全文获取类型
收费全文 | 25879篇 |
免费 | 1697篇 |
国内免费 | 80篇 |
专业分类
耳鼻咽喉 | 181篇 |
儿科学 | 811篇 |
妇产科学 | 625篇 |
基础医学 | 3924篇 |
口腔科学 | 449篇 |
临床医学 | 3725篇 |
内科学 | 4672篇 |
皮肤病学 | 451篇 |
神经病学 | 2718篇 |
特种医学 | 602篇 |
外科学 | 2126篇 |
综合类 | 173篇 |
一般理论 | 26篇 |
预防医学 | 2976篇 |
眼科学 | 446篇 |
药学 | 1888篇 |
1篇 | |
中国医学 | 58篇 |
肿瘤学 | 1804篇 |
出版年
2023年 | 193篇 |
2022年 | 297篇 |
2021年 | 716篇 |
2020年 | 473篇 |
2019年 | 641篇 |
2018年 | 781篇 |
2017年 | 553篇 |
2016年 | 608篇 |
2015年 | 796篇 |
2014年 | 913篇 |
2013年 | 1465篇 |
2012年 | 2038篇 |
2011年 | 2177篇 |
2010年 | 1134篇 |
2009年 | 1067篇 |
2008年 | 1768篇 |
2007年 | 1838篇 |
2006年 | 1789篇 |
2005年 | 1668篇 |
2004年 | 1583篇 |
2003年 | 1448篇 |
2002年 | 1273篇 |
2001年 | 169篇 |
2000年 | 132篇 |
1999年 | 175篇 |
1998年 | 220篇 |
1997年 | 169篇 |
1996年 | 163篇 |
1995年 | 119篇 |
1994年 | 128篇 |
1993年 | 110篇 |
1992年 | 77篇 |
1991年 | 90篇 |
1990年 | 76篇 |
1989年 | 79篇 |
1988年 | 48篇 |
1987年 | 49篇 |
1986年 | 50篇 |
1985年 | 50篇 |
1984年 | 69篇 |
1983年 | 73篇 |
1982年 | 71篇 |
1981年 | 49篇 |
1980年 | 51篇 |
1979年 | 36篇 |
1978年 | 23篇 |
1977年 | 26篇 |
1976年 | 24篇 |
1975年 | 19篇 |
1974年 | 22篇 |
排序方式: 共有10000条查询结果,搜索用时 562 毫秒
971.
972.
Agnes Mattsson Sandra E. Sylvan Anna Asklid Joel Wiggh Maria Winqvist Jeanette Lundin Larry Mansouri Richard Rosenquist Hemming Johansson Anders Österborg Lotta Hansson 《British journal of haematology》2020,191(3):426-432
Bendamustine + rituximab (BR) is the current first-line standard-of-care for chronic lymphocytic leukaemia (CLL) in fit patients aged 66–70 years, whereas chlorambucil + CD20 antibody is recommended in older patients with co-morbidities. This retrospective real-world study investigated whether risk-adapted BR was safe and effective in elderly patients. All 141 CLL patients in the Stockholm region (diagnosed from 2007 to 2016, identified from regional registries) who had received BR as first (n = 84) or later line (n = 57) were analysed. Median age was 72 years, 49% had Binet stage C, 40% had Cumulative Illness Rating Scale (CIRS) score ≥ 6, 20% Eastern Cooperative Oncology Group (ECOG) score 2. None had del(17p). Only 15% of patients aged ≥80 years received full-dose bendamustine and 65% of them postponed rituximab until cycle 2. Corresponding numbers in patients 73–79 years were 21% and 36% and in <73 years, 63% and 33%. Overall response rate was 83% (first line) and 67% (later line) (P < 0·022) equally distributed between age subsets. ECOG, immunoglobulin heavy chain variable region (IGHV) mutational status and cytogenetics, but not treatment line and age, were significant factors on progression-free survival (PFS) in multivariate analysis. Infections and neutropenia/thrombocytopenia (≥grade 3) were similar across age subgroups. In summary, BR was well tolerated even in patients ≥80 years, with similar efficacy and safety as in less old patients, provided that carefully adapted dosing was applied. 相似文献
973.
974.
975.
976.
977.
978.
