全文获取类型
收费全文 | 4175篇 |
免费 | 350篇 |
国内免费 | 5篇 |
专业分类
4530篇 |
出版年
2023年 | 23篇 |
2022年 | 65篇 |
2021年 | 100篇 |
2020年 | 55篇 |
2019年 | 72篇 |
2018年 | 100篇 |
2017年 | 79篇 |
2016年 | 150篇 |
2015年 | 218篇 |
2014年 | 236篇 |
2013年 | 310篇 |
2012年 | 336篇 |
2011年 | 320篇 |
2010年 | 198篇 |
2009年 | 175篇 |
2008年 | 219篇 |
2007年 | 227篇 |
2006年 | 221篇 |
2005年 | 222篇 |
2004年 | 209篇 |
2003年 | 205篇 |
2002年 | 172篇 |
2001年 | 45篇 |
2000年 | 34篇 |
1999年 | 39篇 |
1998年 | 57篇 |
1997年 | 42篇 |
1996年 | 29篇 |
1995年 | 27篇 |
1994年 | 18篇 |
1993年 | 24篇 |
1992年 | 24篇 |
1991年 | 14篇 |
1990年 | 22篇 |
1989年 | 22篇 |
1988年 | 15篇 |
1987年 | 15篇 |
1986年 | 10篇 |
1985年 | 18篇 |
1984年 | 19篇 |
1983年 | 11篇 |
1982年 | 10篇 |
1981年 | 13篇 |
1980年 | 20篇 |
1979年 | 17篇 |
1977年 | 7篇 |
1975年 | 7篇 |
1974年 | 8篇 |
1973年 | 9篇 |
1968年 | 7篇 |
排序方式: 共有4530条查询结果,搜索用时 15 毫秒
101.
102.
Mattsson C Rask E Carlström K Andersson J Eliasson M Ahrén B Söderberg S Olsson T 《Obesity (Silver Spring, Md.)》2007,15(4):887-894
Objective: Reduction of cortisone to cortisol is mediated by 11β‐hydroxysteroid dehydrogenase type 1 (11βHSD1), a putative key enzyme in obesity‐related complications. Experimental studies suggest that adipokines, notably leptin and tumor necrosis factor‐α (TNF‐α), are of importance for 11βHSD1 activity. We hypothesized that the regulation of hepatic preceptor glucocorticoid metabolism is gender‐specific and associated with circulating levels of leptin and TNF‐α receptors and/or sex hormones. Research Methods and Procedures: A total of 34 males and 38 women (14 premenopausal and 22 postmenopausal) underwent physical examination and fasting blood sampling. Insulin sensitivity was tested by euglycemic hyperinsulinemic clamps, and hepatic 11βHSD1 enzyme activity was estimated by the conversion of orally‐ingested cortisone to cortisol. Results: Hepatic 11βHSD1 activity was negatively associated with leptin and soluble TNF (sTNF) r1 and sTNFr2 in males. These correlations remained significant after adjustment for age and insulin sensitivity, and for sTNF‐α receptors also after adjustment of BMI and waist circumference. In contrast, 11β reduction of cortisone was positively associated to leptin in females after adjustment for BMI and waist circumference. Discussion: Hepatic 11β reduction shows different links to circulating adipocyte‐derived hormones in males and females. This emphasizes the need for further studies on tissue‐specific regulation of 11βHSD1 in both genders. 相似文献
103.
