全文获取类型
收费全文 | 9579篇 |
免费 | 832篇 |
国内免费 | 2篇 |
出版年
2023年 | 38篇 |
2022年 | 108篇 |
2021年 | 208篇 |
2020年 | 91篇 |
2019年 | 129篇 |
2018年 | 155篇 |
2017年 | 141篇 |
2016年 | 287篇 |
2015年 | 443篇 |
2014年 | 491篇 |
2013年 | 574篇 |
2012年 | 744篇 |
2011年 | 751篇 |
2010年 | 501篇 |
2009年 | 485篇 |
2008年 | 610篇 |
2007年 | 586篇 |
2006年 | 523篇 |
2005年 | 506篇 |
2004年 | 483篇 |
2003年 | 466篇 |
2002年 | 413篇 |
2001年 | 106篇 |
2000年 | 80篇 |
1999年 | 82篇 |
1998年 | 97篇 |
1997年 | 64篇 |
1996年 | 61篇 |
1995年 | 49篇 |
1994年 | 61篇 |
1993年 | 71篇 |
1992年 | 58篇 |
1991年 | 79篇 |
1990年 | 56篇 |
1989年 | 66篇 |
1988年 | 46篇 |
1987年 | 47篇 |
1986年 | 39篇 |
1985年 | 34篇 |
1984年 | 33篇 |
1983年 | 36篇 |
1981年 | 36篇 |
1980年 | 31篇 |
1979年 | 31篇 |
1978年 | 43篇 |
1977年 | 34篇 |
1976年 | 33篇 |
1972年 | 24篇 |
1971年 | 27篇 |
1966年 | 23篇 |
排序方式: 共有10000条查询结果,搜索用时 31 毫秒
841.
842.
In many clinical cases of radicular pain, no noticeable neuropathology is detected by conventional medical imaging strategies. Superparamagnetic iron oxide (SPIO) nanoparticles were evaluated as magnetic resonance contrast agents to specifically detect neuroinflammation at sites of painful injury in a rat model of cervical nerve root compression. Two separate groups of rats were used: an injury group that underwent controlled transient compression of the dorsal root and a sham group that received the same surgical procedures but no injury. Precontrast magnetic resonance imaging (MRI) was performed 6 days after surgery, followed by administration of SPIO via tail vein injection. After 24 hours, T2*-weighted imaging at the site of root injury revealed a postcontrast enhancement of 72.9 ± 31%. This was significantly greater than that of injured animals prior to SPIO administration (5.3 ± 12.9%). SPIO did not generate any significant postcontrast enhancement in the nerve roots of the sham group. Histology confirmed colocalization of SPIO with macrophage at the injury site. These findings suggest that SPIO-enhanced MRI may be a valuable tool to identify otherwise undetectable nerve root compression and enable improved patient management. 相似文献
843.
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the misfolding and aggregation of distinct proteins in affected tissues, however, the pathogenic cause of disease remains unknown. Recent evidence indicates that endoplasmic reticulum (ER) stress plays a central role in ALS pathogenesis. ER stress activates the unfolded protein response (UPR), a homeostatic response to misfolded proteins. The UPR is initially protective by up-regulation of specific ER stress-regulated genes and inhibition of general protein translation. However, long-term ER stress leads to cell death via apoptotic signaling, thus providing a link to neurodegeneration. Activation of the UPR is one of the earliest events in affected motor neurons of transgenic rodent models expressing ALS-linked mutant superoxide dismutase 1 (SOD1). Recently, genetic manipulation of ER stress in several different SOD1 mouse models was shown to alter disease onset and progression, implicating an active role for the UPR in disease mechanisms. Furthermore, mutations to vesicle-associated membrane protein-associated protein B (VAPB), an ER transmembrane protein involved in ER stress regulation, also cause some cases of familial ALS. ER stress also occurs in spinal cord tissues of human sporadic ALS patients, and recent evidence suggests that perturbation of the ER could occur in ALS cases associated with TAR DNA binding protein 43 (TDP-43), fused in sarcoma (FUS) and valosin containing protein (VCP). Together these findings implicate ER stress as a potential upstream mechanism involved in both familial and sporadic forms of ALS. 相似文献
844.
