全文获取类型
收费全文 | 8480篇 |
免费 | 751篇 |
国内免费 | 1篇 |
出版年
2023年 | 41篇 |
2022年 | 115篇 |
2021年 | 212篇 |
2020年 | 127篇 |
2019年 | 151篇 |
2018年 | 172篇 |
2017年 | 138篇 |
2016年 | 240篇 |
2015年 | 438篇 |
2014年 | 494篇 |
2013年 | 566篇 |
2012年 | 730篇 |
2011年 | 642篇 |
2010年 | 441篇 |
2009年 | 401篇 |
2008年 | 528篇 |
2007年 | 491篇 |
2006年 | 435篇 |
2005年 | 379篇 |
2004年 | 329篇 |
2003年 | 350篇 |
2002年 | 319篇 |
2001年 | 109篇 |
2000年 | 114篇 |
1999年 | 112篇 |
1998年 | 84篇 |
1997年 | 69篇 |
1996年 | 60篇 |
1995年 | 62篇 |
1994年 | 63篇 |
1993年 | 67篇 |
1992年 | 70篇 |
1991年 | 56篇 |
1990年 | 44篇 |
1989年 | 40篇 |
1988年 | 56篇 |
1987年 | 27篇 |
1986年 | 39篇 |
1985年 | 30篇 |
1984年 | 35篇 |
1983年 | 22篇 |
1982年 | 20篇 |
1979年 | 19篇 |
1978年 | 21篇 |
1977年 | 18篇 |
1974年 | 22篇 |
1973年 | 19篇 |
1972年 | 19篇 |
1970年 | 16篇 |
1969年 | 16篇 |
排序方式: 共有9232条查询结果,搜索用时 31 毫秒
961.
Michot C Le Goff C Goldenberg A Abhyankar A Klein C Kinning E Guerrot AM Flahaut P Duncombe A Baujat G Lyonnet S Thalassinos C Nitschke P Casanova JL Le Merrer M Munnich A Cormier-Daire V 《American journal of human genetics》2012,90(4):740-745
Acrodysostosis is a rare autosomal-dominant condition characterized by facial dysostosis, severe brachydactyly with cone-shaped epiphyses, and short stature. Moderate intellectual disability and resistance to multiple hormones might also be present. Recently, a recurrent mutation (c.1102C>T [p.Arg368∗]) in PRKAR1A has been identified in three individuals with acrodysostosis and resistance to multiple hormones. After studying ten unrelated acrodysostosis cases, we report here de novo PRKAR1A mutations in five out of the ten individuals (we found c.1102C>T [p.Arg368∗] in four of the ten and c.1117T>C [p.Tyr373His] in one of the ten). We performed exome sequencing in two of the five remaining individuals and selected phosphodiesterase 4D (PDE4D) as a candidate gene. PDE4D encodes a class IV cyclic AMP (cAMP)-specific phosphodiesterase that regulates cAMP concentration. Exome analysis detected heterozygous PDE4D mutations (c.673C>A [p.Pro225Thr] and c.677T>C [p.Phe226Ser]) in these two individuals. Screening of PDE4D identified heterozygous mutations (c.568T>G [p.Ser190Ala] and c.1759A>C [p.Thr587Pro]) in two additional acrodysostosis cases. These mutations occurred de novo in all four cases. The four individuals with PDE4D mutations shared common clinical features, namely characteristic midface and nasal hypoplasia and moderate intellectual disability. Metabolic screening was normal in three of these four individuals. However, resistance to parathyroid hormone and thyrotropin was consistently observed in the five cases with PRKAR1A mutations. Finally, our study further supports the key role of the cAMP signaling pathway in skeletogenesis. 相似文献
962.
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
963.
964.
