全文获取类型
收费全文 | 807篇 |
免费 | 77篇 |
国内免费 | 3篇 |
出版年
2023年 | 2篇 |
2022年 | 10篇 |
2021年 | 21篇 |
2020年 | 6篇 |
2019年 | 12篇 |
2018年 | 17篇 |
2017年 | 15篇 |
2016年 | 25篇 |
2015年 | 34篇 |
2014年 | 41篇 |
2013年 | 53篇 |
2012年 | 75篇 |
2011年 | 68篇 |
2010年 | 40篇 |
2009年 | 37篇 |
2008年 | 31篇 |
2007年 | 33篇 |
2006年 | 37篇 |
2005年 | 57篇 |
2004年 | 27篇 |
2003年 | 29篇 |
2002年 | 28篇 |
2001年 | 20篇 |
2000年 | 16篇 |
1999年 | 17篇 |
1998年 | 12篇 |
1997年 | 3篇 |
1996年 | 3篇 |
1995年 | 6篇 |
1994年 | 2篇 |
1992年 | 14篇 |
1991年 | 9篇 |
1990年 | 10篇 |
1989年 | 9篇 |
1988年 | 6篇 |
1987年 | 3篇 |
1986年 | 12篇 |
1985年 | 11篇 |
1984年 | 5篇 |
1983年 | 5篇 |
1982年 | 3篇 |
1979年 | 2篇 |
1977年 | 6篇 |
1976年 | 1篇 |
1975年 | 2篇 |
1974年 | 2篇 |
1972年 | 3篇 |
1969年 | 1篇 |
1967年 | 1篇 |
1966年 | 1篇 |
排序方式: 共有887条查询结果,搜索用时 15 毫秒
91.
BACKGROUND/AIMS: Turner's syndrome (TS) is associated with increased insulin resistance and adiposity, which might be associated with type 2 diabetes in later life. We aimed to determine whether the defect in insulin sensitivity is a primary intrinsic defect in TS or dependent on variation in body composition. METHODS: Sixteen women with TS not on growth hormone replacement but receiving oestrogen replacement therapy [age (mean +/- SD): 30.2 +/- 8.5 years; height-corrected fat-free mass: 26.1 +/- 3.1 kg/height] and a control group of 16 normal healthy women (age: 30.1 +/- 8.2 years; height-corrected fat-free mass: 25.9 +/- 2.4 kg/height) were studied. Fasting blood samples were obtained for measurement of glucose, insulin, IGF-I, IGFBP-1, IGFBP-3 and lipid levels. The hyperinsulinaemic euglycaemic clamp was performed to assess peripheral insulin sensitivity (M value), and the Homeostasis Model Assessment (HOMA-S) was used to estimate fasting insulin sensitivity. Body composition was assessed using a dual-energy X-ray absorptiometry scan. RESULTS: Fasting insulin sensitivity (HOMA-S 103.2 +/- 78.6 vs. 193.9 +/- 93.5, p = 0.006) was lower in TS subjects compared to controls as was whole-body insulin sensitivity (M value 2.9 +/- 1.9 vs. 5.5 +/- 2.6 mg/kg/min, p = 0.003). In a multiple regression analysis the Turner karyotype was significantly related to insulin sensitivity (p = 0.008) independent of any differences in fat-free mass and percent whole-body fat mass. CONCLUSION: The increased insulin resistance in women with TS is independent of measures of body composition and may represent an intrinsic defect related to their chromosomal abnormality. 相似文献
92.
