全文获取类型
收费全文 | 4358篇 |
免费 | 374篇 |
国内免费 | 2篇 |
出版年
2023年 | 16篇 |
2022年 | 44篇 |
2021年 | 151篇 |
2020年 | 71篇 |
2019年 | 76篇 |
2018年 | 114篇 |
2017年 | 93篇 |
2016年 | 152篇 |
2015年 | 238篇 |
2014年 | 280篇 |
2013年 | 325篇 |
2012年 | 408篇 |
2011年 | 362篇 |
2010年 | 249篇 |
2009年 | 204篇 |
2008年 | 272篇 |
2007年 | 249篇 |
2006年 | 220篇 |
2005年 | 178篇 |
2004年 | 196篇 |
2003年 | 188篇 |
2002年 | 161篇 |
2001年 | 28篇 |
2000年 | 25篇 |
1999年 | 43篇 |
1998年 | 38篇 |
1997年 | 29篇 |
1996年 | 22篇 |
1995年 | 21篇 |
1994年 | 23篇 |
1993年 | 26篇 |
1992年 | 17篇 |
1991年 | 18篇 |
1990年 | 19篇 |
1989年 | 12篇 |
1988年 | 12篇 |
1987年 | 10篇 |
1986年 | 15篇 |
1985年 | 7篇 |
1984年 | 12篇 |
1983年 | 10篇 |
1982年 | 15篇 |
1981年 | 9篇 |
1980年 | 6篇 |
1979年 | 5篇 |
1978年 | 11篇 |
1977年 | 8篇 |
1974年 | 9篇 |
1969年 | 4篇 |
1965年 | 5篇 |
排序方式: 共有4734条查询结果,搜索用时 31 毫秒
941.
Julienne N. Rutherford Victoria A. deMartelly Donna G. Layne Colon Corinna N. Ross Suzette D. Tardif 《PloS one》2014,9(5)
Background
The impact of the intrauterine environment on the developmental programming of adult female reproductive success is still poorly understood and potentially underestimated. Litter size variation in a nonhuman primate, the common marmoset monkey (Callithrix jacchus), allows us to model the effects of varying intrauterine environments (e.g. nutrient restriction, exposure to male womb-mates) on the risk of losing fetuses in adulthood. Our previous work has characterized the fetuses of triplet pregnancies as experiencing intrauterine nutritional restriction.Methodology/Principal Findings
We used over a decade of demographic data from the Southwest National Primate Research Center common marmoset colony. We evaluated differences between twin and triplet females in the number of pregnancies they produce and the proportion of those pregnancies that ended in fetal loss. We found that triplet females produced the same number of total offspring as twin females, but lost offspring during pregnancy at a significantly higher rate than did twins (38% vs. 13%, p = 0.02). Regardless of their own birth weight or the sex ratio of the litter the experienced as fetuses, triplet females lost more fetuses than did twins. Females with a male littermate experienced a significant increase in the proportion of stillbirths.Conclusions/Significance
These striking findings anchor pregnancy loss in the mother’s own fetal environment and development, underscoring a "Womb to Womb" view of the lifecourse and the intergenerational consequences of development. This has important translational implications for understanding the large proportion of human stillbirths that are unexplained. Our findings provide strong evidence that a full understanding of mammalian life history and reproductive biology requires a developmental foundation. 相似文献942.
David E. Blask Robert T. Dauchy Erin M. Dauchy Lulu Mao Steven M. Hill Michael W. Greene Victoria P. Belancio Leonard A. Sauer Leslie Davidson 《PloS one》2014,9(8)
The central circadian clock within the suprachiasmatic nucleus (SCN) plays an important role in temporally organizing and coordinating many of the processes governing cancer cell proliferation and tumor growth in synchrony with the daily light/dark cycle which may contribute to endogenous cancer prevention. Bioenergetic substrates and molecular intermediates required for building tumor biomass each day are derived from both aerobic glycolysis (Warburg effect) and lipid metabolism. Using tissue-isolated human breast cancer xenografts grown in nude rats, we determined that circulating systemic factors in the host and the Warburg effect, linoleic acid uptake/metabolism and growth signaling activities in the tumor are dynamically regulated, coordinated and integrated within circadian time structure over a 24-hour light/dark cycle by SCN-driven nocturnal pineal production of the anticancer hormone melatonin. Dim light at night (LAN)-induced melatonin suppression disrupts this circadian-regulated host/cancer balance among several important cancer preventative signaling mechanisms, leading to hyperglycemia and hyperinsulinemia in the host and runaway aerobic glycolysis, lipid signaling and proliferative activity in the tumor. 相似文献
943.