Azad A Jackson S Cullinane C Natoli A Neilsen PM Callen DF Maira SM Hackl W McArthur GA Solomon B 《Molecular cancer research : MCR》2011,9(12):1696-1707
DNA-dependent protein kinase (DNA-PK) plays a pivotal role in the repair of DNA double-strand breaks (DSB) and is centrally involved in regulating cellular radiosensitivity. Here, we identify DNA-PK as a key therapeutic target for augmenting accelerated senescence in irradiated human cancer cells. We find that BEZ235, a novel inhibitor of DNA-PK and phosphoinositide 3-kinase (PI3K)/mTOR, abrogates radiation-induced DSB repair resulting in cellular radiosensitization and growth delay of irradiated tumor xenografts. Importantly, radiation enhancement by BEZ235 coincides with a prominent p53-dependent accelerated senescence phenotype characterized by positive β-galactosidase staining, G(2)-M cell-cycle arrest, enlarged and flattened cellular morphology, and increased p21 expression and senescence-associated cytokine secretion. Because this senescence response to BEZ235 is accompanied by unrepaired DNA DSBs, we examined whether selective targeting of DNA-PK also induces accelerated senescence in irradiated cells. Significantly, we show that specific pharmacologic inhibition of DNA-PK, but not PI3K or mTORC1, delays DSB repair leading to accelerated senescence after radiation. We additionally show that PRKDC knockdown using siRNA promotes a striking accelerated senescence phenotype in irradiated cells comparable with that of BEZ235. Thus, in the context of radiation treatment, our data indicate that inhibition of DNA-PK is sufficient for the induction of accelerated senescence. These results validate DNA-PK as an important therapeutic target in irradiated cancer cells and establish accelerated senescence as a novel mechanism of radiosensitization induced by DNA-PK blockade. 相似文献
845.
DNA methylation is an evolutionarily conserved epigenetic modification that is critical for gene silencing and the maintenance of genome integrity. In Arabidopsis thaliana, the de novo DNA methyltransferase, domains rearranged methyltransferase 2 (DRM2), is targeted to specific genomic loci by 24 nt small interfering RNAs (siRNAs) through a pathway termed RNA-directed DNA methylation (RdDM). Biogenesis of the targeting siRNAs is thought to be initiated by the activity of the plant-specific RNA polymerase IV (Pol-IV). However, the mechanism through which Pol-IV is targeted to specific genomic loci and whether factors other than the core Pol-IV machinery are required for Pol-IV activity remain unknown. Through the affinity purification of nuclear RNA polymerase D1 (NRPD1), the largest subunit of the Pol-IV polymerase, we found that several previously identified RdDM components co-purify with Pol-IV, namely RNA-dependent RNA polymerase 2 (RDR2), CLASSY1 (CLSY1), and RNA-directed DNA methylation 4 (RDM4), suggesting that the upstream siRNA generating portion of the RdDM pathway may be more physically coupled than previously envisioned. A homeodomain protein, SAWADEE homeodomain homolog 1 (SHH1), was also found to co-purify with NRPD1; and we demonstrate that SHH1 is required for de novo and maintenance DNA methylation, as well as for the accumulation of siRNAs at specific loci, confirming it is a bonafide component of the RdDM pathway. 相似文献
846.
Zhao J Wu H Khosravi M Cui H Qian X Kelly JA Kaufman KM Langefeld CD Williams AH Comeau ME Ziegler JT Marion MC Adler A Glenn SB Alarcón-Riquelme ME;BIOLUPUS Network;GENLES Network Pons-Estel BA Harley JB Bae SC Bang SY Cho SK Jacob CO Vyse TJ Niewold TB Gaffney PM Moser KL Kimberly RP Edberg JC Brown EE Alarcon GS Petri MA Ramsey-Goldman R Vilá LM Reveille JD James JA Gilkeson GS Kamen DL Freedman BI Anaya JM Merrill JT Criswell LA Scofield RH Stevens AM Guthridge JM Chang DM Song YW Park JA 《PLoS genetics》2011,7(5):e1002079
Systemic lupus erythematosus (SLE), a complex polygenic autoimmune disease, is associated with increased complement activation. Variants of genes encoding complement regulator factor H (CFH) and five CFH-related proteins (CFHR1-CFHR5) within the chromosome 1q32 locus linked to SLE, have been associated with multiple human diseases and may contribute to dysregulated complement activation predisposing to SLE. We assessed 60 SNPs covering the CFH-CFHRs region for association with SLE in 15,864 case-control subjects derived from four ethnic groups. Significant allelic associations with SLE were detected in European Americans (EA) and African Americans (AA), which could be attributed to an intronic CFH SNP (rs6677604, in intron 11, P
meta = 6.6×10−8, OR = 1.18) and an intergenic SNP between CFHR1 and CFHR4 (rs16840639, P
meta = 2.9×10−7, OR = 1.17) rather than to previously identified disease-associated CFH exonic SNPs, including I62V, Y402H, A474A, and D936E. In addition, allelic association of rs6677604 with SLE was subsequently confirmed in Asians (AS). Haplotype analysis revealed that the underlying causal variant, tagged by rs6677604 and rs16840639, was localized to a ∼146 kb block extending from intron 9 of CFH to downstream of CFHR1. Within this block, the deletion of CFHR3 and CFHR1 (CFHR3-1Δ), a likely causal variant measured using multiplex ligation-dependent probe amplification, was tagged by rs6677604 in EA and AS and rs16840639 in AA, respectively. Deduced from genotypic associations of tag SNPs in EA, AA, and AS, homozygous deletion of CFHR3-1Δ (P
meta = 3.2×10−7, OR = 1.47) conferred a higher risk of SLE than heterozygous deletion (P
meta = 3.5×10−4, OR = 1.14). These results suggested that the CFHR3-1Δ deletion within the SLE-associated block, but not the previously described exonic SNPs of CFH, might contribute to the development of SLE in EA, AA, and AS, providing new insights into the role of complement regulators in the pathogenesis of SLE. 相似文献
847.
