全文获取类型
收费全文 | 5798篇 |
免费 | 447篇 |
国内免费 | 1篇 |
专业分类
6246篇 |
出版年
2023年 | 51篇 |
2022年 | 86篇 |
2021年 | 165篇 |
2020年 | 114篇 |
2019年 | 133篇 |
2018年 | 174篇 |
2017年 | 155篇 |
2016年 | 261篇 |
2015年 | 333篇 |
2014年 | 354篇 |
2013年 | 398篇 |
2012年 | 542篇 |
2011年 | 451篇 |
2010年 | 262篇 |
2009年 | 251篇 |
2008年 | 322篇 |
2007年 | 262篇 |
2006年 | 282篇 |
2005年 | 256篇 |
2004年 | 253篇 |
2003年 | 224篇 |
2002年 | 207篇 |
2001年 | 57篇 |
2000年 | 56篇 |
1999年 | 57篇 |
1998年 | 70篇 |
1997年 | 50篇 |
1996年 | 38篇 |
1995年 | 34篇 |
1994年 | 42篇 |
1993年 | 35篇 |
1992年 | 32篇 |
1991年 | 24篇 |
1990年 | 20篇 |
1989年 | 13篇 |
1988年 | 15篇 |
1987年 | 10篇 |
1986年 | 17篇 |
1985年 | 17篇 |
1984年 | 9篇 |
1983年 | 13篇 |
1982年 | 17篇 |
1981年 | 13篇 |
1978年 | 9篇 |
1976年 | 8篇 |
1973年 | 5篇 |
1972年 | 4篇 |
1969年 | 4篇 |
1968年 | 6篇 |
1961年 | 4篇 |
排序方式: 共有6246条查询结果,搜索用时 15 毫秒
71.
Jesús Loureiro Pilar Sandoval Gloria del Peso Guadalupe Gónzalez-Mateo Vanessa Fernández-Millara Beatríz Santamaria Maria Auxiliadora Bajo José Antonio Sánchez-Tomero Gonzalo Guerra-Azcona Rafael Selgas Manuel López-Cabrera Abelardo I. Aguilera 《PloS one》2013,8(4)
Mesothelial-to-mesenchymal transition (MMT) is an auto-regulated physiological process of tissue repair that in uncontrolled conditions such as peritoneal dialysis (PD) can lead to peritoneal fibrosis. The maximum expression of peritoneal fibrosis induced by PD fluids and other peritoneal processes is the encapsulating peritoneal sclerosis (EPS) for which no specific treatment exists. Tamoxifen, a synthetic estrogen, has successfully been used to treat retroperitoneal fibrosis and EPS associated with PD. Hence, we used in vitro and animal model approaches to evaluate the efficacy of Tamoxifen to inhibit the MMT as a trigger of peritoneal fibrosis. In vitro studies were carried out using omentum-derived mesothelial cells (MCs) and effluent-derived MCs. Tamoxifen blocked the MMT induced by transforming growth factor (TGF)-β1, as it preserved the expression of E-cadherin and reduced the expression of mesenchymal-associated molecules such as snail, fibronectin, collagen-I, α-smooth muscle actin, and matrix metalloproteinse-2. Tamoxifen-treatment preserved the fibrinolytic capacity of MCs treated with TGF-β1 and decreased their migration capacity. Tamoxifen did not reverse the MMT of non-epitheliod MCs from effluents, but it reduced the expression of some mesenchymal molecules. In mice PD model, we demonstrated that MMT progressed in parallel with peritoneal membrane thickness. In addition, we observed that Tamoxifen significantly reduced peritoneal thickness, angiogenesis, invasion of the compact zone by mesenchymal MCs and improved peritoneal function. Tamoxifen also reduced the effluent levels of vascular endothelial growth factor and leptin. These results demonstrate that Tamoxifen is a therapeutic option to treat peritoneal fibrosis, and that its protective effect is mediated via modulation of the MMT process. 相似文献
72.
