全文获取类型
收费全文 | 12624篇 |
免费 | 1271篇 |
国内免费 | 4篇 |
出版年
2023年 | 54篇 |
2022年 | 124篇 |
2021年 | 288篇 |
2020年 | 127篇 |
2019年 | 177篇 |
2018年 | 226篇 |
2017年 | 210篇 |
2016年 | 357篇 |
2015年 | 566篇 |
2014年 | 602篇 |
2013年 | 716篇 |
2012年 | 1011篇 |
2011年 | 986篇 |
2010年 | 635篇 |
2009年 | 568篇 |
2008年 | 802篇 |
2007年 | 757篇 |
2006年 | 681篇 |
2005年 | 707篇 |
2004年 | 701篇 |
2003年 | 625篇 |
2002年 | 631篇 |
2001年 | 141篇 |
2000年 | 119篇 |
1999年 | 132篇 |
1998年 | 152篇 |
1997年 | 102篇 |
1996年 | 103篇 |
1995年 | 101篇 |
1994年 | 87篇 |
1993年 | 92篇 |
1992年 | 79篇 |
1991年 | 75篇 |
1990年 | 92篇 |
1989年 | 93篇 |
1988年 | 76篇 |
1987年 | 60篇 |
1986年 | 54篇 |
1985年 | 55篇 |
1984年 | 58篇 |
1983年 | 71篇 |
1982年 | 67篇 |
1981年 | 55篇 |
1980年 | 55篇 |
1979年 | 35篇 |
1978年 | 39篇 |
1977年 | 38篇 |
1975年 | 28篇 |
1973年 | 31篇 |
1971年 | 30篇 |
排序方式: 共有10000条查询结果,搜索用时 24 毫秒
931.
Eric C. Woolf Kara L. Curley Qingwei Liu Gregory H. Turner Julie A. Charlton Mark C. Preul Adrienne C. Scheck 《PloS one》2015,10(6)
Background
The successful treatment of malignant gliomas remains a challenge despite the current standard of care, which consists of surgery, radiation and temozolomide. Advances in the survival of brain cancer patients require the design of new therapeutic approaches that take advantage of common phenotypes such as the altered metabolism found in cancer cells. It has therefore been postulated that the high-fat, low-carbohydrate, adequate protein ketogenic diet (KD) may be useful in the treatment of brain tumors. We have demonstrated that the KD enhances survival and potentiates standard therapy in a mouse model of malignant glioma, yet the mechanisms are not fully understood.Methods
To explore the effects of the KD on various aspects of tumor growth and progression, we used the immunocompetent, syngeneic GL261-Luc2 mouse model of malignant glioma.Results
Tumors from animals maintained on KD showed reduced expression of the hypoxia marker carbonic anhydrase 9, hypoxia inducible factor 1-alpha, and decreased activation of nuclear factor kappa B. Additionally, tumors from animals maintained on KD had reduced tumor microvasculature and decreased expression of vascular endothelial growth factor receptor 2, matrix metalloproteinase-2 and vimentin. Peritumoral edema was significantly reduced in animals fed the KD and protein analyses showed altered expression of zona occludens-1 and aquaporin-4.Conclusions
The KD directly or indirectly alters the expression of several proteins involved in malignant progression and may be a useful tool for the treatment of gliomas. 相似文献932.
Andrew J. Burt H. Manilal William Gregory Perry Raja Khanal K. Peter Pauls James D. Kelly Alireza Navabi 《PloS one》2015,10(10)
Anthracnose, caused by Colletotrichum lindemuthianum, is an important fungal disease of common bean (Phaseolus vulgaris). Alleles at the Co–4 locus confer resistance to a number of races of C. lindemuthianum. A population of 94 F4:5 recombinant inbred lines of a cross between resistant black bean genotype B09197 and susceptible navy bean cultivar Nautica was used to identify markers associated with resistance in bean chromosome 8 (Pv08) where Co–4 is localized. Three SCAR markers with known linkage to Co–4 and a panel of single nucleotide markers were used for genotyping. A refined physical region on Pv08 with significant association with anthracnose resistance identified by markers was used in BLAST searches with the genomic sequence of common bean accession G19833. Thirty two unique annotated candidate genes were identified that spanned a physical region of 936.46 kb. A majority of the annotated genes identified had functional similarity to leucine rich repeats/receptor like kinase domains. Three annotated genes had similarity to 1, 3-β-glucanase domains. There were sequence similarities between some of the annotated genes found in the study and the genes associated with phosphoinositide-specific phosphilipases C associated with Co-x and the COK–4 loci found in previous studies. It is possible that the Co–4 locus is structured as a group of genes with functional domains dominated by protein tyrosine kinase along with leucine rich repeats/nucleotide binding site, phosphilipases C as well as β-glucanases. 相似文献
933.
