etiology of SLE is complex, involving both heritable and environmental factors. Candidate-gene studies and genome-wide association (GWA) scans have been successful in identifying new loci that contribute to disease susceptibility; however, much of the heritable risk has yet to be identified. In this study, we sought to replicate 1,580 variants showing suggestive association with SLE in a previously published GWA scan of European Americans; we tested a multiethnic population consisting of 7,998 SLE cases and 7,492 controls of European, African American, Asian, Hispanic, Gullah, and Amerindian ancestry to find association with the disease. Several genes relevant to immunological pathways showed association with SLE. Three loci exceeded the genome-wide significance threshold: interferon regulatory factor 8 (IRF8; rs11644034; pmeta-Euro = 2.08 × 10−10), transmembrane protein 39A (TMEM39A; rs1132200; pmeta-all = 8.62 × 10−9), and 17q21 (rs1453560; pmeta-all = 3.48 × 10−10) between IKAROS family of zinc finger 3 (AIOLOS; IKZF3) and zona pellucida binding protein 2 (ZPBP2). Fine mapping, resequencing, imputation, and haplotype analysis of IRF8 indicated that three independent effects tagged by rs8046526, rs450443, and rs4843869, respectively, were required for risk in individuals of European ancestry. Eleven additional replicated effects (5 × 10−8 < pmeta-Euro < 9.99 × 10−5) were observed with CFHR1, CADM2, LOC730109/IL12A, LPP, LOC63920, SLU7, ADAMTSL1, C10orf64, OR8D4, FAM19A2, and STXBP6. The results of this study increase the number of confirmed SLE risk loci and identify others warranting further investigation. 相似文献
76.
Andersen GØ Skomedal T Enger M Fidjeland A Brattelid T Levy FO Osnes JB 《American journal of physiology. Heart and circulatory physiology》2004,286(4):H1354-H1360
We studied molecular and functional characteristics as well as hormonal regulation of the Na-K-2Cl cotransporter (NKCC) in the isolated rat heart and cardiomyocytes. NKCC activity was measured as bumetanide-sensitive (86)Rb(+) influx in isolated perfused rat hearts and isolated cardiomyocytes. Stimulation of alpha(1)-adrenoceptors (AR) by phenylephrine (30 microM) increased (86)Rb(+) influx. The NKCC inhibitor bumetanide (50 microM) reduced the response to phenylephrine by 45 +/- 13% (n = 12, P < 0.01). PD-98059 (10 microM), an inhibitor of the activation of the mitogen-activated protein kinases extracellular signal-regulated protein kinase 1 and 2 (ERK1/2), reduced the total response to phenylephrine by 51 +/- 13% (n = 10, P < 0.01) and eliminated the bumetanide-sensitive component, indicating that alpha(1)-AR mediated stimulation of NKCC is dependent on activation of ERK1/2. Inhibitors of protein kinase C or phosphatidylinositol 3-kinase had no effect. The presence of NKCC mRNA and protein was demonstrated in isolated rat cardiomyocytes. Phosphorylation of NKCC after alpha(1)-AR stimulation was shown by immunoprecipitation of the phosphoprotein from (32)P(i) prelabeled cardiomyocytes. Increased phosphorylation of the NKCC protein was also abolished by PD-98059. We conclude that the NKCC is present in rat cardiomyocytes and that ion transport by the cotransporter is regulated by alpha(1)-AR stimulation through phosphorylation of this protein involving the ERK pathway. 相似文献
77.
