全文获取类型
收费全文 | 4141篇 |
免费 | 353篇 |
国内免费 | 2篇 |
专业分类
4496篇 |
出版年
2023年 | 15篇 |
2022年 | 35篇 |
2021年 | 83篇 |
2020年 | 47篇 |
2019年 | 49篇 |
2018年 | 60篇 |
2017年 | 60篇 |
2016年 | 103篇 |
2015年 | 225篇 |
2014年 | 186篇 |
2013年 | 247篇 |
2012年 | 367篇 |
2011年 | 296篇 |
2010年 | 200篇 |
2009年 | 132篇 |
2008年 | 222篇 |
2007年 | 254篇 |
2006年 | 203篇 |
2005年 | 208篇 |
2004年 | 219篇 |
2003年 | 199篇 |
2002年 | 192篇 |
2001年 | 34篇 |
2000年 | 26篇 |
1999年 | 36篇 |
1998年 | 82篇 |
1997年 | 32篇 |
1996年 | 40篇 |
1995年 | 37篇 |
1994年 | 39篇 |
1993年 | 29篇 |
1992年 | 39篇 |
1991年 | 24篇 |
1990年 | 33篇 |
1989年 | 35篇 |
1988年 | 25篇 |
1987年 | 21篇 |
1986年 | 23篇 |
1985年 | 23篇 |
1984年 | 30篇 |
1983年 | 33篇 |
1982年 | 40篇 |
1981年 | 28篇 |
1980年 | 32篇 |
1979年 | 24篇 |
1978年 | 11篇 |
1977年 | 24篇 |
1976年 | 17篇 |
1974年 | 13篇 |
1973年 | 10篇 |
排序方式: 共有4496条查询结果,搜索用时 15 毫秒
101.
Guillaume Allorent Ryutaro Tokutsu Thomas Roach Graham Peers Pierre Cardol Jacqueline Girard-Bascou Daphné Seigneurin-Berny Dimitris Petroutsos Marcel Kuntz Cécile Breyton Fabrice Franck Francis-André Wollman Krishna K. Niyogi Anja Krieger-Liszkay Jun Minagawa Giovanni Finazzi 《The Plant cell》2013,25(2):545-557
Absorption of light in excess of the capacity for photosynthetic electron transport is damaging to photosynthetic organisms. Several mechanisms exist to avoid photodamage, which are collectively referred to as nonphotochemical quenching. This term comprises at least two major processes. State transitions (qT) represent changes in the relative antenna sizes of photosystems II and I. High energy quenching (qE) is the increased thermal dissipation of light energy triggered by lumen acidification. To investigate the respective roles of qE and qT in photoprotection, a mutant (npq4 stt7-9) was generated in Chlamydomonas reinhardtii by crossing the state transition–deficient mutant (stt7-9) with a strain having a largely reduced qE capacity (npq4). The comparative phenotypic analysis of the wild type, single mutants, and double mutants reveals that both state transitions and qE are induced by high light. Moreover, the double mutant exhibits an increased photosensitivity with respect to the single mutants and the wild type. Therefore, we suggest that besides qE, state transitions also play a photoprotective role during high light acclimation of the cells, most likely by decreasing hydrogen peroxide production. These results are discussed in terms of the relative photoprotective benefit related to thermal dissipation of excess light and/or to the physical displacement of antennas from photosystem II. 相似文献
102.
Seth J. Schwartz Erin Phelps Jacqueline V. Lerner Shi Huang C. Hendricks Brown Selva Lewin-Bizan 《应用发育科学》2013,17(4):197-211
The present study was designed to examine the association of positive youth development with the likelihood of tobacco, alcohol, marijuana, hard drug, and sex initiation between 5th and 10th grades. A national, largely middle-class sample of 5,305 adolescents, participating in a longitudinal study funded by the National 4-H Council (although not all participants were enrolled in 4-H or other after-school programs), completed measures of positive youth development (PYD) constructs and of tobacco, alcohol, marijuana, and hard drug use once per year between 5th and 10th grades. At the 9th and 10th grade assessments, adolescents were asked whether they had initiated sexual intercourse and, if so, at what age they had first engaged in intercourse. Although the present sample was somewhat lower risk compared to national averages, survival analysis models indicated that PYD was significantly and negatively associated with the initiation hazards for tobacco use, marijuana use, and sex initiation for girls only, and with hard drug use for both genders. PYD was also positively associated with the odds of condom use across genders. Results are discussed with regard to PYD as a preventive process. 相似文献
103.