944.
Maria Victoria Sanchez Thomas Ebensen Kai Schulze Diego Cargnelutti Paulina Blazejewska Eduardo A. Scodeller Carlos A. Guzmán 《PloS one》2014,9(8)
There is a critical need for new influenza vaccines able to protect against constantly emerging divergent virus strains. This will be sustained by the induction of vigorous cellular responses and humoral immunity capable of acting at the portal of entry of this pathogen. In this study we evaluate the protective efficacy of intranasal vaccination with recombinant influenza nucleoprotein (rNP) co-administrated with bis-(3′,5′)-cyclic dimeric adenosine monophosphate (c-di-AMP) as adjuvant. Immunization of BALB/c mice with two doses of the formulation stimulates high titers of NP-specific IgG in serum and secretory IgA at mucosal sites. This formulation also promotes a strong Th1 response characterized by high secretion of INF-γ and IL-2. The immune response elicited promotes efficient protection against virus challenge. These results suggest that c-di-AMP is a potent mucosal adjuvant which may significantly contribute towards the development of innovative mucosal vaccines against influenza. 相似文献
945.
Thomas Pavelitz Lindsay Renfro Nathan R. Foster Amber Caracol Piri Welsch Victoria Valinluck Lao William B. Grady Donna Niedzwiecki Leonard B. Saltz Monica M. Bertagnolli Richard M. Goldberg Peter S. Rabinovitch Mary Emond Raymond J. Monnat Jr Nancy Maizels 《PloS one》2014,9(10)
Purpose
Colon cancers deficient in mismatch repair (MMR) may exhibit diminished expression of the DNA repair gene, MRE11, as a consequence of contraction of a T11 mononucleotide tract. This study investigated MRE11 status and its association with prognosis, survival and drug response in patients with stage III colon cancer.Patients and Methods
Cancer and Leukemia Group B 89803 (Alliance) randomly assigned 1,264 patients with stage III colon cancer to postoperative weekly adjuvant bolus 5-fluorouracil/leucovorin (FU/LV) or irinotecan+FU/LV (IFL), with 8 year follow-up. Tumors from these patients were analyzed to determine stability of a T11 tract in the MRE11 gene. The primary endpoint was overall survival (OS), and a secondary endpoint was disease-free survival (DFS). Non-proportional hazards were addressed using time-dependent covariates in Cox analyses.Results
Of 625 tumor cases examined, 70 (11.2%) exhibited contraction at the T11 tract in one or both MRE11 alleles and were thus predicted to be deficient in MRE11 (dMRE11). In pooled treatment analyses, dMRE11 patients showed initially reduced DFS and OS but improved long-term DFS and OS compared with patients with an intact MRE11 T11 tract. In the subgroup of dMRE11 patients treated with IFL, an unexplained early increase in mortality but better long-term DFS than IFL-treated pMRE11 patients was observed.Conclusions
Analysis of this relatively small number of patients and events showed that the dMRE11 marker predicts better prognosis independent of treatment in the long-term. In subgroup analyses, dMRE11 patients treated with irinotecan exhibited unexplained short-term mortality. MRE11 status is readily assayed and may therefore prove to be a useful prognostic marker, provided that the results reported here for a relatively small number of patients can be generalized in independent analyses of larger numbers of samples.Trial Registration
ClinicalTrials.gov NCT00003835相似文献946.