Rafael Luis Kessler Maurilio José Soares Christian Macagnan Probst Marco Aurélio Krieger 《PloS one》2013,8(1)
The protozoan parasite Trypanosoma cruzi displays similarities to fungi in terms of its sterol lipid biosynthesis, as ergosterol and other 24-alkylated sterols are its principal endogenous sterols. The sterol pathway is thus a potential drug target for the treatment of Chagas disease. We describe here a comparative study of the growth inhibition, ultrastructural and physiological changes leading to the death of T. cruzi cells following treatment with the sterol biosynthesis inhibitors (SBIs) ketoconazole and lovastatin. We first calculated the drug concentration inhibiting epimastigote growth by 50% (EC50/72 h) or killing all cells within 24 hours (EC100/24 h). Incubation with inhibitors at the EC50/72 h resulted in interesting morphological changes: intense proliferation of the inner mitochondrial membrane, which was corroborated by flow cytometry and confocal microscopy of the parasites stained with rhodamine 123, and strong swelling of the reservosomes, which was confirmed by acridine orange staining. These changes to the mitochondria and reservosomes may reflect the involvement of these organelles in ergosterol biosynthesis or the progressive autophagic process culminating in cell lysis after 6 to 7 days of treatment with SBIs at the EC50/72 h. By contrast, treatment with SBIs at the EC100/24 h resulted in rapid cell death with a necrotic phenotype: time-dependent cytosolic calcium overload, mitochondrial depolarization and reservosome membrane permeabilization (RMP), culminating in cell lysis after a few hours of drug exposure. We provide the first demonstration that RMP constitutes the “point of no return” in the cell death cascade, and propose a model for the necrotic cell death of T. cruzi. Thus, SBIs trigger cell death by different mechanisms, depending on the dose used, in T. cruzi. These findings shed new light on ergosterol biosynthesis and the mechanisms of programmed cell death in this ancient protozoan parasite. 相似文献
73.
Monica Martinez-Haro Mark A. Taggart Hugues Lefranc Rosa C. Martín-Doimeadiós Andy J. Green Rafael Mateo 《PloS one》2013,8(2)
Lead exposure in waterfowl was studied using noninvasive fecal sampling in the Guadalquivir Marshes in Spain, an area affected by the 1998 Aznalcóllar mine disaster. Feces of greylag geese (Anser anser, n = 191) and purple gallinule (Porphyrio porphyrio, n = 91) were collected from three different impacted sites (Entremuros, Caracoles and Cerro de los Ánsares) during the winters of 2004 to 2008. Lead and aluminium (an indicator of sediment ingestion) and Pb isotope signatures (to discriminate between sources of Pb exposure) were analyzed in freeze-dried, acid digested samples. The concentrations of fecal porphyrins and biliverdin were determined as noninvasive biomarkers to study Pb exposure effects. Results showed a decrease in Pb exposure over time in wintering greylag geese. In contrast, for purple gallinule resident in the Entremuros a clear trend was not evident. For both species, sediment ingestion appeared to be the main source of exposure to Pb. In the Entremuros, some samples from purple gallinule were detected with higher Pb levels than expected for simple soil ingestion, and these had Pb isotopic profiles compatible with mining sludge or Pb shot. Whilst fecal Pb isotopic profiles were effective in differentiating between samples from sites with different levels and sources of pollution, the combined use of element ratios (such as Pb/Al) and other non-traditional stable isotope signatures may also prove worthwhile. Overall, the fecal Pb levels detected were below those described in feces for waterfowl from other uncontaminated areas(<10 µg/g d.w.). Despite this, for both species fecal Pb levels were positively correlated with porphyrin excretion, and for purple gallinule, with the coproporphyrin III/I ratio, suggesting some subtle effects on heme synthesis in birds. Ten years after the mine spill, Pb contamination in birds by this pollution source was still detectable and subtlethal effects may persist. 相似文献
74.