The discovery that genetic mutations in several cellular pathways can increase lifespan has lent support to the notion that pharmacological inhibition of aging pathways can be used to extend lifespan and to slow the onset of age‐related diseases. However, so far, only few compounds with such activities have been described. Here, we have conducted a chemical genetic screen for compounds that cause the extension of chronological lifespan of Schizosaccharomyces pombe. We have characterized eight natural products with such activities, which has allowed us to uncover so far unknown anti‐aging pathways in S. pombe. The ionophores monensin and nigericin extended lifespan by affecting vacuolar acidification, and this effect depended on the presence of the vacuolar ATPase (V‐ATPase) subunits Vma1 and Vma3. Furthermore, prostaglandin J2 displayed anti‐aging properties due to the inhibition of mitochondrial fission, and its effect on longevity required the mitochondrial fission protein Dnm1 as well as the G‐protein‐coupled glucose receptor Git3. Also, two compounds that inhibit guanosine monophosphate (GMP) synthesis, mycophenolic acid (MPA) and acivicin, caused lifespan extension, indicating that an imbalance in guanine nucleotide levels impinges upon longevity. We furthermore have identified diindolylmethane (DIM), tschimganine, and the compound mixture mangosteen as inhibiting aging. Taken together, these results reveal unanticipated anti‐aging activities for several phytochemicals and open up opportunities for the development of novel anti‐aging therapies. 相似文献
104.
Aamer Sandoo Neil Chanchlani James Hodson Jacqueline P Smith Karen M Douglas George D Kitas 《Arthritis research & therapy》2013,15(6):R203
Introduction
Patients with rheumatoid arthritis (RA) are at an increased risk for cardiovascular disease (CVD). An early manifestation of CVD is endothelial dysfunction which can lead to functional and morphological vascular abnormalities. Classical CVD risk factors and inflammation are both implicated in causing endothelial dysfunction in RA. The objective of the present study was to examine the effect of baseline inflammation, cumulative inflammation, and classical CVD risk factors on the vasculature following a six-year follow-up period.Methods
A total of 201 RA patients (155 females, median age (25th to 75th percentile): 61 years (53 to 67)) were examined at baseline (2006) for presence of classical CVD risk factors and determination of inflammation using C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). At follow-up (2012) patients underwent assessments of microvascular and macrovascular endothelium-dependent and endothelium-independent function, along with assessment of carotid atherosclerosis. The CRP and ESR were recorded from the baseline study visit to the follow-up visit for each patient to calculate cumulative inflammatory burden.Results
Classical CVD risk factors, but not RA disease-related inflammation, predicted microvascular endothelium-dependent and endothelium-independent function, macrovascular endothelium-independent function and carotid atherosclerosis. These findings were similar in a sub-group of patients free from CVD, and not receiving non-steroidal anti-inflammatory drugs, cyclooxygenase 2 inhibitors or biologics. Cumulative inflammation was not associated with microvascular and macrovascular endothelial function, but a weak association was apparent between area under the curve for CRP and carotid atherosclerosis.Conclusions
Classical CVD risk factors may be better long-term predictors of vascular function and morphology than systemic disease-related inflammation in patients with RA. Further studies are needed to confirm if assessments of vascular function and morphology are predictive of long-term CV outcomes in RA. 相似文献105.
