全文获取类型
收费全文 | 3649篇 |
免费 | 372篇 |
国内免费 | 1篇 |
出版年
2021年 | 45篇 |
2020年 | 20篇 |
2019年 | 41篇 |
2018年 | 40篇 |
2017年 | 42篇 |
2016年 | 86篇 |
2015年 | 151篇 |
2014年 | 159篇 |
2013年 | 237篇 |
2012年 | 254篇 |
2011年 | 235篇 |
2010年 | 156篇 |
2009年 | 145篇 |
2008年 | 202篇 |
2007年 | 205篇 |
2006年 | 215篇 |
2005年 | 218篇 |
2004年 | 229篇 |
2003年 | 177篇 |
2002年 | 200篇 |
2001年 | 65篇 |
2000年 | 37篇 |
1999年 | 75篇 |
1998年 | 63篇 |
1997年 | 35篇 |
1996年 | 30篇 |
1995年 | 35篇 |
1994年 | 34篇 |
1993年 | 44篇 |
1992年 | 39篇 |
1991年 | 26篇 |
1990年 | 32篇 |
1989年 | 30篇 |
1988年 | 27篇 |
1987年 | 22篇 |
1986年 | 18篇 |
1985年 | 15篇 |
1984年 | 34篇 |
1983年 | 20篇 |
1982年 | 20篇 |
1981年 | 37篇 |
1980年 | 20篇 |
1979年 | 15篇 |
1978年 | 15篇 |
1977年 | 14篇 |
1974年 | 21篇 |
1973年 | 13篇 |
1972年 | 14篇 |
1969年 | 13篇 |
1963年 | 12篇 |
排序方式: 共有4022条查询结果,搜索用时 31 毫秒
991.
Protein misfolding in the endoplasmic reticulum (ER) activates a set of intracellular signaling pathways, collectively termed the Unfolded Protein Response (UPR). UPR signaling promotes cell survival by reducing misfolded protein levels. If homeostasis cannot be restored, UPR signaling promotes cell death. The molecular basis for the switch between prosurvival and proapoptotic UPR function is poorly understood. The ER-resident proteins, PERK and IRE1, control two key UPR signaling pathways. Protein misfolding concomitantly activates PERK and IRE1 and has clouded insight into their contributions toward life or death cell fates. Here, we employed chemical-genetic strategies to activate individually PERK or IRE1 uncoupled from protein misfolding. We found that sustained PERK signaling impaired cell proliferation and promoted apoptosis. By contrast, equivalent durations of IRE1 signaling enhanced cell proliferation without promoting cell death. These results demonstrate that extended PERK and IRE1 signaling have opposite effects on cell viability. Differential activation of PERK and IRE1 may determine life or death decisions after ER protein misfolding. 相似文献
992.
Vanesa Esteban Silvia Heringer-Walther Anja Sterner-Kock Ron de Bruin Sandra van den Engel Yong Wang Sergio Mezzano Jesus Egido Heinz-Peter Schultheiss Marta Ruiz-Ortega Thomas Walther 《PloS one》2009,4(4)
Angiotensin (Ang) II mediates pathophysiologial changes in the kidney. Ang-(1–7) by interacting with the G protein-coupled receptor Mas may also have important biological activities.In this study, renal deficiency for Mas diminished renal damage in models of renal insufficiency as unilateral ureteral obstruction and ischemia/reperfusion injury while the infusion of Ang-(1–7) to wild-type mice pronounced the pathological outcome by aggravating the inflammatory response. Mas deficiency inhibited NF-κB activation and thus the elevation of inflammation-stimulating cytokines, while Ang-(1–7) infusion had proinflammatory properties in experimental models of renal failure as well as under basal conditions. The Ang-(1–7)-mediated NF-κB activation was Mas dependent but did not involve Ang II receptors. Therefore, the blockade of the NF-κB-activating properties of the receptor Mas could be a new strategy in the therapy of failing kidney. 相似文献
993.