Glen M. Boyle Marjorie M. A. D'Souza Carly J. Pierce Ryan A. Adams Aaron S. Cantor Jenny P. Johns Lidia Maslovskaya Victoria A. Gordon Paul W. Reddell Peter G. Parsons 《PloS one》2014,9(10)
Intra-lesional chemotherapy for treatment of cutaneous malignancies has been used for many decades, allowing higher local drug concentrations and less toxicity than systemic agents. Here we describe a novel diterpene ester, EBC-46, and provide preclinical data supporting its use as an intra-lesional treatment. A single injection of EBC-46 caused rapid inflammation and influx of blood, followed by eschar formation and rapid tumor ablation in a range of syngeneic and xenograft models. EBC-46 induced oxidative burst from purified human polymorphonuclear cells, which was prevented by the Protein Kinase C inhibitor bisindolylmaleimide-1. EBC-46 activated a more specific subset of PKC isoforms (PKC-βI, -βII, -α and -γ) compared to the structurally related phorbol 12-myristate 13-acetate (PMA). Although EBC-46 showed threefold less potency for inhibiting cell growth than PMA in vitro, it was more effective for cure of tumors in vivo. No viable tumor cells were evident four hours after injection by ex vivo culture. Pharmacokinetic profiles from treated mice indicated that EBC-46 was retained preferentially within the tumor, and resulted in significantly greater local responses (erythema, oedema) following intra-lesional injection compared with injection into normal skin. The efficacy of EBC-46 was reduced by co-injection with bisindolylmaleimide-1. Loss of vascular integrity following treatment was demonstrated by an increased permeability of endothelial cell monolayers in vitro and by CD31 immunostaining of treated tumors in vivo. Our results demonstrate that a single intra-lesional injection of EBC-46 causes PKC-dependent hemorrhagic necrosis, rapid tumor cell death and ultimate cure of solid tumors in pre-clinical models of cancer. 相似文献
947.
948.
Esther Conde Ana Suárez-Gauthier Amparo Benito Pilar Garrido Rosario García-Campelo Michele Biscuola Luis Paz-Ares David Hardisson Javier de Castro M. Carmen Camacho Delvys Rodriguez-Abreu Ihab Abdulkader Josep Ramirez Noemí Reguart Marta Salido Lara Pijuán Edurne Arriola Julián Sanz Victoria Folgueras Noemí Villanueva Javier Gómez-Román Manuel Hidalgo Fernando López-Ríos 《PloS one》2014,9(9)
Background
Based on the excellent results of the clinical trials with ALK-inhibitors, the importance of accurately identifying ALK positive lung cancer has never been greater. However, there are increasing number of recent publications addressing discordances between FISH and IHC. The controversy is further fuelled by the different regulatory approvals. This situation prompted us to investigate two ALK IHC antibodies (using a novel ultrasensitive detection-amplification kit) and an automated ALK FISH scanning system (FDA-cleared) in a series of non-small cell lung cancer tumor samples.Methods
Forty-seven ALK FISH-positive and 56 ALK FISH-negative NSCLC samples were studied. All specimens were screened for ALK expression by two IHC antibodies (clone 5A4 from Novocastra and clone D5F3 from Ventana) and for ALK rearrangement by FISH (Vysis ALK FISH break-apart kit), which was automatically captured and scored by using Bioview''s automated scanning system.Results
All positive cases with the IHC antibodies were FISH-positive. There was only one IHC-negative case with both antibodies which showed a FISH-positive result. The overall sensitivity and specificity of the IHC in comparison with FISH were 98% and 100%, respectively.Conclusions
The specificity of these ultrasensitive IHC assays may obviate the need for FISH confirmation in positive IHC cases. However, the likelihood of false negative IHC results strengthens the case for FISH testing, at least in some situations. 相似文献949.
950.
Verónica Williner María Victoria Torres Débora Azevedo Carvalho Natalia K?nig 《ZooKeys》2014,(457):159-170
The relative growth of a number of morphological dimensions of the South American freshwater crab Trichodactylus
borellianus (Trichodactylidae) were compared and related to sexual dimorphism. Crabs were collected from ponds in the Middle Paraná River in Argentina. A regression model with segmented relationship was used to test for relative growth between these measurements where breakpoints infer the body size at which crabs reach sexual maturity. In both sexes the carapace width and the length, height, and thickness of the right and left chelae were measured, as well as the male pleopod length and the female abdomen width. All of these measurements were found to show positive allometry with the exception of the male pleopod length and the left chelae, which did not show a breakpoint. In females the breakpoint for the abdomen width inferred a morphological sexual maturity at carapace width 6.9 mm. In males the break point for the pleopod length was at carapace width 6.6 mm, with that for the chelae measurements was between carapace widths 6.4 and 6.9 mm. The relative growth pattern in Trichodactylus
borellianus was found to be similar to that recorded for other species of the family Trichodactylidae. 相似文献