Stephanie J. Gros Nina Kurschat Astrid Drenckhan Thorsten Dohrmann Evelyn Forberich Katharina Effenberger Uta Reichelt Robert M. Hoffman Klaus Pantel Jussuf T. Kaifi Jakob R. Izbicki 《PloS one》2012,7(10)
A functional linkage of the structurally unrelated receptors HER2 and CXCR4 has been suggested for breast cancer but has not been evaluated for esophageal carcinoma. The inhibition of HER2 leads to a reduction of primary tumor growth and metastases in an orthotopic model of esophageal carcinoma. The chemokine receptor CXCR4 has been implicated in metastatic dissemination of various tumors and correlates with poor survival in esophageal carcinoma. The aim of this study was to investigate a correlation between the expression levels of HER2 and CXCR4 and to evaluate the involvemnent of CXCR4-expression in HER2-positive esophageal carcinoma. The effects of HER2-inhibition with trastuzumab and of CXCR4-inhibition with AMD3100 on primary tumor growth, metastatic homing, and receptor expression were evaluated in vitro and in an orthotopic model of metastatic esophageal carcinoma using MRI for imaging. The clinical relevance of HER2- and CXCR4-expression was examined in esophageal carcinoma patients. A significant correlation of HER2- and CXCR4-expression in primary tumor and metastases exists in the orthotopic model. Trastuzumab and AMD3100 treatment led to a significant reduction of primary tumor growth, metastases and micrometastases. HER2-expression was significantly elevated under AMD3100 treatment in the primary tumor and particularly in the metastases. The positive correlation between HER2- and CXCR4-expression was validated in esophageal cancer patients. The correlation of CXCR4- and HER2-expression and the elevation of HER2-expression and reduction of metastases through CXCR4-inhibition suggest a possible functional linkage and a role in tumor dissemination in HER2-positive esophageal carcinoma. 相似文献
78.
Astrid Barrio 《Ethnic and racial studies》2017,40(10):1776-1794
The ethnic outbidding thesis explains party polarization as a consequence of political changes amongst voters. We argued instead that party elites’ extreme position on the national identity cleavage can help polarizing strategies to prevail over moderate strategies in a context of increasing political uncertainty, without previous voters’ polarization. We test successfully this hypothesis in Catalonia by analysing the polarization of political parties and people’s demands for self-government in Catalonia since the early 2000s. We also find that the result of this outbidding pattern of competition was a reduction in the gap between elites’ and voters’ views on national identity. The analysis employs a set of unique data on party elites and activists’ national identity, from several surveys conducted on the delegates at party conferences of the main Catalan parties between 1996 and 2012. Our data provide empirical support for the argument that ethnic polarization is mainly an elite-driven process. 相似文献
79.
Jiska Jebbink Astrid Wolters Febilla Fernando Gijs Afink Joris van der Post Carrie Ris-Stalpers 《生物化学与生物物理学报:疾病的分子基础》2012,1822(12):1960-1969
Preeclampsia is characterised by new onset hypertension and proteinuria and is a major obstetrical problem for both mother and foetus. Haemolysis elevated liver enzymes and low platelets (HELLP) syndrome is an obstetrical emergency and most cases occur in the presence of preeclampsia. Preeclampsia and HELLP are complicated syndromes with a wide variety in severity of clinical symptoms and gestational age at onset. The pathophysiology depends not only on periconceptional conditions and the foetal and placental genotype, but also on the capability of the maternal system to deal with pregnancy. Genetically, preeclampsia is a complex disorder and despite numerous efforts no clear mode of inheritance has been established. A minor fraction of HELLP cases is caused by foetal homozygous LCHAD deficiency, but for most cases the genetic background has not been elucidated yet. At least 178 genes have been described in relation to preeclampsia or HELLP syndrome. Confined placental mosaicism (CPM) is documented to cause early onset preeclampsia in some cases; the overall contribution of CPM to the occurrence of preeclampsia has not been adequately investigated yet. This article is part of a Special Issue entitled: Molecular Genetics of Human Reproductive Failure. 相似文献
80.
Farwick A Jordan U Fuellen G Huchon D Catzeflis F Brosius J Schmitz J 《Systematic biology》2006,55(6):936-948
Transposed elements constitute an attractive, useful source of phylogenetic markers to elucidate the evolutionary history of their hosts. Frequent and successive amplifications over evolutionary time are important requirements for utilizing their presence or absence as landmarks of evolution. Although transposed elements are well distributed in rodent taxa, the generally high degree of genomic sequence divergence among species complicates our access to presence/absence data. With this in mind we developed a novel, high-throughput computational strategy, called CPAL (Conserved Presence/Absence Locus-finder), to identify genome-wide distributed, phylogenetically informative transposed elements flanked by highly conserved regions. From a total of 232 extracted chromosomal mouse loci we randomly selected 14 of these plus 2 others from previous test screens and attempted to amplify them via PCR in representative rodent species. All loci were amplifiable and ultimately contributed 31 phylogenetically informative markers distributed throughout the major groups of Rodentia. 相似文献