Cintia Roodveldt Adahir Labrador-Garrido Elena Gonzalez-Rey Christian C. Lachaud Tim Guilliams Rafael Fernandez-Montesinos Alicia Benitez-Rondan Gema Robledo Abdelkrim Hmadcha Mario Delgado Christopher M. Dobson David Pozo 《PloS one》2013,8(11)
In recent years, it has become accepted that α-synuclein (αSyn) has a key role in the microglia-mediated neuroinflammation, which accompanies the development of Parkinson’s disease and other related disorders, such as Dementia with Lewy Bodies and Alzheimer’s disease. Nevertheless, the cellular and molecular mechanisms underlying its pathological actions, especially in the sporadic forms of the diseases, are not completely understood. Intriguingly, several epidemiological and animal model studies have revealed a link between certain microbial infections and the onset or progression of sporadic forms of these neurodegenerative disorders. In this work, we have characterized the effect of toll-like receptor (TLR) stimulation on primary murine microglial cultures and analysed the impact of priming cells with extracellular wild-type (Wt) αSyn on the subsequent TLR stimulation of cells with a set of TLR ligands. By assaying key interleukins and chemokines we report that specific stimuli, in particular Pam3Csk4 (Pam3) and single-stranded RNA40 (ssRNA), can differentially affect the TLR2/1- and TLR7-mediated responses of microglia when pre-conditioned with αSyn by augmenting IL-6, MCP-1/CCL2 or IP-10/CXCL10 secretion levels. Furthermore, we report a skewing of αSyn-primed microglia stimulated with ssRNA (TLR7) or Pam3 (TLR2/1) towards intermediate but at the same time differential, M1/M2 phenotypes. Finally, we show that the levels and intracellular location of activated caspase-3 protein change significantly in αSyn-primed microglia after stimulation with these particular TLR agonists. Overall, we report a remarkable impact of non-aggregated αSyn pre-sensitization of microglia on TLR-mediated immunity, a phenomenon that could contribute to triggering the onset of sporadic α-synuclein-related neuropathologies. 相似文献
75.
76.
Carmen Capel Irene Albaladejo Isabel Egea Isabel L. Massaretto Fernando J. Yuste-Lisbona Benito Pineda Begoña García-Sogo Trinidad Angosto Francisco B. Flores Vicente Moreno Rafael Lozano María C. Bolarín Juan Capel 《Plant, cell & environment》2020,43(7):1722-1739
Increasing evidences highlight the importance of DEAD-box RNA helicases in plant development and stress responses. In a previous study, we characterized the tomato res mutant (restored cell structure by salinity), showing chlorosis and development alterations that reverted under salt-stress conditions. Map-based cloning demonstrates that RES gene encodes SlDEAD39, a chloroplast-targeted DEAD-box RNA helicase. Constitutive expression of SlDEAD39 complements the res mutation, while the silencing lines had a similar phenotype than res mutant, which is also reverted under salinity. Functional analysis of res mutant proved SlDEAD39 is involved in the in vivo processing of the chloroplast, 23S rRNA, at the hidden break-B site, a feature also supported by in vitro binding experiments of the protein. In addition, our results show that other genes coding for chloroplast-targeted DEAD-box proteins are induced by salt-stress, which might explain the rescue of the res mutant phenotype. Interestingly, salinity restored the phenotype of res adult plants by increasing their sugar content and fruit yield. Together, these results propose an unprecedented role of a DEAD-box RNA helicase in regulating plant development and stress response through the proper ribosome and chloroplast functioning, which, in turn, represents a potential target to improve salt tolerance in tomato crops. 相似文献
77.
Plant and Soil - We examined how restoration affects the structure and function of grasslands belowground by relating changes in the morphology and architecture of root systems of dominant plants... 相似文献
78.
79.
Francielle C. Mosele Rafael Bissi Ricci Phablo Abreu José C. Rosa Neto 《Journal of cellular physiology》2020,235(9):6183-6193
Activation, proliferation, and differentiation of satellite cells can be influenced by extracellular factors, such as adiponectin. This adipokine has been proposed as a regulator of in vitro myogenesis, but its action on in vivo regeneration is not still elucidated. We used C57BL/6 (wild-type [WT]) and adiponectin knockout (AdKO) mice injured with barium chloride at periods of 3, 7, and 14 days after injury. The AdKO presented a higher number of centralized nuclei after 7 days, and a reduction in myogenic genes was observed after 3 days. Moreover, these mice presented an increase in anti-inflammatory cytokines after 3 and 7 days, and an increase in the M2 gene marker and proinflammatory cytokines after 7 days. The WT demonstrated an increase in adiponectin messenger RNA after 7 days. These results demonstrate that adiponectin is important in tissue remodeling during regeneration and that its deficiency does not compromise the maturation of muscle fibers, due to an increase in anti-inflammatory response; however, there is a possible impairment in proinflammatory response and an increase in centralized myonuclei. 相似文献
80.
Cecilia Díaz-Castelazo Ingrid R. Sánchez-Galván Paulo R. Guimar?es Jr Rafael L. Galdini Raimundo Víctor Rico-Gray 《Annals of botany》2013,111(6):1285-1293