全文获取类型
收费全文 | 12544篇 |
免费 | 893篇 |
国内免费 | 6篇 |
专业分类
13443篇 |
出版年
2023年 | 119篇 |
2022年 | 240篇 |
2021年 | 427篇 |
2020年 | 304篇 |
2019年 | 373篇 |
2018年 | 475篇 |
2017年 | 414篇 |
2016年 | 569篇 |
2015年 | 701篇 |
2014年 | 803篇 |
2013年 | 845篇 |
2012年 | 960篇 |
2011年 | 888篇 |
2010年 | 505篇 |
2009年 | 497篇 |
2008年 | 585篇 |
2007年 | 568篇 |
2006年 | 476篇 |
2005年 | 436篇 |
2004年 | 394篇 |
2003年 | 344篇 |
2002年 | 301篇 |
2001年 | 215篇 |
2000年 | 193篇 |
1999年 | 161篇 |
1998年 | 83篇 |
1997年 | 69篇 |
1996年 | 71篇 |
1995年 | 67篇 |
1994年 | 70篇 |
1993年 | 41篇 |
1992年 | 92篇 |
1991年 | 105篇 |
1990年 | 70篇 |
1989年 | 73篇 |
1988年 | 66篇 |
1987年 | 71篇 |
1986年 | 81篇 |
1985年 | 57篇 |
1984年 | 57篇 |
1983年 | 47篇 |
1982年 | 44篇 |
1981年 | 37篇 |
1980年 | 30篇 |
1979年 | 34篇 |
1978年 | 41篇 |
1977年 | 33篇 |
1975年 | 42篇 |
1973年 | 29篇 |
1972年 | 30篇 |
排序方式: 共有10000条查询结果,搜索用时 0 毫秒
51.
Lakhdar Ghazouani Nesrine Abboud Sonia Ben Hadj Khalifa Claire Perret Viviane Nicaud Wassim Youssef Almawi François Cambien Touhami Mahjoub 《Molecular biology reports》2011,38(1):495-501
P-selectin (SELP) and its counter-receptor, P-selectin glycoprotein ligand-1 (PSGL-1), play key role in the transient attachment
of leukocytes to endothelial cells predisposing to coronary heart disease (CHD). In the current report, 293 angiographically
proven CHD patients and 327 age, gender, and race-matched controls were included. Our aim was to evaluate the contribution
to CHD of the following SNPs: C-2123G, G-1969A and T715P in SELP, Met62Ile and the VNTR variants in PSGL-1 gene in a North African population from Tunisia. While there were no significant differences in the distribution of SELP
or PSGL-1 alleles or genotypes between patients and controls, a trend for a significant association of the C-2123G genotypes
distribution with incident CHD was observed (P = 0.06). Assuming an additive model of transmission, the risk was 74% higher among subjects carrying the GG genotypes in
comparison to those carrying the CC genotype (OR = 1.74 [1.01–2.98], P = 0.04) and 80% higher in the recessive model (OR = 1.80 [1.08–3.01], P = 0.02). Haplotype analysis did not identify any specific SELP or PSGL-1 haplotypes to be associated with CHD. The present
study demonstrated no evidence of association between individual SELP or PSGL-1 SNPs or haplotypes with incident CHD. However,
this study replicates absence of association of the mostly studied SNP, T715P, previously reported in individuals with African
origin. 相似文献
52.