Magali Meyer Jérémie Sellam Soraya Fellahi Salma Kotti Jean-Philippe Bastard Olivier Meyer Frédéric Lioté Tabassome Simon Jacqueline Capeau Francis Berenbaum 《Arthritis research & therapy》2013,15(6):R210
Introduction
Adipokines such as adiponectin, leptin, and visfatin/nicotinamide phosphoribosyltransferase (NAMPT) have recently emerged as pro-inflammatory mediators involved in the pathophysiology of rheumatoid arthritis (RA). We aimed to determine whether serum adipokine levels independently predicted early radiographic disease progression in early RA.Methods
In total, 791 patients were included from the prospective Etude et Suivi des POlyarthrites Indifférenciées Récentes (ESPOIR) cohort who met the American College of Rheumatology-European League Against Rheumatism criteria for RA (n = 632) or had undifferentiated arthritis (UA) (n = 159). Enzyme-linked immunosorbent assay (ELISA) was used to assess baseline serum levels of adiponectin, leptin, and visfatin/NAMPT. In the RA group, we tested the association of serum adipokine levels and (a) baseline radiographic damage and (b) radiographic disease progression, defined as a change >0 or ≥5 in total Sharp-van der Heijde Score (∆SHS) between inclusion and 1 year (∆SHS ≥1 or rapid radiographic progression: ∆SHS ≥5), adjusting for confounders (age, sex, body-mass index, insulin resistance, C-reactive protein level, Disease Activity Score in 28 joints, Health Assessment Questionnaire score, autoantibody status, steroid use, and radiographic evidence of RA damage at inclusion).Results
Adiponectin level was independently associated with baseline total SHS (adjusted β = 0.12; P = 0.006). It was also associated with ∆SHS ≥1 (adjusted odds ratio (aOR) = 1.84 (1.25 to 2.72)) involving erosive as well as narrowing disease progression (aOR = 1.73 (1.17 to 2.55) and 1.93 (1.04 to 3.57), respectively). Serum adiponectin level predicted ∆SHS ≥5 (aOR = 2.0 (1.14 to 3.52)). Serum leptin level was independently associated only with ∆SHS >0 (aOR = 1.59 (1.05 to 2.42)). Conversely, serum visfatin/NAMPT level and radiographic disease progression were unrelated. Considering the receiver-operated characteristic curves, the best adiponectin cut-offs were 4.14 μg/ml for ∆SHS ≥1 and 6.04 μg/ml for ∆SHS ≥5, with a good specificity (58% and 75% for ∆SHS ≥1 and ∆SHS ≥5, respectively) and high negative predictive values (75% and 92% for ∆SHS ≥1 or ∆SHS ≥5, respectively).Conclusion
Serum adiponectin level is a simple useful biomarker associated with early radiographic disease progression in early RA, independent of RA-confounding factors and metabolic status. 相似文献106.
John S. Driscoll Victor E. Marquez Jacqueline Plowman 《Nucleosides, nucleotides & nucleic acids》2013,32(5-6):1131-1133
Abstract CPE-C is a potent antitumor and antiviral agent. It is active against a variety of preclinical murine and human xenograft tumor models in vivo as well as DNA and RNA viruses in vitro. 相似文献
107.
José Alexandre F. Diniz-Filho Thannya N. Soares Jacqueline S. Lima Ricardo Dobrovolski Victor Lemes Landeiro Mariana Pires de Campos Telles Thiago F. Rangel Luis Mauricio Bini 《Genetics and molecular biology》2013,36(4):475-485
The comparison of genetic divergence or genetic distances, estimated by pairwise FST and related statistics, with geographical distances by Mantel test is one of the most popular approaches to evaluate spatial processes driving population structure. There have been, however, recent criticisms and discussions on the statistical performance of the Mantel test. Simultaneously, alternative frameworks for data analyses are being proposed. Here, we review the Mantel test and its variations, including Mantel correlograms and partial correlations and regressions. For illustrative purposes, we studied spatial genetic divergence among 25 populations of Dipteryx alata (“Baru”), a tree species endemic to the Cerrado, the Brazilian savannas, based on 8 microsatellite loci. We also applied alternative methods to analyze spatial patterns in this dataset, especially a multivariate generalization of Spatial Eigenfunction Analysis based on redundancy analysis. The different approaches resulted in similar estimates of the magnitude of spatial structure in the genetic data. Furthermore, the results were expected based on previous knowledge of the ecological and evolutionary processes underlying genetic variation in this species. Our review shows that a careful application and interpretation of Mantel tests, especially Mantel correlograms, can overcome some potential statistical problems and provide a simple and useful tool for multivariate analysis of spatial patterns of genetic divergence. 相似文献
108.