Parent overweight predicts daughters' increase in BMI and disinhibited overeating from 5 to 13 years
Objective: To assess whether parental overweight status and disinhibited overeating are predictive of daughters’ accelerated weight gain and disinhibited overeating. Research Methods and Procedures: Participants were part of a longitudinal study of girls (N = 197) and their parents. Measured height and weight were used to calculate BMI [weight (kilograms)/height (meters)2]. Parents’ disinhibited eating behavior was assessed using the Eating Inventory. Girls’ disinhibited eating was assessed using a behavioral protocol to measure eating in the absence of hunger. Girls were classified based on parental overweight at study entry into four groups: neither, mother only, father only, or both parents overweight. Results: Girls with both parents overweight had the most rapid increases in BMI from 5 to 13 years of age; BMI increased most slowly among the neither parent overweight group, with intermediate increases in BMI among mother only and father only overweight groups. Daughters with both parents overweight at study entry were eight times more likely to be overweight at age 13, controlling for daughters’ weight at age 5. Girls with both parents overweight had higher levels of disinhibited eating across all ages than all other groups. Although girls in all parental weight status groups showed increases in disinhibited eating over time, girls with both parents overweight had larger increases in disinhibited eating over time compared with all other groups. Discussion: Girls growing up in families differing in parental overweight had divergent developmental trajectories for BMI and disinhibited overeating. Findings reveal the need to focus prevention efforts on overweight parents of young children. 相似文献
104.
105.
Mirella Georgouli Cecilia Herraiz Eva Crosas-Molist Bruce Fanshawe Oscar Maiques Anna Perdrix Pahini Pandya Irene Rodriguez-Hernandez Kristina M. Ilieva Gaia Cantelli Panagiotis Karagiannis Silvia Mele Hoyin Lam Debra H. Josephs Xavier Matias-Guiu Rosa M. Marti Frank O. Nestle Jose L. Orgaz Victoria Sanz-Moreno 《Cell》2019,176(4):757-774.e23
106.
Leigh‐Ann Woolley Hayley M. Geyle Brett P. Murphy Sarah M. Legge Russell Palmer Christopher R. Dickman John Augusteyn Sarah Comer Tim S. Doherty Charlie Eager Glenn Edwards Dan K.P. Harley Ian Leiper Peter J. McDonald Hugh W. McGregor Katherine E. Moseby Cecilia Myers John L. Read Joanna Riley Danielle Stokeld Jeff M. Turpin John C.Z. Woinarski 《Mammal Review》2019,49(4):354-368
- 相似文献
107.
Cecilia Nigro Alessia Leone Michele Longo Immacolata Prevenzano Thomas H. Fleming Antonella Nicolò Luca Parrillo Rosa Spinelli Pietro Formisano Peter P. Nawroth Francesco Beguinot Claudia Miele 《生物化学与生物物理学报:疾病的分子基础》2019,1865(1):73-85
Impaired angiogenesis leads to long-term complications and is a major contributor of the high morbidity in patients with Diabetes Mellitus (DM). Methylglyoxal (MGO) is a glycolysis byproduct that accumulates in DM and is detoxified by the Glyoxalase 1 (Glo1). Several studies suggest that MGO contributes to vascular complications through mechanisms that remain to be elucidated. In this study we have clarified for the first time the molecular mechanism involved in the impairment of angiogenesis induced by MGO accumulation.Angiogenesis was evaluated in mouse aortic endothelial cells isolated from Glo1-knockdown mice (Glo1KD MAECs) and their wild-type littermates (WT MAECs). Reduction in Glo1 expression led to an accumulation of MGO and MGO-modified proteins and impaired angiogenesis of Glo1KD MAECs. Both mRNA and protein levels of the anti-angiogenic HoxA5 gene were increased in Glo1KD MAECs and its silencing improved both their migration and invasion. Nuclear NF-?B-p65 was increased 2.5-fold in the Glo1KD as compared to WT MAECs. Interestingly, NF-?B-p65 binding to HoxA5 promoter was also 2-fold higher in Glo1KD MAECs and positively regulated HoxA5 expression in MAECs. Consistent with these data, both the exposure to a chemical inhibitor of Glo1 “SpBrBzGSHCp2” (GI) and to exogenous MGO led to the impairment of migration and the increase of HoxA5 mRNA and NF-?B-p65 protein levels in microvascular mouse coronary endothelial cells (MCECs).This study demonstrates, for the first time, that MGO accumulation increases the antiangiogenic factor HoxA5 via NF-?B-p65, thereby impairing the angiogenic ability of endothelial cells. 相似文献
108.