Aberrant Nuclear Factor-κappaB (NF-κB) activation due to rapid IκBα turnover and high basal IκBα kinase (IKK) activity has been frequently observed in prostate cancer. Apigenin, a naturally occurring plant flavone, exhibits anti-proliferative, anti-inflammatory and anti-carcinogenic activities by inhibiting NF-κB pathway, through a mechanism not fully understood. We found that apigenin feeding in microgram doses (bioavailable in humans) inhibited prostate tumorigenesis in TRAMP mice by interfering with NF-κB signaling. Apigenin feeding to TRAMP mice (20 and 50 μg/mouse/day, 6 days/week for 20 weeks) exhibited significant decrease in tumor volumes of the prostate and completely abolished metastasis, which correlated with inhibition of NF-κB activation and binding to the DNA. Apigenin intake blocked phosphorylation and degradation of IκBα by inhibiting IKK activation, which in turn led to suppression of NF-κB activation. The expression of NF-κB-regulated gene products involved in proliferation (cyclin D1, and COX-2), anti-apoptosis (Bcl-2 and Bcl-xL), and angiogenesis (vascular endothelial growth factor) were also downregulated after apigenin feeding. These events correlated with the induction of apoptosis in tumor cells, as evident by increased cleaved caspase-3 labeling index in the dorsolateral prostate. Our results provide convincing evidence that apigenin inhibits IKK activation and restores the expression of IκBα, preventing it’s phosphorylation in a fashion similar to that elicited by IKK and proteasomal inhibitors through suppression of NF-κB signaling pathway. 相似文献
934.
935.
Shirley J. Semple Jamila K. Stockman Eileen V. Pitpitan Steffanie A. Strathdee Claudia V. Chavarin Doroteo V. Mendoza Gregory A. Aarons Thomas L. Patterson 《PloS one》2015,10(11)
Background
Globally, client-perpetrated violence against female sex workers (FSWs) has been associated with multiple health-related harms, including high-risk sexual behavior and increased exposure to HIV/STIs. This study examined correlates of client-perpetrated sexual, physical, and economic violence (e.g., robbery) against FSWs in 13 cities throughout Mexico.Methods
FSWs (N = 1,089) who were enrolled in a brief, evidence-based, sexual risk reduction intervention for FSWs (Mujer Segura) were interviewed about their work context, including experiences of violence perpetrated by clients, sexual risk and substance use practices, financial need, and social supports. Three broad categories of factors (sociodemographic, work context, behavioral and social characteristics of FSWs) were examined as correlates of sexual, physical, and economic violence.Results
The prevalence of different types of client-perpetrated violence against FSWs in the past 6 months was: sexual (11.7%), physical (11.8%), economic (16.9%), and any violence (22.6%). Greater financial need, self-identification as a street worker, and lower perceived emotional support were independently associated with all three types of violence. Alcohol use before or during sex with clients in the past month was associated with physical and sexual violence. Using drugs before or during sex with clients, injection drug use in the past month, and population size of city were associated with sexual violence only, and FSWs’ alcohol use score (AUDIT-C) was associated with economic violence only.Conclusions
Correlates of client-perpetrated violence encompassed sociodemographic, work context, and behavioral and social factors, suggesting that approaches to violence prevention for FSWs must be multi-dimensional. Prevention could involve teaching FSWs strategies for risk avoidance in the workplace (e.g., avoiding use of alcohol with clients), enhancement of FSWs’ community-based supports, development of interventions that deliver an anti-violence curriculum to clients, and programs to address FSWs’ financial need by increasing their economic opportunities outside of the sex trade. 相似文献936.
