全文获取类型
收费全文 | 495篇 |
免费 | 39篇 |
出版年
2023年 | 2篇 |
2022年 | 4篇 |
2021年 | 9篇 |
2020年 | 5篇 |
2019年 | 9篇 |
2018年 | 5篇 |
2017年 | 8篇 |
2016年 | 4篇 |
2015年 | 19篇 |
2014年 | 17篇 |
2013年 | 35篇 |
2012年 | 30篇 |
2011年 | 34篇 |
2010年 | 19篇 |
2009年 | 16篇 |
2008年 | 27篇 |
2007年 | 23篇 |
2006年 | 28篇 |
2005年 | 15篇 |
2004年 | 20篇 |
2003年 | 21篇 |
2002年 | 17篇 |
2001年 | 10篇 |
2000年 | 19篇 |
1999年 | 13篇 |
1998年 | 9篇 |
1997年 | 3篇 |
1996年 | 8篇 |
1995年 | 8篇 |
1994年 | 8篇 |
1993年 | 3篇 |
1992年 | 8篇 |
1991年 | 10篇 |
1990年 | 12篇 |
1989年 | 14篇 |
1988年 | 8篇 |
1987年 | 3篇 |
1986年 | 3篇 |
1985年 | 7篇 |
1984年 | 3篇 |
1983年 | 1篇 |
1982年 | 2篇 |
1981年 | 4篇 |
1980年 | 1篇 |
1979年 | 2篇 |
1978年 | 2篇 |
1977年 | 3篇 |
1975年 | 1篇 |
1970年 | 1篇 |
1969年 | 1篇 |
排序方式: 共有534条查询结果,搜索用时 15 毫秒
71.
Homeostasis is a key feature of cellular lifespan. Maintenance of cellular homeostasis influences the rate of aging and is determined by several factors, including efficient proteolysis of damaged proteins. Protein degradation is predominantly catalyzed by the proteasome. Specifically, the proteasome is responsible for cell clearance of abnormal, denatured or in general damaged proteins as well as for the regulated degradation of short-lived proteins. As proteasome has an impaired function during aging, emphasis has been given recently in identifying ways of its activation. A number of studies have shown that the proteasome can be activated by genetic manipulations as well as by factors that affect its conformation and stability. Importantly the developed proteasome activated cell lines exhibit an extended lifespan. This review article discusses in details the various factors that are involved in proteasome biosynthesis and assembly and how they contribute to its activation. Finally as few natural compounds have been identified having proteasome activation properties, we discuss the advantages of this novel antiaging strategy. 相似文献
72.
Martin K?bel Steve E Kalloger Niki Boyd Steven McKinney Erika Mehl Chana Palmer Samuel Leung Nathan J Bowen Diana N Ionescu Ashish Rajput Leah M Prentice Dianne Miller Jennifer Santos Kenneth Swenerton C. Blake Gilks David Huntsman 《PLoS medicine》2008,5(12)
Background
Although it has long been appreciated that ovarian carcinoma subtypes (serous, clear cell, endometrioid, and mucinous) are associated with different natural histories, most ovarian carcinoma biomarker studies and current treatment protocols for women with this disease are not subtype specific. With the emergence of high-throughput molecular techniques, distinct pathogenetic pathways have been identified in these subtypes. We examined variation in biomarker expression rates between subtypes, and how this influences correlations between biomarker expression and stage at diagnosis or prognosis.Methods and Findings
In this retrospective study we assessed the protein expression of 21 candidate tissue-based biomarkers (CA125, CRABP-II, EpCam, ER, F-Spondin, HE4, IGF2, K-Cadherin, Ki-67, KISS1, Matriptase, Mesothelin, MIF, MMP7, p21, p53, PAX8, PR, SLPI, TROP2, WT1) in a population-based cohort of 500 ovarian carcinomas that was collected over the period from 1984 to 2000. The expression of 20 of the 21 biomarkers differs significantly between subtypes, but does not vary across stage within each subtype. Survival analyses show that nine of the 21 biomarkers are prognostic indicators in the entire cohort but when analyzed by subtype only three remain prognostic indicators in the high-grade serous and none in the clear cell subtype. For example, tumor proliferation, as assessed by Ki-67 staining, varies markedly between different subtypes and is an unfavourable prognostic marker in the entire cohort (risk ratio [RR] 1.7, 95% confidence interval [CI] 1.2%–2.4%) but is not of prognostic significance within any subtype. Prognostic associations can even show an inverse correlation within the entire cohort, when compared to a specific subtype. For example, WT1 is more frequently expressed in high-grade serous carcinomas, an aggressive subtype, and is an unfavourable prognostic marker within the entire cohort of ovarian carcinomas (RR 1.7, 95% CI 1.2%–2.3%), but is a favourable prognostic marker within the high-grade serous subtype (RR 0.5, 95% CI 0.3%–0.8%).Conclusions
The association of biomarker expression with survival varies substantially between subtypes, and can easily be overlooked in whole cohort analyses. To avoid this effect, each subtype within a cohort should be analyzed discretely. Ovarian carcinoma subtypes are different diseases, and these differences should be reflected in clinical research study design and ultimately in the management of ovarian carcinoma. 相似文献73.
74.