109.
Augusto Varese Joy Nakawesi Ana Farias Freja C. M. Kirsebom Michelle Paulsen Rinat Nuriev Cecilia Johansson 《PLoS pathogens》2022,18(2)
Respiratory syncytial virus (RSV) can cause bronchiolitis and viral pneumonia in young children and the elderly. Lack of vaccines and recurrence of RSV infection indicate the difficulty in eliciting protective memory immune responses. Tissue resident memory T cells (TRM) can confer protection from pathogen re-infection and, in human experimental RSV infection, the presence of lung CD8+ TRM cells correlates with a better outcome. However, the requirements for generating and maintaining lung TRM cells during RSV infection are not fully understood. Here, we use mouse models to assess the impact of innate immune response determinants in the generation and subsequent expansion of the TRM cell pool during RSV infection. We show that CD8+ TRM cells expand independently from systemic CD8+ T cells after RSV re-infection. Re-infected MAVS and MyD88/TRIF deficient mice, lacking key components involved in innate immune recognition of RSV and induction of type I interferons (IFN-α/β), display impaired expansion of CD8+ TRM cells and reduction in antigen specific production of granzyme B and IFN-γ. IFN-α treatment of MAVS deficient mice during primary RSV infection restored TRM cell expansion upon re-challenge but failed to recover TRM cell functionality. Our data reveal how innate immunity, including the axis controlling type I IFN induction, instructs and regulates CD8+ TRM cell responses to RSV infection, suggesting possible mechanisms for therapeutic intervention. 相似文献
110.
Mariana Bresque Karina Cal Valentina Prez-Torrado Laura Colman Jorge Rodríguez-Duarte Cecilia Vilaseca Leonardo Santos María Pía Garat Santiago Ruiz Frances Evans Rosina Dapueto Paola Contreras Aldo Calliari Carlos Escande 《The Journal of biological chemistry》2022,298(3)
Acute and chronic inflammations are key homeostatic events in health and disease. Sirtuins (SIRTs), a family of NAD-dependent protein deacylases, play a pivotal role in the regulation of these inflammatory responses. Indeed, SIRTs have anti-inflammatory effects through a myriad of signaling cascades, including histone deacetylation and gene silencing, p65/RelA deacetylation and inactivation, and nucleotide‑binding oligomerization domain, leucine rich repeat, and pyrin domain‑containing protein 3 inflammasome inhibition. Nevertheless, recent findings show that SIRTs, specifically SIRT6, are also necessary for mounting an active inflammatory response in macrophages. SIRT6 has been shown to positively regulate tumor necrosis factor alpha (TNFα) secretion by demyristoylating pro-TNFα in the cytoplasm. However, how SIRT6, a nuclear chromatin-binding protein, fulfills this function in the cytoplasm is currently unknown. Herein, we show by Western blot and immunofluorescence that in macrophages and fibroblasts there is a subpopulation of SIRT6 that is highly unstable and quickly degraded via the proteasome. Upon lipopolysaccharide stimulation in Raw 264.7, bone marrow, and peritoneal macrophages, this population of SIRT6 is rapidly stabilized and localizes in the cytoplasm, specifically in the vicinity of the endoplasmic reticulum, promoting TNFα secretion. Furthermore, we also found that acute SIRT6 inhibition dampens TNFα secretion both in vitro and in vivo, decreasing lipopolysaccharide-induced septic shock. Finally, we tested SIRT6 relevance in systemic inflammation using an obesity-induced chronic inflammatory in vivo model, where TNFα plays a key role, and we show that short-term genetic deletion of SIRT6 in macrophages of obese mice ameliorated systemic inflammation and hyperglycemia, suggesting that SIRT6 plays an active role in inflammation-mediated glucose intolerance during obesity. 相似文献