Kazuyuki Kitatani Masayuki Wada David Perry Toshinori Usui Ying Sun Lina M. Obeid Nobuo Yaegashi Gregory A. Grabowski Yusuf A. Hannun 《PloS one》2015,10(8)
Gaucher’s disease is caused by defects in acid β-glucosidase 1 (GBA1) and has been also proposed as an inflammatory disease. GBA1 cleaves glucosylceramide to form ceramide, an established bioactive lipid, and defects in GBA1 lead to aberrant accumulation in glucosylceramide and insufficient formation of ceramide. We investigated if the pro-inflammatory kinase p38 is activated in Gaucher’s disease, since ceramide has been proposed to suppress p38 activation. Three Gaucher’s disease mouse models were employed, and p38 was found to be activated in lung and liver tissues of all Gaucher’s disease mice. Most interestingly, neuronopathic Gaucher’s disease type mice, but not non-neuronopathic ones, displayed significant activation of p38 and up-regulation of p38-inducible proinflammatory cytokines in brain tissues. In addition, all type of Gaucher’s disease mice also showed increases in serum IL-6. As cellular signalling is believed to represent an in vivo inflammatory phenotype in Gaucher’s disease, activation of p38 and possibly its-associated formation of proinflammatory cytokines were assessed in fibroblasts established from neuronopathic Gaucher’s disease mice. In mouse Gaucher’s disease cells, p38 activation and IL-6 formation by TNF-α treatment were enhanced as compared to those of wild type. Furthermore, human fibroblasts from Gaucher’s disease patients also displayed increases in p38 activation and IL-6 formation as comparison to healthy counterpart. These results raise the potential that proinflammatory responses such as p38 activation and IL-6 formation are augmented in Gaucher’s disease. 相似文献
937.
Background
Vascular patterning depends on coordinated timing of arteriovenous specification of endothelial cells and the concomitant hemodynamic forces supplied by the onset of cardiac function. Using a combination of 3D imaging by OPT and embryo registration techniques, we sought to identify structural differences between three different mouse models of cardiovascular perturbation.Results
Endoglin mutant mice shared a high degree of similarity to Mlc2a mutant mice, which have been shown to have a primary developmental heart defect causing secondary vessel remodeling failures. Dll4 mutant mice, which have well-characterized arterial blood vessel specification defects, showed distinct differences in vascular patterning when compared to the disruptions seen in Mlc2a -/- and Eng -/- models. While Mlc2a -/- and Eng -/- embryos exhibited significantly larger atria than wild-type, Dll4 -/- embryos had significantly smaller hearts than wild-type, but this quantitative volume decrease was not limited to the developing atrium. Dll4 -/- embryos also had atretic dorsal aortae and smaller trunks, suggesting that the cardiac abnormalities were secondary to primary arterial blood vessel specification defects.Conclusions
The similarities in Eng -/- and Mlc2a -/- embryos suggest that Eng -/- mice may suffer from a primary heart developmental defect and secondary defects in vessel patterning, while defects in Dll4 -/- embryos are consistent with primary defects in vessel patterning. 相似文献938.
Gregory I. Holwell Olga Kazakova Felicity Evans James C. O’Hanlon Katherine L. Barry 《PloS one》2015,10(6)
Genital asymmetry is relatively common and widespread throughout the animal kingdom. The functional significance of genital asymmetry is however, poorly understood for most species. Male praying mantids of the genus Ciulfina are remarkable in possessing complex and directionally asymmetric genital phallomeres in some species, and chirally dimorphic/antisymmetric genitalia in others. Here we explore the chiral dimorphism in male genitalia of Ciulfina baldersoni which appear to exhibit genital antisymmetry. We test whether genital orientation influences mating success, copulation duration and the attachment duration of spermatophores. Additionally we investigate genital interactions between male and females using x-ray micro-computed tomography (micro-CT) and scanning electron microscopy (SEM). Lastly we assess whether genital asymmetry is associated with non-genital morphological asymmetry of a range of traits. Our results highlight the complex functional morphology of genitalia in this praying mantis species and yet demonstrate no functional difference between dextral and sinistral morphs other than the direction of attachment with both morphs enjoying equal levels of mating success. Chiral morphs also did not strongly associate with any other forms of asymmetry. We therefore conclude that genital chirality in Ciulfina baldersoni is a likely case of antisymmetry with no functional significance to genital orientation, and is likely to be selectively neutral. 相似文献
939.
The host ranges of plant pathogens and herbivores are phylogenetically constrained, so that closely related plant species are more likely to share pests and pathogens. Here we conducted a reanalysis of data from published experimental studies to test whether the severity of host-enemy interactions follows a similar phylogenetic signal. The impact of herbivores and pathogens on their host plants declined steadily with phylogenetic distance from the most severely affected focal hosts. The steepness of this phylogenetic signal was similar to that previously measured for binary-response host ranges. Enemy behavior and development showed similar, but weaker phylogenetic signal, with oviposition and growth rates declining with evolutionary distance from optimal hosts. Phylogenetic distance is an informative surrogate for estimating the likely impacts of a pest or pathogen on potential plant hosts, and may be particularly useful in early assessing risk from emergent plant pests, where critical decisions must be made with incomplete host records. 相似文献
940.
Michael Andrew Pest Courtney Alice Pest Melina Rodrigues Bellini Qingping Feng Frank Beier 《PloS one》2015,10(11)