全文获取类型
收费全文 | 1615篇 |
免费 | 121篇 |
国内免费 | 2篇 |
专业分类
1738篇 |
出版年
2023年 | 7篇 |
2022年 | 26篇 |
2021年 | 29篇 |
2020年 | 20篇 |
2019年 | 23篇 |
2018年 | 42篇 |
2017年 | 36篇 |
2016年 | 51篇 |
2015年 | 82篇 |
2014年 | 88篇 |
2013年 | 113篇 |
2012年 | 124篇 |
2011年 | 111篇 |
2010年 | 84篇 |
2009年 | 78篇 |
2008年 | 98篇 |
2007年 | 103篇 |
2006年 | 102篇 |
2005年 | 82篇 |
2004年 | 76篇 |
2003年 | 63篇 |
2002年 | 59篇 |
2001年 | 17篇 |
2000年 | 11篇 |
1999年 | 16篇 |
1998年 | 20篇 |
1997年 | 14篇 |
1996年 | 11篇 |
1995年 | 8篇 |
1994年 | 12篇 |
1993年 | 14篇 |
1992年 | 13篇 |
1991年 | 17篇 |
1990年 | 9篇 |
1989年 | 6篇 |
1988年 | 4篇 |
1987年 | 6篇 |
1986年 | 3篇 |
1985年 | 3篇 |
1984年 | 11篇 |
1983年 | 4篇 |
1982年 | 6篇 |
1981年 | 4篇 |
1979年 | 3篇 |
1978年 | 6篇 |
1976年 | 2篇 |
1975年 | 5篇 |
1974年 | 3篇 |
1972年 | 4篇 |
1968年 | 2篇 |
排序方式: 共有1738条查询结果,搜索用时 15 毫秒
161.
Sandoval-Acuña C Lopez-Alarcón C Aliaga ME Speisky H 《Chemico-biological interactions》2012,199(1):18-28
Mitochondrial dysfunction plays a major role in the development of oxidative stress and cytotoxicity induced by non-steroidal anti-inflammatory drugs (NSAIDs). A major objective of the present study was to investigate whether in vitro the NSAIDs, aspirin, indomethacin, diclofenac, piroxicam and ibuprofen, which feature different chemical structures, are able to inhibit mitochondrial complex I. All NSAIDs were effective inhibitors when added both, directly to mitochondria isolated from rat duodenum epithelium (50 μM) or to Caco-2 cells (250 μM). In the former system, complex I inhibition was concentration-dependent and susceptible to competition and reversion by the addition of coenzyme Q (32.5-520 μM). Based on reports suggesting a potential gastro-protective activity of quercetin, the ability of this flavonoid to protect isolated mitochondria against NSAIDs-induced complex I inhibition was evaluated. Low micromolar concentrations of quercetin (1-20 μM) protected against such inhibition, in a concentration dependent manner. In the case of aspirin, quercetin (5 μM) increased the IC50 by 10-fold. In addition, the present study shows that quercetin (5-10 μM) can behave as a "coenzyme Q-mimetic" molecule, allowing a normal electron flow along the whole electron transporting chain (complexes I, II, III and IV). The exposed findings reveal that complex I inhibition is a common deleterious effect of NSAIDs at the mitochondrial level, and that such effect is, for all tested agents, susceptible to be prevented by quercetin. Data provided here supports the contention that the protective action of quercetin resides on its, here for first time-shown, ability to behave as a coenzyme Q-like molecule. 相似文献
162.