Milton Maciel Jr. Fábia da Silva Pereira Cruz Marli Tenório Cordeiro Márcia Archer da Motta Klécia Marília Soares de Melo Cassemiro Rita de Cássia Carvalho Maia Regina Célia Bressan Queiroz de Figueiredo Ricardo Galler Marcos da Silva Freire Joseph Thomas August Ernesto T. A. Marques Rafael Dhalia 《PLoS neglected tropical diseases》2015,9(4)
Attenuated yellow fever (YF) virus 17D/17DD vaccines are the only available protection from YF infection, which remains a significant source of morbidity and mortality in the tropical areas of the world. The attenuated YF virus vaccine, which is used worldwide, generates both long-lasting neutralizing antibodies and strong T-cell responses. However, on rare occasions, this vaccine has toxic side effects that can be fatal. This study presents the design of two non-viral DNA-based antigen formulations and the characterization of their expression and immunological properties. The two antigen formulations consist of DNA encoding the full-length envelope protein (p/YFE) or the full-length envelope protein fused to the lysosomal-associated membrane protein signal, LAMP-1 (pL/YFE), aimed at diverting antigen processing/presentation through the major histocompatibility complex II precursor compartments. The immune responses triggered by these formulations were evaluated in H2b and H2d backgrounds, corresponding to the C57Bl/6 and BALB/c mice strains, respectively. Both DNA constructs were able to induce very strong T-cell responses of similar magnitude against almost all epitopes that are also generated by the YF 17DD vaccine. The pL/YFE formulation performed best overall. In addition to the T-cell response, it was also able to stimulate high titers of anti-YF neutralizing antibodies comparable to the levels elicited by the 17DD vaccine. More importantly, the pL/YFE vaccine conferred 100% protection against the YF virus in intracerebrally challenged mice. These results indicate that pL/YFE DNA is an excellent vaccine candidate and should be considered for further developmental studies. 相似文献
53.
Elsa Leitão Ana Catarina Costa Claudia Brito Lionel Costa Rita Pombinho 《Cell cycle (Georgetown, Tex.)》2014,13(6):928-940
Listeria monocytogenes (Lm) is a human intracellular pathogen widely used to uncover the mechanisms evolved by pathogens to establish infection. However, its capacity to perturb the host cell cycle was never reported. We show that Lm infection affects the host cell cycle progression, increasing its overall duration but allowing consecutive rounds of division. A complete Lm infectious cycle induces a S-phase delay accompanied by a slower rate of DNA synthesis and increased levels of host DNA strand breaks. Additionally, DNA damage/replication checkpoint responses are triggered in an Lm dose-dependent manner through the phosphorylation of DNA-PK, H2A.X, and CDC25A and independently from ATM/ATR. While host DNA damage induced exogenously favors Lm dissemination, the override of checkpoint pathways limits infection. We propose that host DNA replication disturbed by Lm infection culminates in DNA strand breaks, triggering DNA damage/replication responses, and ensuring a cell cycle delay that favors Lm propagation. 相似文献
54.
Erpan Ahat Sarah Bui Jianchao Zhang Felipe da Veiga Leprevost Lisa Sharkey Whitney Reid Alexey I. Nesvizhskii Henry L. Paulson Yanzhuang Wang 《The Journal of biological chemistry》2022,298(8)
Recent studies demonstrated that the Golgi reassembly stacking proteins (GRASPs), especially GRASP55, regulate Golgi-independent unconventional secretion of certain cytosolic and transmembrane cargoes; however, the underlying mechanism remains unknown. Here, we surveyed several neurodegenerative disease–related proteins, including mutant huntingtin (Htt-Q74), superoxide dismutase 1 (SOD1), tau, and TAR DNA–binding protein 43 (TDP-43), for unconventional secretion; our results show that Htt-Q74 is most robustly secreted in a GRASP55-dependent manner. Using Htt-Q74 as a model system, we demonstrate that unconventional secretion of Htt is GRASP55 and autophagy dependent and is enhanced under stress conditions such as starvation and endoplasmic reticulum stress. Mechanistically, we show that GRASP55 facilitates Htt secretion by tethering autophagosomes to lysosomes to promote autophagosome maturation and subsequent lysosome secretion and by stabilizing p23/TMED10, a channel for translocation of cytoplasmic proteins into the lumen of the endoplasmic reticulum–Golgi intermediate compartment. Moreover, we found that GRASP55 levels are upregulated by various stresses to facilitate unconventional secretion, whereas inhibition of Htt-Q74 secretion by GRASP55 KO enhances Htt aggregation and toxicity. Finally, comprehensive secretomic analysis identified novel cytosolic cargoes secreted by the same unconventional pathway, including transgelin (TAGLN), multifunctional protein ADE2 (PAICS), and peroxiredoxin-1 (PRDX1). In conclusion, this study defines the pathway of GRASP55-mediated unconventional protein secretion and provides important insights into the progression of Huntington’s disease. 相似文献
55.