Song D Yuen VG Yao L McNeill JH 《Canadian journal of physiology and pharmacology》2006,84(11):1139-1143
Previous experiments have shown that chronic estrogen treatment via subcutaneous implants prevented insulin-induced blood pressure elevation and increased insulin sensitivity in ovariectomized female rats. In vitro vascular studies were performed using isolated mesenteric arteries to determine the effect of chronic estrogen and insulin treatments on vascular responses to vasoconstrictor agents. Female Wistar rats were assigned to the following groups: sham-operated, sham-operated plus insulin, sham-operated plus insulin plus estrogen, ovariectomized, ovariectomized plus insulin, and ovariectomized plus insulin plus estrogen. Chronic insulin and estrogen treatments were initiated with subcutaneous placement of insulin implants (2 U/d) and 17beta-estradiol implants (0.5 mg/pellet, 60 day release) at the back of the neck. After 8 weeks of treatment, mesenteric arteries were isolated for assessment of constrictor responses to norepinephrine and the thromboxane A2 analogue U46619 in the presence or absence of the endothelium. The results show that chronic estrogen treatment attenuated the vascular constrictor responses to norepinephrine and U46619 only in endothelium intact vessels. Incubation with insulin did not significantly affect norepinephrine-induced vascular smooth muscle contraction. The study provides evidence that the mechanism by which estrogen prevents insulin-induced blood pressure elevation in insulin-treated ovariectomized rats is by influencing endothelium-derived vasoactive factors such as thromboxane A2. 相似文献
93.
Arikawa E Cheung C Sekirov I Battell ML Yuen VG McNeill JH 《Canadian journal of physiology and pharmacology》2006,84(8-9):823-833
Increased vasoconstrictor response to norepinephrine (NE) and endothelin (ET)-1 in arteries from diabetic animals is ameliorated by chronic endothelin receptor blockade with bosentan and was absent in endothelium-denuded arteries, suggesting the involvement of ET-1 and an endothelium-derived contracting factor such as thromboxane A2 (TxA2). To examine this possibility, we determined the effects of acute blockade of ET receptors or inhibition of TxA2 synthesis on the vascular function of superior mesenteric arteries (SMA) and renal arteries (RA) isolated from nondiabetic and 11-week streptozotocin (STZ) diabetic rats chronically treated with either bosentan or vehicle. Both in vitro incubation with bosentan and a selective ETA receptor blocker, BQ123, eradicated the increase in NE contractile responses in diabetic SMA. Additionally, in vitro incubation with the thromboxane synthase inhibitor, dazmegrel, abrogated the exaggerated NE and ET-1 contractile responses in diabetic SMA. Conversely, in RA, no significant acute effect of bosentan, BQ123, nor dazmegrel on vascular responses to NE was observed. Dazmegrel incubation attenuated the maximum contractile responses to ET-1 in diabetic RA; however, these responses in diabetic RA remained significantly greater than those of other groups. Diabetic RA but not SMA exhibited an enhanced contractile response to the TxA2 analogue U46619, which was corrected by chronic bosentan treatment. Immunohistochemical analyses in diabetic SMA revealed an increase in ETA receptor level that was normalized by chronic bosentan treatment. These data indicate that an interaction between ET-1 and TxA2 may be involved in mediating the exaggerated vasoconstrictor responses in diabetic arteries. Furthermore, the underlying mechanisms appear to be vessel specific. 相似文献
94.
Yuen B Boncompagni S Feng W Yang T Lopez JR Matthaei KI Goth SR Protasi F Franzini-Armstrong C Allen PD Pessah IN 《FASEB journal》2012,26(3):1311-1322
Mutation T4825I in the type 1 ryanodine receptor (RYR1(T4825I/+)) confers human malignant hyperthermia susceptibility (MHS). We report a knock-in mouse line that expresses the isogenetic mutation T4826I. Heterozygous RYR1(T4826I/+) (Het) or homozygous RYR1(T4826I/T4826I) (Hom) mice are fully viable under typical rearing conditions but exhibit genotype- and sex-dependent susceptibility to environmental conditions that trigger MH. Hom mice maintain higher core temperatures than WT in the home cage, have chronically elevated myoplasmic[Ca(2+)](rest), and present muscle damage in soleus with a strong sex bias. Mice subjected to heat stress in an enclosed 37°C chamber fail to trigger MH regardless of genotype, whereas heat stress at 41°C invariably triggers fulminant MH in Hom, but not Het, mice within 20 min. WT and Het female mice fail to maintain euthermic body temperature when placed atop a bed whose surface is 37°C during halothane anesthesia (1.75%) and have no hyperthermic response, whereas 100% Hom mice of either sex and 17% of the Het males develop fulminant MH. WT mice placed on a 41°C bed maintain body temperature while being administered halothane, and 40% of the Het females and 100% of the Het males develop fulminant MH within 40 min. Myopathic alterations in soleus were apparent by 12 mo, including abnormally distributed and enlarged mitochondria, deeply infolded sarcolemma, and frequent Z-line streaming regions, which were more severe in males. These data demonstrate that an MHS mutation within the S4-S5 cytoplasmic linker of RYR1 confers genotype- and sex-dependent susceptibility to pharmacological and environmental stressors that trigger fulminant MH and promote myopathy. 相似文献
95.