E Ainsua-Enrich D Alvarez-Errico AM Gilfillan C Picado J Sayós J Rivera M Martín 《Journal of immunology (Baltimore, Md. : 1950)》2012,189(6):2727-2734
Adaptor molecules are essential in organizing signaling molecules and in coordinating and compartmentalizing their activity. SH3-binding protein 2 (3BP2) is a cytoplasmic adaptor protein mainly expressed by hematopoietic cells that has been shown to act as a positive regulator in T, B, and NK cell signal transduction. 3BP2 is an important regulator of cytotoxic granule release in NK cells. Mast cells (MCs) similarly degranulate following Ag-dependent aggregation of the FcεRI on the cell surface. Activation of these cells induces the release of preformed inflammatory mediators and the de novo synthesis and secretion of cytokines and chemokines. Thus, MCs participate in both innate and acquired responses. We observed that 3BP2 is expressed in human MCs (huMCs) from diverse origins. Moreover, 3BP2 coimmunoprecipitates with essential MC signaling mediators such as Lyn, Syk, and phospholipase C γ; thus, a role for this adaptor in MC function was postulated. In the present work, we used the short hairpin RNA lentiviral targeting approach to silence 3BP2 expression in huMCs. Our findings point to a requirement for 3BP2 in optimal immediate and late MCs responses such as degranulation and IL-8 or GM-CSF secretion. 3BP2 was determined to be necessary for optimal phosphorylation of Syk, linker for activation of T cells, and phospholipase C γ(1), critical signals for calcium release from intracellular stores. Taken together, our results show that by participating in FcεRI- mediated signal transduction 3BP2 is an important regulator of huMC activation. Thus, 3BP2 could be a potential therapeutic target for IgE-dependent MC-mediated inflammatory disease. 相似文献
163.
Piotrowski P Lianeri M Wudarski M Olesińska M Jagodziński PP 《Molecular biology reports》2012,39(9):8861-8866
The STAT4 has been found to be a susceptible gene in the development of systemic lupus erythematosus (SLE) in various populations. There are evident population differences in the context of clinical manifestations of SLE, therefore we investigated the prevalence of the STAT4 G > C (rs7582694) polymorphism in patients with SLE (n = 253) and controls (n = 521) in a sample of the Polish population. We found that patients with the STAT4 C/G and CC genotypes exhibited a 1.583-fold increased risk of SLE incidence (95 % CI = 1.168-2.145, p = 0.003), with OR for the C/C versus C/G and G/G genotypes was 1.967 (95 % CI = 1.152-3.358, p = 0.0119). The OR for the STAT4 C allele frequency showed a 1.539-fold increased risk of SLE (95 % CI = 1.209-1.959, p = 0.0004). We also observed an increased frequency of STAT4 C/C and C/G genotypes in SLE patients with renal symptoms OR = 2.259 (1.365-3.738, p = 0.0014), (p (corr) = 0.0238) and in SLE patients with neurologic manifestations OR = 2.867 (1.467-5.604, p = 0.0016), (p (corr) = 0.0272). Moreover, we found a contribution of STAT4 C/C and C/G genotypes to the presence of the anti-snRNP Ab OR = 3.237 (1.667-6.288, p = 0.0003), (p (corr) = 0.0051) and the presence of the anti-Scl-70 Ab OR = 2.665 (1.380-5.147, p = 0.0028), (p (corr) = 0.0476). Our studies confirmed an association of the STAT4 C (rs7582694) variant with the development of SLE and occurrence of some clinical manifestations of the disease. 相似文献
164.
Batch cultures of the green microalga Chlorella vulgaris and cyanobacterium Planktothrix isothrix and their corresponding co-cultures were grown in municipal wastewater in order to study their growth as well as the nitrogen
(NH4–N) and phosphorus (PO43−–P) removal. The cultures were grown under two irradiances of 20 and 60 μmol photons m−2 s−1 in shaken and unshaken conditions. The co-culture of unshaken Chlorella and Planktothrix showed the greatest growth under both irradiances. The monoalgal Planktotrix cultures showed better growth when unshaken than when shaken, whereas Chlorella cultures grew better when mixed, but only at the higher irradiance. The highest percentage of nitrogen removal (up to 80%)
was attained by the unshaken co-cultures of Chlorella and Planktothrix. The amount of nitrogen recycled in the biomass reached up to 85% of that removed. Shaken monoalgal cultures of Chlorella showed phosphorus removal under both irradiances. They completely removed the initial phosphorus concentration (7.47 ± 0.17 mg L−1) within 96 and 48 h under 20 and 60 μmol photons m−2 s−1, respectively. 相似文献
165.