848.
Treatment of PARP-1-expressing cells with the combination of a DNA methylating agent (MMS) and the PARP inhibitor 4-amino-1,8-naphthalimide (4-AN) leads to an ATR/Chk1-dependent S phase checkpoint and cell death by apoptosis. Activation of ATM/Chk2 is involved in sustaining the S phase checkpoint, and double strand break (DSB) accumulation was demonstrated. NBS1, part of the MRN complex that responds to DSBs, is known to modulate ATR- and ATM-dependent checkpoint responses to UV and IR, but a role in the response to PARP inhibition has not been addressed. Here we show that the S phase checkpoint observed 4-8h after MMS+4-AN treatment was absent in cells deficient in NBS1, but was present in NBS1-complemented (i.e., functionally wild-type) cells, indicating a critical role for NBS1 in this checkpoint response. NBS1 was phosphorylated in response to MMS+4-AN treatment, and this was partially ATR- and ATM-dependent, suggesting involvement of both upstream kinases. NBS1 expression had little effect on ATR-mediated phosphorylation of Chk1 and ATM-mediated phosphorylation of Chk2 in response to MMS+4-AN. Phosphorylation of SMC1 was also observed in response to MMS+4-AN treatment. In the absence of ATM and NBS1, phosphorylation of SMC1 was weak, especially at early times after MMS+4-AN treatment. In the absence of ATR activation, reduced SMC1 phosphorylation was seen over a 24h time course. These results suggested that both ATR and ATM phosphorylate SMC1 in response to MMS+4-AN and that this phosphorylation is enhanced by phospho-NBS1. The loss of the MMS+4-AN-induced S phase checkpoint in NBS1-deficient cells may be due to a reduced cellular level of the critical downstream effector, phospho-SMC1. 相似文献
849.
Review of Florida Red Tide and Human Health Effects 总被引:1,自引:0,他引:1
Fleming LE Kirkpatrick B Backer LC Walsh CJ Nierenberg K Clark J Reich A Hollenbeck J Benson J Cheng YS Naar J Pierce R Bourdelais AJ Abraham WM Kirkpatrick G Zaias J Wanner A Mendes E Shalat S Hoagland P Stephan W Bean J Watkins S Clarke T Byrne M Baden DG 《Harmful algae》2011,10(2):224-233
This paper reviews the literature describing research performed over the past decade on the known and possible exposures and human health effects associated with Florida red tides. These harmful algal blooms are caused by the dinoflagellate, Karenia brevis, and similar organisms, all of which produce a suite of natural toxins known as brevetoxins. Florida red tide research has benefited from a consistently funded, long term research program, that has allowed an interdisciplinary team of researchers to focus their attention on this specific environmental issue-one that is critically important to Gulf of Mexico and other coastal communities. This long-term interdisciplinary approach has allowed the team to engage the local community, identify measures to protect public health, take emerging technologies into the field, forge advances in natural products chemistry, and develop a valuable pharmaceutical product. The Review includes a brief discussion of the Florida red tide organisms and their toxins, and then focuses on the effects of these toxins on animals and humans, including how these effects predict what we might expect to see in exposed people. 相似文献
850.
Chung MH Richardson BA Tapia K Benki-Nugent S Kiarie JN Simoni JM Overbaugh J Attwa M John-Stewart GC 《PLoS medicine》2011,8(3):e1000422