Jun Ki Son Ho Yul Choo June Yeol Choi Chae Hoon Paik Chung Gyoo Park 《Journal of Asia》2009,12(3):159-163
Egg parasitism of the bean bug, Riptortus clavatus (Thunberg) (Hemiptera: Alydidae), was surveyed using individual egg bags in a sweet persimmon orchard and at Gyeongsang National University (GNU) campus, Korea in 2006. The effect of (E)-2-hexenyl (Z)-3-hexenoate (E2HZ3H), one component of R. clavatus aggregation pheromone, on the parasitism enhancement was tested at GNU campus and in a soybean field in 2005 and 2006, respectively. In 2006, two egg parasitoid species, Ooencyrtus nezarae Ishii (Hymenoptera: Encyrtidae) and Gryon japonicum (Ashmead) (Hymenoptera: Scelionidae), emerged from R. clavatus eggs. Parasitism by O. nezarae was 9.4–48.3% in mid August to mid September in GNU campus and 6.7–30.0% at the orchard. Total parasitism by G. japonicum (2.5%) at both sites throughout the experimental period was lower than that by O. nezarae (12.5%). This survey revealed nearly no activity of the two species after October at both sites. G. japonicum was solitary and O. nezarae could be either solitary or gregarious. From a single R. clavatus egg, one female or one male G. japonicum emerged. However, an average of 4.3 O. nezarae emerged from one host egg. It took 12.6 d for G. japonicum and 12.0 d for O. nezarae to emerge from R. clavatus eggs in the laboratory. Treatment with E2HZ3H increased parasitism by O. nezarae in both years, but did not increase parasitism by G. japonicum. This suggests that E2HZ3H can be used as a kairomone to reduce the density of R. clavatus in the fields where natural parasitism by O. nezarae is high. 相似文献
994.
Seok Choi Jeong June Choi Jae Yeoul Jun Jae Woong Koh Sang Hun Kim Dong Hee Kim Myoung-Yun Pyo Sangzin Choi Jin Pub Son Inki Lee Miwon Son Mirim Jin 《Molecules and cells》2009,27(3):307-312
The interstitial cells of Cajal (ICC) are pacemaking cells required for gastrointestinal motility. The possibility of whether
DA-9701, a novel prokinetic agent formulated with Pharbitis Semen and Corydalis Tuber, modulates pacemaker activities in the
ICC was tested using the whole cell patch clamp technique. DA-9701 produced membrane depolarization and increased tonic inward
pacemaker currents in the voltage-clamp mode. The application of flufenamic acid, a non-selective cation channel blocker,
but not niflumic acid, abolished the generation of pacemaker currents induced by DA-9701. Pretreatment with a Ca2+-free solution and thapsigargin, a Ca2+-ATPase inhibitor in the endoplasmic reticulum, abolished the generation of pacemaker currents. In addition, the tonic inward
currents were inhibited by U-73122, an active phospholipase C inhibitor, but not by GDP-β-S, which permanently binds G-binding
proteins. Furthermore, the protein kinase C inhibitors, chelerythrine and calphostin C, did not block the DA-9701-induced
pacemaker currents. These results suggest that DA-9701 might affect gastrointestinal motility by the modulation of pacemaker
activity in the ICC, and the activation is associated with the non-selective cationic channels via external Ca2+ influx, phospholipase C activation, and Ca2+ release from internal storage in a G protein-independent and protein kinase C-independent manner. 相似文献
995.
Meir M. Barak Selly Geiger Netta Lev-Tov Chattah Ron Shahar Steve Weiner 《Journal of structural biology》2009,168(3):511-520
In order to understand whole tooth behavior under load the biomechanical role of enamel and dentin has to be determined. We approach this question by comparing the deformation pattern and stiffness of intact teeth under load with the deformation pattern and stiffness of the same teeth after the enamel has been mechanically compromised by introducing a defect. FE models of intact human premolars, based on high resolution micro-CT scans, were generated and validated by in vitro electronic speckle pattern interferometry (ESPI) experiments. Once a valid FE model was established, we exploit the flexibility of the FE model to gain more insight into whole tooth function. Results show that the enamel cap is an intrinsically stiff biological structure and its morphology dictates the way a whole tooth will mechanically behave under load. The mechanical properties of the enamel cap were sufficient to mechanically maintain almost its entire stiffness function under load even when a small defect (cavity simulating caries) was introduced into its structure and breached the crown integrity. We conclude that for the most part, that enamel and not dentin dictates the mechanical behavior of the whole tooth. 相似文献
996.