Belokon YN Gugkaeva ZT Hakobyan KV Maleev VI Moskalenko MA Khrustalev VN Saghyan AS Tsaloev AT Babievsky KK 《Amino acids》2012,43(1):299-308
(S)- and (R)-BIMBOL were efficient PT catalysts of asymmetric Michael addition of prochiral Ni-PBP-Gly (1) to acrylic esters and malonic esters to Ni-PBP-Δ-Ala (2) correspondingly. The salient feature of the catalysis is opposite configurations of Glu prepared via the two paths with BIMBOL of the same configuration and a perspective novel catalytic procedure for the synthesis of Gla derivatives. 相似文献
166.
Eduardo Díaz-Rubio Auxiliadora Gómez-Espa?a Bartomeu Massutí Javier Sastre Margarita Reboredo José Luis Manzano Fernando Rivera MaJosé Safont Clara Montagut Encarnación González Manuel Benavides Eugenio Marcuello Andrés Cervantes Purificación Martínez de Prado Carlos Fernández-Martos Antonio Arrivi Inmaculada Bando Enrique Aranda Spanish Cooperative Group for the Treatment of Digestive Tumors 《PloS one》2012,7(10)
Background
In the MACRO study, patients with metastatic colorectal cancer (mCRC) were randomised to first-line treatment with 6 cycles of capecitabine and oxaliplatin (XELOX) plus bevacizumab followed by either single-agent bevacizumab or XELOX plus bevacizumab until disease progression. An additional retrospective analysis was performed to define the prognostic value of tumour KRAS status on progression-free survival (PFS), overall survival (OS) and response rates.Methodology/Principal Findings
KRAS data (tumour KRAS status and type of mutation) were collected by questionnaire from participating centres that performed KRAS analyses. These data were then cross-referenced with efficacy data for relevant patients in the MACRO study database. KRAS status was analysed in 394 of the 480 patients (82.1%) in the MACRO study. Wild-type (WT) KRAS tumours were found in 219 patients (56%) and mutant (MT) KRAS in 175 patients (44%). Median PFS was 10.9 months for patients with WT KRAS and 9.4 months for patients with MT KRAS tumours (p = 0.0038; HR: 1.40; 95% CI:1.12–1.77). The difference in OS was also significant: 26.7 months versus 18.0 months for WT versus MT KRAS, respectively (p = 0.0002; HR: 1.55; 95% CI: 1.23–1.96). Univariate and multivariate analyses showed that KRAS was an independent variable for both PFS and OS. Responses were observed in 126 patients (57.5%) with WT KRAS tumours and 76 patients (43.4%) with MT KRAS tumours (p = 0.0054; OR: 1.77; 95% CI: 1.18–2.64).Conclusions/Significance
This analysis of the MACRO study suggests a prognostic role for tumour KRAS status in patients with mCRC treated with XELOX plus bevacizumab. For both PFS and OS, KRAS status was an independent factor in univariate and multivariate analyses. 相似文献167.
Ileana Herrera Maria-Josefina Hernandez Margarita Lampo Jafet M. Nassar 《Population Ecology》2012,54(1):225-237
Biological invasions have a great impact on biodiversity and ecosystem functioning worldwide. Kalanchoe daigremontiana is a noxious invasive plant in arid zones. Besides being toxic for domestic animals and wildlife, this species inhibits the
growth of native plants. Its rapid proliferation in Cerro Saroche National Park (Venezuela) is of great concern because this
area hosts several species endemic to the scarce arid zones in the Caribbean. The traits of K. daigremontiana that contribute to its invasive success are unknown. Based on empirical data, we derived a stage structured, stochastic and
density-dependent model, to identify characteristics relevant for its establishment. Sensitivity analyses revealed that the
establishment of K. daigremontiana depends exclusively on plantlet recruitment. Because asexual plantlets reproduce in less than 1 year populations are able
to increase rapidly during the initial phases of invasion, when extinction risks are higher. Sexual seedlings, on the contrary,
require a minimum of 3 years to reproduce. As a result, seedling recruitment contributes little to the transient dynamics
of the population and therefore cannot warrant the successful establishment of the species. Simulations of various management
strategies show that eradication through plant removal may only be achieved if harvest begins shortly after introduction.