96.
Leelahavanichkul A Bocharov AV Kurlander R Baranova IN Vishnyakova TG Souza AC Hu X Doi K Vaisman B Amar M Sviridov D Chen Z Remaley AT Csako G Patterson AP Yuen PS Star RA Eggerman TL 《Journal of immunology (Baltimore, Md. : 1950)》2012,188(6):2749-2758
Class B scavenger receptors (SR-Bs), such as SR-BI/II or CD36, bind lipoproteins but also mediate bacterial recognition and phagocytosis. In evaluating whether blocking receptors can prevent intracellular bacterial proliferation, phagocyte cytotoxicity, and proinflammatory signaling in bacterial infection/sepsis, we found that SR-BI/II- or CD36-deficient phagocytes are characterized by a reduced intracellular bacterial survival and a lower cytokine response and were protected from bacterial cytotoxicity in the presence of antibiotics. Mice deficient in either SR-BI/II or CD36 are protected from antibiotic-treated cecal ligation and puncture (CLP)-induced sepsis, with greatly increased peritoneal granulocytic phagocyte survival (8-fold), a drastic diminution in peritoneal bacteria counts, and a 50-70% reduction in systemic inflammation (serum levels of IL-6, TNF-α, and IL-10) and organ damage relative to CLP in wild-type mice. The survival rate of CD36-deficient mice after CLP was 58% compared with 17% in control mice. When compensated for mineralocorticoid and glucocorticoid deficiency, SR-BI/II-deficient mice had nearly a 50% survival rate versus 5% in mineralo-/glucocorticoid-treated controls. Targeting SR-B receptors with L-37pA, a peptide that functions as an antagonist of SR-BI/II and CD36 receptors, also increased peritoneal granulocyte counts, as well as reduced peritoneal bacteria and bacterium-induced cytokine secretion. In the CLP mouse sepsis model, L-37pA improved survival from 6 to 27%, reduced multiple organ damage, and improved kidney function. These results demonstrate that the reduction of both SR-BI/II- and CD36-dependent bacterial invasion and inflammatory response in the presence of antibiotic treatment results in granulocyte survival and local bacterial containment, as well as reduces systemic inflammation and organ damage and improves animal survival during severe infections. 相似文献
97.
Gene P. Ables Kryscilla Jian Zhang Yang Silke Vogel Antonio Hernandez-Ono Shuiqing Yu Jason J. Yuen Susan Birtles Linda K. Buckett Andrew V. Turnbull Ira J. Goldberg William S. Blaner Li-Shin Huang Henry N. Ginsberg 《Journal of lipid research》2012,53(11):2364-2379
Acyl CoA:diacylglycerol acyltransferase (DGAT) 1 catalyzes the final step of
triglyceride (TG) synthesis. We show that acute administration of a DGAT1 inhibitor
(DGAT1i) by oral gavage or genetic deletion of intestinal Dgat1
(intestine-Dgat1−/−)
markedly reduced postprandial plasma TG and retinyl ester excursions by inhibiting
chylomicron secretion in mice. Loss of DGAT1 activity did not affect the efficiency
of retinol esterification, but it did reduce TG and retinoid accumulation in the
small intestine. In contrast, inhibition of microsomal triglyceride transfer protein
(MTP) reduced chylomicron secretion after oral fat/retinol loads, but with
accumulation of dietary TG and retinoids in the small intestine. Lack of intestinal
accumulation of TG and retinoids in DGAT1i-treated or
intestine-Dgat1−/− mice
resulted, in part, from delayed gastric emptying associated with increased plasma
levels of glucagon-like peptide (GLP)-1. However, neither bypassing the stomach
through duodenal oil injection nor inhibiting the receptor for GLP-1 normalized
postprandial TG or retinyl esters excursions in the absence of DGAT1 activity. In
summary, intestinal DGAT1 inhibition or deficiency acutely delayed gastric emptying
and inhibited chylomicron secretion; however, the latter occurred when gastric
emptying was normal or when lipid was administered directly into the small intestine.