Keratinocyte migration plays an important role in cutaneous wound healing by supporting the process of reepithelialisation. During directional migration cells develop a polarised shape with an asymmetric distribution of a variety of signalling molecules in their plasma membrane. Here, we investigated front-to-back differences of the physical properties of the plasma membrane of migrating keratinocyte-like HaCaT cells. Using FRAP and fluorescence lifetime analysis, both under TIR illumination, we demonstrate a reduced viscosity of the plasma membrane in the lamellipodia of migrating HaCaT cells compared with the cell rears. This asymmetry is most likely caused by a reduced cholesterol content of the lamellipodia as demonstrated by filipin staining. siRNA-mediated silencing of the cholesterol transporter ABCA1, which is known to redistribute cholesterol from rafts to non-raft regions, as well as pharmacological inhibition of this transporter with glibenclamide, strongly diminished the viscosity gradient of the plasma membrane. In addition, HaCaT cell migration was inhibited by glibenclamide treatment. These data suggest a preferential role of non-raft cholesterol in the establishment of the asymmetric plasma membrane viscosity. 相似文献
965.
Lefevre S Sliwa D Auchère F Brossas C Ruckenstuhl C Boggetto N Lesuisse E Madeo F Camadro JM Santos R 《FEBS letters》2012,586(2):143-148
Friedreich ataxia is the most common recessive neurodegenerative disease and is caused by reduced expression of mitochondrial frataxin. Frataxin depletion causes impairment in iron-sulfur cluster and heme biosynthesis, disruption of iron homeostasis and hypersensitivity to oxidants. Currently no pharmacological treatment blocks disease progression, although antioxidant therapies proved to benefit patients. We show that sensitivity of yeast frataxin-deficient cells to hydrogen peroxide is partially mediated by the metacaspase. Metacaspase deletion in frataxin-deficient cells results in recovery of antioxidant capacity and heme synthesis. In addition, our results suggest that metacaspase is associated with mitochondrial respiration, intracellular redox control and genomic stability. 相似文献
966.
967.
Bergenfelz C Medrek C Ekström E Jirström K Janols H Wullt M Bredberg A Leandersson K 《Journal of immunology (Baltimore, Md. : 1950)》2012,188(11):5448-5458
A well-orchestrated inflammatory reaction involves the induction of effector functions and, at a later stage, an active downregulation of this potentially harmful process. In this study we show that under proinflammatory conditions the noncanonical Wnt protein, Wnt5a, induces immunosuppressive macrophages. The suppressive phenotype induced by Wnt5a is associated with induction of IL-10 and inhibition of the classical TLR4-NF-κB signaling. Interestingly, this phenotype closely resembles that observed in reprogrammed monocytes in sepsis patients. The Wnt5a-induced feedback inhibition is active both during in vitro LPS stimulation of macrophages and in patients with sepsis caused by LPS-containing, gram-negative bacteria. Furthermore, using breast cancer patient tissue microarrays, we find a strong correlation between the expression of Wnt5a in malignant epithelial cells and the frequency of CD163(+) anti-inflammatory tumor-associated macrophages. In conclusion, our data point out Wnt5a as a potential target for an efficient therapeutic modality in severe human diseases as diverse as sepsis and malignancy. 相似文献
968.
KM Smith M Guerau-de-Arellano S Costinean JL Williams A Bottoni G Mavrikis Cox AR Satoskar CM Croce MK Racke AE Lovett-Racke CC Whitacre 《Journal of immunology (Baltimore, Md. : 1950)》2012,189(4):1567-1576
Th cell programming and function is tightly regulated by complex biological networks to prevent excessive inflammatory responses and autoimmune disease. The importance of microRNAs (miRNAs) in this process is highlighted by the preferential Th1 polarization of Dicer-deficient T cells that lack miRNAs. Using genetic knockouts, we demonstrate that loss of endogenous miR-29, derived from the miR-29ab1 genomic cluster, results in unrestrained T-bet expression and IFN-γ production. miR-29b regulates T-bet and IFN-γ via a direct interaction with the 3' untranslated regions, and IFN-γ itself enhances miR-29b expression, establishing a novel regulatory feedback loop. miR-29b is increased in memory CD4(+) T cells from multiple sclerosis (MS) patients, which may reflect chronic Th1 inflammation. However, miR-29b levels decrease significantly upon T cell activation in MS patients, suggesting that this feedback loop is dysregulated in MS patients and may contribute to chronic inflammation. miR-29 thus serves as a novel regulator of Th1 differentiation, adding to the understanding of T cell-intrinsic regulatory mechanisms that maintain a balance between protective immunity and autoimmunity. 相似文献
969.