If a rapid response is not possible, reducing the survival and growth rates of plantlets through biological control is an
alternative option. Thus, a strict control of dispersal of plantlets by humans and a continuous monitoring of new invasions
should be the first priority for reducing further impact on native species. 相似文献
168.
Margarita Hernández-Restrepo Carolina Silvera-Simón Julio Mena-Portales ángel Mercado-Sierra Josep Guarro Josepa Gené 《Mycological Progress》2012,11(1):191-199
Diplococcium dimorphosporum sp. nov., D. racemosum sp. nov., D. singulare sp. nov. and D. pulneyense Subram. & Sekar collected from plant debris in natural areas of Spain are described and illustrated. The first species is
characterized principally by the production of branched conidiophores and short chains of conidia. Diplococcium singulare has unbranched conidiophores, and conidia produced usually at the tip of conidiophores and from lateral spherical conidiogenous
cells. In addition, both species develop a Selenosporella synanamorph with narrow falcate conidia. Diplococcium racemosum produces branched, verrucose conidiophores, and verrucose conidia in long branched chains. Diplococcium pulneyense is the second record, being described for first time on the natural substratum and re-described in pure culture. A key to
currently accepted species of Diplococcium is provided. 相似文献
169.
Alexandrova A Petrov L Georgieva A Kirkova M Kukan M 《Cell biochemistry and function》2008,26(3):392-398
In vivo effects of N-benzyloxycarbonyl (Cbz)-Leu-Leu-leucinal (MG132) on chymotryptic-like (ChT-L), tryptic-like, and post-glutamyl peptide hydrolytic-like proteasome activities, protein oxidation, lipid peroxidation (LP), glutathione (GSH) level, as well as on the activity of antioxidant enzymes (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and glutathione-reductase) in the rat liver were studied. The possibility of MG132 provoking the formation of free oxygen radicals was also assayed in primary hepatocytes. The following results were obtained: (1) In vivo, MG132 did not change the spontaneous LP, but increased Fe-induced LP and the amount of oxidized proteins; it decreased the GSH level in liver. From the proteasome activities studied in liver cytosol only ChT-L activity was significantly decreased after MG132 administration. Furthermore, MG132 increased antioxidant enzyme activities of SOD, CAT, and GSH-Px. (2) In vitro, MG132 increased free radical oxygen species in hepatocytes; this effect disappeared in the presence of CAT or mannitol. In conclusion, since nowadays proteasome inhibitors are entering into the swing of laboratory and clinical practice, the present data could provide useful information for MG132 action. Consequently, future in vivo experiments with MG132 could highlight the possibility of its use at different pathological conditions. 相似文献
170.
John P. Norman Seth W. Perry Holly M. Reynolds Michelle Kiebala Karen L. De Mesy Bentley Margarita Trejo David J. Volsky Sanjay B. Maggirwar Stephen Dewhurst Eliezer Masliah Harris A. Gelbard 《PloS one》2008,3(11)
Neurologic disease caused by human immunodeficiency virus type 1 (HIV-1) is ultimately refractory to highly active antiretroviral therapy (HAART) because of failure of complete virus eradication in the central nervous system (CNS), and disruption of normal neural signaling events by virally induced chronic neuroinflammation. We have previously reported that HIV-1 Tat can induce mitochondrial hyperpolarization in cortical neurons, thus compromising the ability of the neuron to buffer calcium and sustain energy production for normal synaptic communication. In this report, we demonstrate that Tat induces rapid loss of ER calcium mediated by the ryanodine receptor (RyR), followed by the unfolded protein response (UPR) and pathologic dilatation of the ER in cortical neurons in vitro. RyR antagonism attenuated both Tat-mediated mitochondrial hyperpolarization and UPR induction. Delivery of Tat to murine CNS in vivo also leads to long-lasting pathologic ER dilatation and mitochondrial morphologic abnormalities. Finally, we performed ultrastructural studies that demonstrated mitochondria with abnormal morphology and dilated endoplasmic reticulum (ER) in brain tissue of patients with HIV-1 inflammation and neurodegeneration. Collectively, these data suggest that abnormal RyR signaling mediates the neuronal UPR with failure of mitochondrial energy metabolism, and is a critical locus for the neuropathogenesis of HIV-1 in the CNS. 相似文献