Luís F. Ribeiro Tatiana Catarino Sandra D. Santos Marion Benoist J. Fiona van Leeuwen José A. Esteban Ana Luísa Carvalho 《Proceedings of the National Academy of Sciences of the United States of America》2014,111(1):E149-E158
Ghrelin is a peptide mainly produced by the stomach and released into circulation, affecting energy balance and growth hormone release. These effects are guided largely by the expression of the ghrelin receptor growth hormone secretagogue type 1a (GHS-R1a) in the hypothalamus and pituitary. However, GHS-R1a is expressed in other brain regions, including the hippocampus, where its activation enhances memory retention. Herein we explore the molecular mechanism underlying the action of ghrelin on hippocampal-dependent memory. Our data show that GHS-R1a is localized in the vicinity of hippocampal excitatory synapses, and that its activation increases delivery of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic-type receptors (AMPARs) to synapses, producing functional modifications at excitatory synapses. Moreover, GHS-R1a activation enhances two different paradigms of long-term potentiation in the hippocampus, activates the phosphatidylinositol 3-kinase, and increases GluA1 AMPAR subunit and stargazin phosphorylation. We propose that GHS-R1a activation in the hippocampus enhances excitatory synaptic transmission and synaptic plasticity by regulating AMPAR trafficking. Our study provides insights into mechanisms that may mediate the cognition-enhancing effect of ghrelin, and suggests a possible link between the regulation of energy metabolism and learning.The appetite-stimulating peptide ghrelin is a 28-aa peptide predominantly produced by X/A-like cells in the oxyntic glands of the stomach as well as in the intestine (1), and secreted into the blood stream. This peptide promotes pituitary growth hormone secretion, through activation of the growth hormone secretagogue type 1a receptor (GHS-R1a) or ghrelin receptor (2). Additionally, ghrelin is involved in the regulation of energy balance by increasing food intake and reducing fat utilization (3). Plasma ghrelin levels rise before meals and decrease thereafter (4), a pattern which is consistent with the implication of ghrelin in preprandial hunger and meal initiation. Ghrelin is secreted into the circulation and crosses the blood–brain barrier (5, 6), but there is also evidence for ghrelin synthesis locally in the brain (2, 7, 8). The GHS-R1a receptor mRNA was initially found in the hypothalamus and in the pituitary gland (9), and later detected in the hippocampus (10). GHS-R1a is a G protein-coupled seven-transmembrane domain receptor (3), which can signal through guanine nucleotide-binding protein (G protein) subunit alpha 11 (Gq class) to activate phosphatidylinositol-specific phospholipase C, generating 1,4,5-triphosphate (IP3) responsible for Ca2+ intracellular release from endoplasmic reticulum, and diacylglicerol, which in turn activates protein kinase C (PKC) (11). Ghrelin receptor activation is also coupled to the phosphatidylinositol 3 (PI3)-kinase signaling cascade in different cellular systems through a pertussis toxin-sensitive G protein (Gi/oα) (11), and to protein kinase A (PKA) in isolated hypothalamic neurons, modulating N-type Ca2+ channels (12).The finding that GHS-R1a is expressed in the hippocampus raises the possibility that ghrelin, similarly to other appetite-regulating hormones such as leptin (13), may affect brain functions other than those related to endocrine and metabolic regulation (14). Indeed, in the last few years several studies have shown that ghrelin increases memory retention in rodents, and that the hippocampus participates in this effect (6, 15–17). Ghrelin-deficient mice exhibit decreased novel object recognition, a type of memory test dependent on hippocampal function (6), suggesting that endogenous ghrelin has a physiological role in improving learning and memory. Additionally, high-fat and high-glucose diets, which inhibit ghrelin secretion (18, 19), impair hippocampus-dependent synaptic plasticity and spatial memory (20, 21). On the other hand, caloric restriction, which results in an increase in the circulating levels of ghrelin (22), decreases aging-related deficiencies in cognitive processes (23) while increasing learning consolidation and facilitating synaptic plasticity (24). Recent evidence suggests an enhancing effect of ghrelin on long-term potentiation (LTP) in the hippocampus (6, 17), a form of activity-dependent synaptic plasticity which is the cellular correlate for learning and memory (25). However, conclusive evidence is still lacking because one study did not observe effects of ghrelin on LTP induced by theta burst stimulation (6), whereas the other only detected effects of ghrelin on a late phase of LTP [2 h after high-frequency stimulation (17)].Although the function of ghrelin as a cognitive enhancer is well documented, the molecular mechanisms that underlie this function are still poorly understood. Here we have tested whether the activation of GHS-R1a affects the trafficking of α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors (AMPARs), crucial for the expression of changes in synaptic strength in the hippocampus (26). We report that GHS-R1a localizes to excitatory synapses and that its activation induces the synaptic delivery of GluA1-containing AMPAR (GluA1-AMPAR) in rat hippocampal cultures and in CA1 cells in organotypic hippocampal slices. These changes enhance excitatory synaptic transmission. Furthermore, we show that ghrelin receptor activation enhances LTP expression in the CA3–CA1 synapse in organotypic hippocampal slices, and increases the synaptic and cell-surface trafficking of GluA1-AMPAR induced by chemical LTP in hippocampal cultures. Finally, we demonstrate that ghrelin receptor activation in the hippocampus increases the phosphorylation of GluA1 and stargazin. Taken together our data indicate that ghrelin receptor activation regulates AMPARs trafficking underlying synaptic plasticity and learning. 相似文献
979.
980.
Xuguang Zhang Susan C. McGeoch Alexandra M. Johnstone Grietje Holtrop Alan A. Sneddon Sandra M. MacRury Ian L. Megson Donald W. M. Pearson Prakash Abraham Baukje De Roos Gerald E. Lobley Niamh O’Kennedy 《Journal of thrombosis and thrombolysis》2014,37(4):455-463
This study investigated the impact of either type 2 diabetes or obesity, separately or in combination, on the absolute amounts of microparticles (MP) and the pathways by which these are associated with either condition. The concentrations of circulating MP derived from platelets (PMP), leukocytes (LMP) and monocytes (MMP), together with their specific activation markers, were compared in 30 subjects who were characterised across 4 cohorts as obese or type 2 diabetes. The subjects with type 2 diabetes had elevated concentrations of total PMP (P = 0.003), and PMP that were fibrinogen-positive (P = 0.04), tissue factor-positive (P < 0.001), P-selectin-positive (P = 0.03). Type 2 diabetes did not alter either total or activated LMP or MMP. Obesity per se did not impact on any MP measurement. Elevated concentrations of plasma PMP occurred in subjects with type 2 diabetes, whether they were obese or non-obese. In contrast, obesity in the absence of type 2 diabetes had no effect. The increased concentrations of specific marker-positive PMP in the subjects with diabetes might reflect potential pathways by which PMP may contribute to the pathogenesis of atherosclerosis and type 2 diabetes. 相似文献