997.
Rokus Renirie Christel Pierlot Ron Wever Jean-Marie Aubry 《Journal of Molecular Catalysis .B, Enzymatic》2009,56(4):259-264
Non-ionic microemulsions compatible with the enzyme vanadium chloroperoxidase were designed to perform singlet oxygenation of apolar substrates. The media were based on mono- and polydisperse ethoxylated fatty alcohols (CiEj), octane and aqueous buffer. “Fish” diagrams were determined to identify the Winsor-boundaries and to formulate a monophasic Winsor IV microemulsion with a minimal surfactant concentration, ensuring less singlet oxygen (1O2) loss than in an aqueous system, thus creating a high oxygenation efficiency. The enzyme was shown to be fully stable in the microemulsion for at least 10 h, converting H2O2 into a constant flow of 1O2 in the aqueous microdomains. Part of the 1O2 diffuses into the organic compartments prior to fast physical deactivation of 1O2 by water molecules. In the apolar domains 1O2 quantitatively converts the model substrate 9,10-dimethylanthracene into its corresponding endoperoxide. Near-IR chemiluminescence measurements confirm that the 1O2 signal in the microemulsion is higher than in simple aqueous buffer. In a well-stirred (water/octane) biphasic system endoperoxide formation is also observed but the conversion rate is much lower, most likely due to stronger physical quenching of 1O2. 相似文献
998.
Ninette Amariglio Abraham Hirshberg Bernd W Scheithauer Yoram Cohen Ron Loewenthal Luba Trakhtenbrot Nurit Paz Maya Koren-Michowitz Dalia Waldman Leonor Leider-Trejo Amos Toren Shlomi Constantini Gideon Rechavi 《PLoS medicine》2009,6(2)
Background
Neural stem cells are currently being investigated as potential therapies for neurodegenerative diseases, stroke, and trauma. However, concerns have been raised over the safety of this experimental therapeutic approach, including, for example, whether there is the potential for tumors to develop from transplanted stem cells.Methods and Findings
A boy with ataxia telangiectasia (AT) was treated with intracerebellar and intrathecal injection of human fetal neural stem cells. Four years after the first treatment he was diagnosed with a multifocal brain tumor. The biopsied tumor was diagnosed as a glioneuronal neoplasm. We compared the tumor cells and the patient''s peripheral blood cells by fluorescent in situ hybridization using X and Y chromosome probes, by PCR for the amelogenin gene X- and Y-specific alleles, by MassArray for the ATM patient specific mutation and for several SNPs, by PCR for polymorphic microsatellites, and by human leukocyte antigen (HLA) typing. Molecular and cytogenetic studies showed that the tumor was of nonhost origin suggesting it was derived from the transplanted neural stem cells. Microsatellite and HLA analysis demonstrated that the tumor is derived from at least two donors.Conclusions
This is the first report of a human brain tumor complicating neural stem cell therapy. The findings here suggest that neuronal stem/progenitor cells may be involved in gliomagenesis and provide the first example of a donor-derived brain tumor. Further work is urgently needed to assess the safety of these therapies. 相似文献999.