56.
Paulo Bentes de Carvalho-Neto Marcelo dos Santos Marcos Brasilino de Carvalho Ana Maria da Cunha Mercante Viviane Priscila Pina dos Santos Patrícia Severino Eloiza Helena Tajara Iuri Drumond Louro Adriana Madeira álvares da Silva-Conforti 《PloS one》2013,8(7)
FAS/FASL altered expression may cause tumor protecting immunomodulation, with a direct impact on patient prognosis. FAS expression was studied in 60 squamous cell carcinomas of the oral cavity. FAS expression did not show a significant association with tumor histopathological characteristics, but was significantly associated with lymph node positivity. FAS expression was significantly associated with disease specific death and negative FAS expression was an independent risk factor, increasing risk 4 times when compared to positive expression. When FAS and FASL expression results were combined, we were able to define high, intermediate and low risk profiles. Disease-free and disease-specific survival were significantly correlated with FAS/FASL expression profiles. The high risk category was an independent marker for earlier disease relapse and disease-specific death, with approximately 4- and 6-fold increased risk, respectively, when compared to the low risk profile. Risk profiles based on FAS/FASL expression showed that high risk was significantly associated with increased disease relapse and death, as well as shorter disease-free or disease-specific survival. This categorization, added to patient clinical data, may facilitate the choice of therapy, minimizing treatment failure and increasing disease control. 相似文献
57.
Effect of genetic modifications by selection for immunological tolerance on fungus infection in mice
da Silva AC Bezerra LM Aguiar TS Tavares D Araujo LM Pinto CE Ribeiro OG 《Microbes and infection / Institut Pasteur》2001,3(3):215-222
Two strains of mice genetically selected for extreme phenotypes of immunological tolerance to ovalbumin, susceptible (TS) and resistant (TR), were experimentally infected with Sporothrix schenckii. The objective was to observe whether the genetic modifications produced by the selection might be associated with interstrain differences in adaptive immune and innate responses to infection. Therefore, we evaluated the LD(50), CFU, phagocytic index, fungicidal activity, pro-inflammatory cytokines, specific antibody titres, and the delayed-type hypersensitivity reactivity. TR mice were tenfold more susceptible to infection than TS mice, as shown by LD(50) (5 x 10(6) conidia i.v.). In TS mice, the resistance was a consequence of the tissue fungal load reduction, consistent specific T-cell-mediated immunity, and tumour necrosis factor (TNF)-alpha activity at onset of infection. In TR mice, these responses were not precociously detected. Therefore, the absence of CD4(+) T-cell response in the first week of infection might explain the non-clearance of pathogen in TR mice. However, TR mice did show an increase in TNF level and delayed-type hypersensitivity response after the first week post-infection; there was also expansion and increase in granulomatous foci and CFU in the spleen. The expansion of granulomatous foci and the increase in TNF-alpha and tissue fungal load to damaging levels induced severe tissue destruction, general failure of the organs, cachexy and death in TR mice. The results show that genetic selection for extreme phenotypes of immunological tolerance also modified the responses to S. schenckii infection. 相似文献
58.