Angiopoietin‐like proteins (ANGPTLs) are secreted proteins possessing an amino‐terminal coiled‐coil domain and a carboxyl‐terminal fibrinogen‐like domain and are known as angiogenic factors. Several members of ANGPTLs also regulate lipid metabolism independently of angiogenic effects, but most of their functions during vertebrate development are not demonstrated. To ascertain their developmental functions, we examined the expression patterns of Angptl1, 2, 3, 4, 5, and 7 orthologues during chick development using whole‐mount in situ hybridization. Angptl1 was first detected at embryonic day 3 (E3) in the somite. At E4, Angptl1 was expressed in somite‐derivatives and limb mesenchyme. Angptl2 was first detected at E3 in the hindbrain. At E4, Angptl2 was expressed in neuroepithelium of forebrain and hindbrain and partly in the heart. Angptl3 was first detected at E3 and continued to be expressed in the liver and yolk sac at E4. Angptl4 was first detected at E3 in the somites and liver. At E4, Angptl4 was also observed in the heart. Angptl5 was not detected in these developmental stages. Angptl7 was first detected at E3 in the ectoderm overlying the lenses of the eyes. At E4, Angptl7 was specifically expressed in cornea. These data suggest that each member of the ANGPTL family could be related to angiogenesis during various organogeneses of the developing chick embryo. 相似文献
75.
76.
Yukiko Kaneko Toshihide Kimura Midori Souma Yuka Kimura Ichiro Niki 《FEBS letters》2009,583(2):377-38
We examined the expression of the major H2S-producing enzymes, cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE). CBS was ubiquitously distributed in the mouse pancreas, but CSE was found only in the exocrine. Freshly isolated islets expressed CBS, while CSE was faint. However, high glucose increased the CSE expression in the beta-cells. l-Cysteine or NaHS suppressed islet cell apoptosis with high glucose, and increased glutathione content in MIN6 beta-cells. Pretreatment with l-cysteine improved the secretory responsiveness following stimulation with glucose. The CSE inhibitor dl-propargylglycine antagonized these l-cysteine effects. We suggest H2 S may function as an ‘intrinsic brake’ which protects beta-cells from glucotoxicity. 相似文献
77.
Hattori Y Asano T Niki Y Kondoh H Kirihata M Yamaguchi Y Wakamiya T 《Bioorganic & medicinal chemistry》2006,14(10):3258-3262
Magnetic resonance imaging (MRI) and boron-neutron capture therapy (BNCT) are quite attractive techniques for diagnosis and treatment of cancer, respectively. In order to progress the study on both MRI and BNCT, the novel compounds containing 19F and 10B atoms in a single molecule were designed and synthesized. In the present paper, the syntheses and the internalization rates into tumor cells of these compounds are elucidated. 相似文献
78.
Niki Tzioumaki Evangelia Tsoukala Stella Manta Christos Kiritsis Jan Balzarini Dimitri Komiotis 《Carbohydrate research》2011,(2):328
A novel series of exomethylene- and keto-exomethylene-d-glucopyranonucleosides with thymine, uracil, and 5-fluorouracil as heterocyclic bases have been designed and synthesized. Wittig condensation of the 3-keto glucoside 1 gave the corresponding 1,2:5,6-di-O-isopropylidene-3-deoxy-3-methylene-d-glucofuranose (2), which after hydrolysis and acetylation led to the precursor 1,2,4,6-tetra-O-acetyl-3-deoxy-3-methylene-d-glucopyranose (4).Compound 4 was condensed with silylated thymine, uracil, and 5-fluorouracil, respectively, deacetylated and acetalated to afford 1-(3′-deoxy-4′,6′-O-isopropylidene-3′-methylene-β-d-glucopyranosyl)pyrimidines 7a–c. Oxidation of the free hydroxyl group in the 2′-position of the sugar moiety led to the formation of the labile 1-(3′-deoxy-4′,6′-O-isopropylidene-3′-methylene-β-d-glucopyranosyl-2′-ulose)pyrimidines 8a–c. Finally, deisopropylidenation of the resulted derivatives 8a–c afforded the diol nucleosides 9a–c. The target keto-exomethylene analogs 9a–c were more cytostatic against a variety of tumor cell lines than the corresponding saturated-hydroxy-exomethylene derivatives 6. In particular, the 5-fluorouracil derivative 9c was highly cytostatic at an IC50 (50% inhibitory concentration) ranging between 0.56 and 9.4 μg/mL, which was comparable to the free parental 5-fluorouracil base. 相似文献
79.
Niki M Takai S Kusuhara Y Ninomiya Y Yoshida R 《Cellular and molecular neurobiology》2011,31(7):1033-1040
In taste bud cells, glutamate may elicit two types of responses, as an umami tastant and as a neurotransmitter. Glutamate
applied to apical membrane of taste cells would elicit taste responses whereas glutamate applied to basolateral membrane may
act as a neurotransmitter. Using restricted stimulation to apical or basolateral membrane of taste cells, we examined responses
of taste cells to glutamate stimulation, separately. Apical application of monosodium glutamate (MSG, 0.3 M) increased firing
frequency in some of mouse fungiform taste cells that evoked action potentials. These cells were tested with other basic taste
compounds, NaCl (salty), saccharin (sweet), HCl (sour), and quinine (bitter). MSG-sensitive taste cells could be classified
into sweet-best (S-type), MSG-best (M-type), and NaCl or other electrolytes-best (N- or E/H-type) cells. Furthermore, S- and
M-type could be classified into two sub-types according to the synergistic effect between MSG and inosine-5′-monophosphate
(S1, M1 with synergism; S2, M2 without synergism). Basolateral application of glutamate (100 μM) had almost no effect on the
mean spontaneous firing rates in taste cells. However, about 10% of taste cells tested showed transient increases in spontaneous
firing rates (>mean + 2 standard deviation) after basolateral application of glutamate. These results suggest the existence
of multiple types of umami-sensitive taste cells and the existence of glutamate receptor(s) on the basolateral membrane of
a subset of taste cells. 相似文献
80.
Poornima Gopal Niki L Reynaert Jean L J M Scheijen Casper G Schalkwijk Frits M E Franssen Emiel F M Wouters Erica P A Rutten 《Respiratory research》2014,15(1):24