Bruna Comparsi Daiane F. Meinerz Jeferson L. Franco Thaís Posser Alessandro de Souza Prestes Sílvio Terra Stefanello Danúbia B. dos Santos Caroline Wagner Marcelo Farina Michael Aschner Alcir L. Dafre Jo?o B. T. Rocha 《Molecular and cellular biochemistry》2012,370(1-2):173-182
In this study, we investigated the effect of diphenyl ditelluride (PhTe)2 administration (10 and 50?μmol/kg) on adult mouse behavioral performance as well as several parameters of oxidative stress in the brain and liver. Adult mice were injected with (PhTe)2 or canola oil subcutaneously (s.c.) daily for 7?days. Results demonstrated that (PhTe)2 induced prominent signs of toxicity (body weight loss), behavioral alterations and increased in lipid peroxidation in brain. 50?μmol/kg (PhTe)2 inhibited blood δ-aminolevulinic acid dehydratase (δ-ALA-D), a redox sensitive enzyme. (PhTe)2 caused an increase in cerebral non-protein thiol (NPSH) and protein thiol (PSH) groups. In the liver, 50?μmol/kg (PhTe)2 decreased NPSH, but did not alter the content of protein thiol groups. (PhTe)2 decreased cerebral antioxidant enzymes (catalase (CAT), superoxide dismutase (SOD), glutathione reductase (GR), glutathione peroxidase (GPx), and thioredoxin reductase (TrxR). In liver, (PhTe)2 increase SOD and GR and decreased GPx activity. Results obtained herein suggest that the brain was more susceptible to oxidative stress induced by (PhTe)2 than the liver. Furthermore, we have demonstrated for the first time that TrxR is an in vivo target for (PhTe)2. Combined, these results highlight a novel molecular mechanism involved in the toxicity of (PhTe)2. In particular the inhibition of important selenoenzymes (TrxR and GPx) seems to be involved in the neurotoxicity associated with (PhTe)2 exposure in adult mice. 相似文献
970.
Wasse LK Sunderland C King JA Batterham RL Stensel DJ 《Journal of applied physiology (Bethesda, Md. : 1985)》2012,112(4):552-559
The reason for high altitude anorexia is unclear but could involve alterations in the appetite hormones ghrelin and peptide YY (PYY). This study examined the effect of resting and exercising in hypoxia (12.7% O(2); ~4,000 m) on appetite, energy intake, and plasma concentrations of acylated ghrelin and PYY. Ten healthy males completed four, 7-h trials in an environmental chamber in a random order. The four trials were control-normoxia, control-hypoxia, exercise-normoxia, and exercise-hypoxia. During exercise trials, participants ran for 60 min at 70% of altitude-specific maximal oxygen consumption (Vo(2max)) and then rested. Participants rested throughout control trials. A standardized meal was consumed at 2 h and an ad libitum buffet meal at 5.5 h. Area under the curve values for hunger (assessed using visual analog scales) tended to be lower during hypoxic trials than normoxic trials (repeated-measures ANOVA, P = 0.07). Ad libitum energy intake was lower (P = 0.001) in hypoxia (5,291 ± 2,189 kJ) than normoxia (7,718 ± 2,356 kJ; means ± SD). Mean plasma acylated ghrelin concentrations were lower in hypoxia than normoxia (82 ± 66 vs. 100 ± 69 pg/ml; P = 0.005) while PYY concentrations tended to be higher in normoxia (32 ± 4 vs. 30 ± 3 pmol/l; P = 0.059). Exercise suppressed hunger and acylated ghrelin and increased PYY but did not influence ad libitum energy intake. These findings confirm that hypoxia suppresses hunger and food intake. Further research is required to determine if decreased concentrations of acylated ghrelin orchestrate this suppression. 相似文献