Karen Page David S. Guttery Nathalie Zahra Lindsay Primrose Shona R. Elshaw J. Howard Pringle Kevin Blighe Stephanie D. Marchese Allison Hills Laura Woodley Justin Stebbing R. Charles Coombes Jacqueline A. Shaw 《PloS one》2013,8(10)
Circulating nucleic acids (CNAs) are under investigation as a liquid biopsy in cancer. However there is wide variation in blood processing and methods for isolation of circulating free DNA (cfDNA) and microRNAs (miRNAs). Here we compare the extraction efficiency and reproducibility of 4 commercially available kits for cfDNA and 3 for miRNA using spike-in of reference templates. We also compare the effects of increasing time between venepuncture and centrifugation and differential centrifugation force on recovery of CNAs. cfDNA was quantified by TaqMan qPCR and targeted deep sequencing. miRNA profiles were assessed with TaqMan low-density arrays and assays. The QIAamp® DNA Blood Mini and Circulating nucleic acid kits gave the highest recovery of cfDNA and efficient recovery (>90%) of a 564bp spike-in. Moreover, targeted sequencing revealed overlapping cfDNA profiles and variant depth, including detection of HER2 gene amplification, using the Ion AmpliSeq™Cancer Hotspot Panel v2. Highest yields of miRNA and the synthetic Arabidopsis thaliana miR-159a spike-in were obtained using the miRNeasy Serum/Plasma kit, with saturation above 200 µl of plasma. miRNA profiles showed significant variation with increasing time before centrifugation (p<0.001) and increasing centrifugation force, with depletion of platelet associated miRNAs, whereas cfDNA was unaffected. However, sample replicates showed excellent reproducibility on TaqMan low density arrays (ρ = 0.96, p<0.0001). We also successfully generated miRNA profiles for plasma samples stored > 12 years, highlighting the potential for analysis of stored sample biobanks. In the era of the liquid biopsy, standardisation of methods is required to minimise variation, particularly for miRNA. 相似文献
109.
Mahban Irandoust Julian Alvarez Zarate Isabelle Hubeek Ellen M. van Beek Karin Schornagel Aart J. F. Broekhuizen Mercan Akyuz Arjan A. van de Loosdrecht Ruud Delwel Peter J. Valk Edwin Sonneveld Pamela Kearns Ursula Creutzig Dirk Reinhardt Eveline S. J. M. de Bont Eva A. Coenen Marry M. van den Heuvel-Eibrink C. Michel Zwaan Gertjan J. L. Kaspers Jacqueline Cloos Timo K. van den Berg 《PloS one》2013,8(1)
Background
Recent studies show the importance of interactions between CD47 expressed on acute myeloid leukemia (AML) cells and the inhibitory immunoreceptor, signal regulatory protein-alpha (SIRPα) on macrophages. Although AML cells express SIRPα, its function has not been investigated in these cells. In this study we aimed to determine the role of the SIRPα in acute myeloid leukemia.Design and Methods
We analyzed the expression of SIRPα, both on mRNA and protein level in AML patients and we further investigated whether the expression of SIRPα on two low SIRPα expressing AML cell lines could be upregulated upon differentiation of the cells. We determined the effect of chimeric SIRPα expression on tumor cell growth and programmed cell death by its triggering with an agonistic antibody in these cells. Moreover, we examined the efficacy of agonistic antibody in combination with established antileukemic drugs.Results
By microarray analysis of an extensive cohort of primary AML samples, we demonstrated that SIRPα is differentially expressed in AML subgroups and its expression level is dependent on differentiation stage, with high levels in FAB M4/M5 AML and low levels in FAB M0–M3. Interestingly, AML patients with high SIRPα expression had a poor prognosis. Our results also showed that SIRPα is upregulated upon differentiation of NB4 and Kasumi cells. In addition, triggering of SIRPα with an agonistic antibody in the cells stably expressing chimeric SIRPα, led to inhibition of growth and induction of programmed cell death. Finally, the SIRPα-derived signaling synergized with the activity of established antileukemic drugs.Conclusions
Our data indicate that triggering of SIRPα has antileukemic effect and may function as a potential therapeutic target in AML. 相似文献110.
Carolyn J. Heckman Rachel Chandler Jacqueline D. Kloss Amy Benson Deborah Rooney Teja Munshi Susan D. Darlow Clifford Perlis Sharon L. Manne David W. Oslin 《Journal of visualized experiments : JoVE》2013,(75)
Ultraviolet radiation (UV) therapy is sometimes used as a treatment for various common skin conditions, including psoriasis, acne, and eczema. The dosage of UV light is prescribed according to an individual''s skin sensitivity. Thus, to establish the proper dosage of UV light to administer to a patient, the patient is sometimes screened to determine a minimal erythema dose (MED), which is the amount of UV radiation that will produce minimal erythema (sunburn or redness caused by engorgement of capillaries) of an individual''s skin within a few hours following exposure. This article describes how to conduct minimal erythema dose (MED) testing. There is currently no easy way to determine an appropriate UV dose for clinical or research purposes without conducting formal MED testing, requiring observation hours after testing, or informal trial and error testing with the risks of under- or over-dosing. However, some alternative methods are discussed. 相似文献