Tatiana P. da Silva Carmem B. W. Giacoia-Gripp Carolina A. Schmaltz Flavia M. Sant` Anna Valeria Rolla Mariza G. Morgado 《PloS one》2013,8(6)
Introduction
The profile of immune activation markers in tuberculosis and HIV-infected patients is already known. The impact of simultaneous infections on the immune parameters is still not fully explored.Methods
We conducted a prospective study to estimate trajectories of activated T cell subsets and the profile of anti- and pro-inflammatory cytokines in a group of HIV-TB individuals, previously naïve for HAART, recruited from a randomized clinical trial during TB treatment and first antiretroviral therapy with efavirenz. Patients were evaluated according to the immunosuppression levels at baseline as group 1 (CD4<200 cells/mm3) and group 2 (CD4>200 cells/mm3). These parameters were measured at the time of HAART initiation (started about 30 days after the onset of TB treatment) and at the follow-up visits after 30, 60, 90 and 180 days. Trajectories were estimated using least squares estimates of the coefficients of a restricted cubic spline function in time after adjusting for subject effects, bootstrapping it 500 times.Results
Increase of CD4 T cell counts and suppression of HIV viral load were observed for all patients under HAART and TB treatment. Descendent trajectories were observed for the activated CD8+/CD38+ and CD3+/HLA-DR+ T cell subsets, and for plasma concentration of gamma- interferon (IFN-γ). Except for TNF-α and IL-2 discrete variations were observed for the other cytokines. Differences in the trajectories of these parameters were observed for groups 1 and 2. Higher values of IFN-γ, IL-2, IL-6 and IL-10 were observed for group 1 from the baseline to two months after treatment initiation, whereas reduced levels of TNF-α were observed for this group between 60 and 120 days of HAART.Conclusion
Independent of the immunosuppression profile at baseline, HIV-TB patients under HAART were able to recover the CD4+ T cell counts, and control viral replication and immune activation parameters over time. 相似文献59.
Infestation of Trialeurodes variabilis (Quaintance) was observed in October 2004, in papaya plants of cultivar Sunrise Solo, under screenhouse conditions, in Cruz das Almas, State of Bahia, Brazil. In infested leaves, around 20% of parasitism on nymphs was verified. Leaves with parasitized nymphs were kept in laboratory until emergence of the parasitoid, identified as Encarsia hispida De Santis. This is the first time that this parasitoid was detected on T. variabilis nymphs in Brazil. 相似文献
60.
Marcelle Bens Sophie Vimont Sanae Ben Mkaddem Cécilia Chassin Jean‐Michel Goujon Viviane Balloy Michel Chignard Catherine Werts Alain Vandewalle 《Cellular microbiology》2014,16(10):1503-1517
Uropathogenic Escherichia coli (UPEC) colonizing kidneys is the main cause of acute pyelonephritis. TLR5 that senses flagellin was shown to be highly expressed in the bladder and to participate in host defence against flagellated UPEC, although its role in kidneys still remains elusive. Here we show that TLR5 is expressed in renal medullary collecting duct (MCD) cells, which represent a preferential site of UPEC adhesion. Flagellin, like lipopolysaccharide, stimulated the production of the chemoattractant chemokines CXCL1 and CXCL2, and subsequent migration capacity of neutrophils in cultured wild‐type (WT) and Tlr4?/? MCDs, but not in Tlr5?/? MCDs. UPEC can translocate across intact MCD layers without altering tight junctions. Strikingly, the invasion capacity and transcellular translocation of the UPEC strain HT7 were significantly lower in Tlr5?/? than in WT MCDs. The non‐motile HT7ΔfliC mutant lacking flagellin also exhibited much lower translocation capacities than the HT7 isolates. Finally, Tlr5?/? kidneys exhibited less infiltrating neutrophils than WT kidneys one day after the transurethral inoculation of HT7, and greater delayed renal bacterial loads in the day 4 post‐infected Tlr5?/? kidneys. Overall, these findings indicate that the epithelial TLR5 participates to renal antibacterial defence, but paradoxically favours the translocation of UPEC across intact MCD cell layers. 相似文献