Long-term hepatic retinoid metabolism was not impacted by DGAT1 inhibition. 相似文献
98.
Yuen HF Abramczyk O Montgomery G Chan KK Huang YH Sasazuki T Shirasawa S Gopesh S Chan KW Fennell D Janne P El-Tanani M Murray JT 《Bioscience reports》2012,32(4):413-422
Inhibition of the PI3K (phosphoinositide 3-kinase)/Akt/mTORC1 (mammalian target of rapamycin complex 1) and Ras/MEK [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase]/ERK pathways for cancer therapy has been pursued for over a decade with limited success. Emerging data have indicated that only discrete subsets of cancer patients have favourable responses to these inhibitors. This is due to genetic mutations that confer drug insensitivity and compensatory mechanisms. Therefore understanding of the feedback mechanisms that occur with respect to specific genetic mutations may aid identification of novel biomarkers that predict patient response. In the present paper, we show that feedback between the PI3K/Akt/mTORC1 and Ras/MEK/ERK pathways is cell-line-specific and highly dependent on the activating mutation of K-Ras or overexpression c-Met. We found that cell lines exhibited differential signalling and apoptotic responses to PD184352, a specific MEK inhibitor, and PI103, a second-generation class I PI3K inhibitor. We reveal that feedback from the PI3K/Akt/mTORC1 to the Ras/MEK/ERK pathway is present in cancer cells harbouring either K-Ras activating mutations or amplification of c-Met but not the wild-type counterparts. Moreover, we demonstrate that inhibition of protein phosphatase activity by OA (okadaic acid) restored PI103-mediated feedback in wild-type cells. Together, our results demonstrate a novel mechanism for feedback between the PI3K/Akt/mTORC1 and the Ras/MEK/ERK pathways that only occurs in K-Ras mutant and c-Met amplified cells but not the isogenic wild-type cells through a mechanism that may involve inhibition of a specific endogenous phosphatase(s) activity. We conclude that monitoring K-Ras and c-Met status are important biomarkers for determining the efficacy of PI103 and other PI3K/Akt inhibitors in cancer therapy. 相似文献
99.
Investigation of the biosynthetic potential of endophytes in traditional Chinese anticancer herbs 总被引:1,自引:0,他引:1
Traditional Chinese medicine encompasses a rich empirical knowledge of the use of plants for the treatment of disease. In addition, the microorganisms associated with medicinal plants are also of interest as the producers of the compounds responsible for the observed plant bioactivity. The present study has pioneered the use of genetic screening to assess the potential of endophytes to synthesize bioactive compounds, as indicated by the presence of non-ribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) genes. The total DNA extracts of 30 traditional Chinese herbs, were screened for functional genes involved in the biosynthesis of bioactive compounds. The four PCR screens were successful in targeting four bacterial PKS, six bacterial NRPS, ten fungal PKS and three fungal NRPS gene fragments. Analysis of the detected endophyte gene fragments afforded consideration of the possible bioactivity of the natural products produced by endophytes in medicinal herbs. This investigation describes a rapid method for the initial screening of medicinal herbs and has highlighted a subset of those plants that host endophytes with biosynthetic potential. These selected plants can be the focus of more comprehensive endophyte isolation and natural product studies. 相似文献
100.
Patrick C. Y. Woo Ching-Wan Lam Emily W. T. Tam Chris K. F. Leung Samson S. Y. Wong Susanna K. P. Lau Kwok-Yung Yuen 《PLoS neglected tropical diseases》2012,6(10)