Matthew K. Nock Irving Hwang Nancy Sampson Ronald C. Kessler Matthias Angermeyer Annette Beautrais Guilherme Borges Evelyn Bromet Ronny Bruffaerts Giovanni de Girolamo Ron de Graaf Silvia Florescu Oye Gureje Josep Maria Haro Chiyi Hu Yueqin Huang Elie G. Karam Norito Kawakami Viviane Kovess Daphna Levinson Jose Posada-Villa Rajesh Sagar Toma Tomov Maria Carmen Viana David R. Williams 《PLoS medicine》2009,6(8)
Background
Suicide is a leading cause of death worldwide. Mental disorders are among the strongest predictors of suicide; however, little is known about which disorders are uniquely predictive of suicidal behavior, the extent to which disorders predict suicide attempts beyond their association with suicidal thoughts, and whether these associations are similar across developed and developing countries. This study was designed to test each of these questions with a focus on nonfatal suicide attempts.Methods and Findings
Data on the lifetime presence and age-of-onset of Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) mental disorders and nonfatal suicidal behaviors were collected via structured face-to-face interviews with 108,664 respondents from 21 countries participating in the WHO World Mental Health Surveys. The results show that each lifetime disorder examined significantly predicts the subsequent first onset of suicide attempt (odds ratios [ORs] = 2.9–8.9). After controlling for comorbidity, these associations decreased substantially (ORs = 1.5–5.6) but remained significant in most cases. Overall, mental disorders were equally predictive in developed and developing countries, with a key difference being that the strongest predictors of suicide attempts in developed countries were mood disorders, whereas in developing countries impulse-control, substance use, and post-traumatic stress disorders were most predictive. Disaggregation of the associations between mental disorders and nonfatal suicide attempts showed that these associations are largely due to disorders predicting the onset of suicidal thoughts rather than predicting progression from thoughts to attempts. In the few instances where mental disorders predicted the transition from suicidal thoughts to attempts, the significant disorders are characterized by anxiety and poor impulse-control. The limitations of this study include the use of retrospective self-reports of lifetime occurrence and age-of-onset of mental disorders and suicidal behaviors, as well as the narrow focus on mental disorders as predictors of nonfatal suicidal behaviors, each of which must be addressed in future studies.Conclusions
This study found that a wide range of mental disorders increased the odds of experiencing suicide ideation. However, after controlling for psychiatric comorbidity, only disorders characterized by anxiety and poor impulse-control predict which people with suicide ideation act on such thoughts. These findings provide a more fine-grained understanding of the associations between mental disorders and subsequent suicidal behavior than previously available and indicate that mental disorders predict suicidal behaviors similarly in both developed and developing countries. Future research is needed to delineate the mechanisms through which people come to think about suicide and subsequently progress from ideation to attempts. Please see later in the article for Editors'' Summary 相似文献1000.
A common yet poorly understood evolutionary transition among flowering plants is a switch from outbreeding to an inbreeding mode of mating. The model plant Arabidopsis thaliana evolved to an inbreeding state through the loss of self-incompatibility, a pollen-rejection system in which pollen recognition by the stigma is determined by tightly linked and co-evolving alleles of the S-locus receptor kinase (SRK) and its S-locus cysteine-rich ligand (SCR). Transformation of A. thaliana, with a functional AlSRKb-SCRb gene pair from its outcrossing relative A. lyrata, demonstrated that A. thaliana accessions harbor different sets of cryptic self-fertility–promoting mutations, not only in S-locus genes, but also in other loci required for self-incompatibility. However, it is still not known how many times and in what manner the switch to self-fertility occurred in the A. thaliana lineage. Here, we report on our identification of four accessions that are reverted to full self-incompatibility by transformation with AlSRKb-SCRb, bringing to five the number of accessions in which self-fertility is due to, and was likely caused by, S-locus inactivation. Analysis of S-haplotype organization reveals that inter-haplotypic recombination events, rearrangements, and deletions have restructured the S locus and its genes in these accessions. We also perform a Quantitative Trait Loci (QTL) analysis to identify modifier loci associated with self-fertility in the Col-0 reference accession, which cannot be reverted to full self-incompatibility. Our results indicate that the transition to inbreeding occurred by at least two, and possibly more, independent S-locus mutations, and identify a novel unstable modifier locus that contributes to self-fertility in Col-0. 相似文献