全文获取类型
收费全文 | 1187篇 |
免费 | 91篇 |
出版年
2024年 | 2篇 |
2023年 | 2篇 |
2022年 | 7篇 |
2021年 | 25篇 |
2020年 | 15篇 |
2019年 | 19篇 |
2018年 | 14篇 |
2017年 | 22篇 |
2016年 | 20篇 |
2015年 | 47篇 |
2014年 | 59篇 |
2013年 | 78篇 |
2012年 | 120篇 |
2011年 | 80篇 |
2010年 | 44篇 |
2009年 | 41篇 |
2008年 | 81篇 |
2007年 | 77篇 |
2006年 | 73篇 |
2005年 | 79篇 |
2004年 | 65篇 |
2003年 | 77篇 |
2002年 | 52篇 |
2001年 | 8篇 |
2000年 | 12篇 |
1999年 | 17篇 |
1998年 | 19篇 |
1997年 | 14篇 |
1996年 | 8篇 |
1995年 | 11篇 |
1994年 | 10篇 |
1993年 | 4篇 |
1992年 | 10篇 |
1991年 | 5篇 |
1990年 | 5篇 |
1989年 | 4篇 |
1988年 | 2篇 |
1987年 | 5篇 |
1985年 | 5篇 |
1984年 | 4篇 |
1983年 | 2篇 |
1982年 | 2篇 |
1977年 | 4篇 |
1976年 | 2篇 |
1974年 | 5篇 |
1973年 | 4篇 |
1972年 | 3篇 |
1971年 | 2篇 |
1960年 | 1篇 |
1948年 | 4篇 |
排序方式: 共有1278条查询结果,搜索用时 15 毫秒
71.
Damien P. Higgins Tracey L. Rogers Andrew D. Irvine Sophie A. Hall-Aspland 《Marine Mammal Science》2002,18(2):483-499
We immobilized 200–550-kg leopard seals ( Hydrurga leptonyx ) on sea ice in Prydz Bay, Antarctica (68°25'S, 77°10'E) between November 1997 and February 2000. Midazolam (0.18–0.27 mg/kg)/ pethidine (1.0–1.5 mg/kg) was administered by dart to 16 leopard seals. Unpredictable immobilization, poor airway maintenance, and our inability to fully assess the suitability of flumazenil (0.003–0.01 mg/kg), naloxone (0.01–0.013 mg/kg), and naltrexone (0.05–0.12 mg/kg) as reversal agents limited suitability of midazolam/pethidine. Tiletamine/zolazepam 1:1 (0.5–1.5 mg/kg) was, therefore, administered to 19 leopard seals. It produced faster induction (19 ± 3 min), more effective and reliable response to dose (rank correlation: r s = 0.88, n = 18), and better pulmonary ventilation and faster return of cognitive function upon recovery, in comparison to midazolam/pethidine. Best results were achieved with tiletamine/zolazepam (1.2–1.4 mg/kg) which safely immobilized seven of nine seals for 20–30 min. Entry to the water upon darting was minimized, but not eliminated, by the use of lightweight air-pressurized darts and a thorough knowledge of leopard seal behavior. 相似文献
72.
Young RL Page AJ O'Donnell TA Cooper NJ Blackshaw LA 《American journal of physiology. Gastrointestinal and liver physiology》2007,292(2):G501-G511
Metabotropic glutamate receptors (mGluR) are classified into group I, II, and III mGluR. Group I (mGluR1, mGluR5) are excitatory, whereas group II and III are inhibitory. mGluR5 antagonism potently reduces triggering of transient lower esophageal sphincter relaxations and gastroesophageal reflux. Transient lower esophageal sphincter relaxations are mediated via a vagal pathway and initiated by distension of the proximal stomach. Here, we determined the site of action of mGluR5 in gastric vagal pathways by investigating peripheral responses of ferret gastroesophageal vagal afferents to graded mechanical stimuli in vitro and central responses of nucleus tractus solitarius (NTS) neurons with gastric input in vivo in the presence or absence of the mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP). mGluR5 were also identified immunohistochemically in the nodose ganglia and NTS after extrinsic vagal inputs had been traced from the proximal stomach. Gastroesophageal vagal afferents were classified as mucosal, tension, or tension-mucosal (TM) receptors. MPEP (1-10 microM) inhibited responses to circumferential tension of tension and TM receptors. Responses to mucosal stroking of mucosal and TM receptors were unaffected. MPEP (0.001-10 nmol icv) had no major effect on the majority of NTS neurons excited by gastric distension or on NTS neurons inhibited by distension. mGluR5 labeling was abundant in gastric vagal afferent neurons and sparse in fibers within NTS vagal subnuclei. We conclude that mGluR5 play a prominent role at gastroesophageal vagal afferent endings but a minor role in central gastric vagal pathways. Peripheral mGluR5 may prove a suitable target for reducing mechanosensory input from the periphery, for therapeutic benefit. 相似文献
73.
Cytoskeletal anchoring of GLAST determines susceptibility to brain damage: an identified role for GFAP 总被引:3,自引:0,他引:3
Sullivan SM Lee A Björkman ST Miller SM Sullivan RK Poronnik P Colditz PB Pow DV 《The Journal of biological chemistry》2007,282(40):29414-29423
Glial fibrillary acidic protein (GFAP) is an enigmatic protein; it currently has no unambiguously defined role. It is expressed in the cytoskeleton of astrocytes in the mammalian brain. We have used co-immunoprecipitation to identify in vivo binding partners for GFAP in the rat and pig brain. We demonstrate interactions between GFAP, the glutamate transporter GLAST, the PDZ-binding protein NHERF1, and ezrin. These interactions are physiologically relevant; we demonstrate in vitro that transport of D-aspartate (a glutamate analogue) is significantly increased in the presence of GFAP and NHERF1. Moreover, we demonstrate in vivo that expression of GFAP is essential in retaining GLAST in the plasma membranes of astrocytes after an hypoxic insult. These data indicate that the cytoskeleton of the astrocyte plays an important role in protecting the brain against glutamate-mediated excitotoxicity. 相似文献
74.
West Nile virus-induced neuroinflammation: glial infection and capsid protein-mediated neurovirulence
下载免费PDF全文
![点击此处可从《Journal of virology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
van Marle G Antony J Ostermann H Dunham C Hunt T Halliday W Maingat F Urbanowski MD Hobman T Peeling J Power C 《Journal of virology》2007,81(20):10933-10949
West Nile virus (WNV) infection causes neurological disease at all levels of the neural axis, accompanied by neuroinflammation and neuronal loss, although the underlying mechanisms remain uncertain. Given the substantial activation of neuroinflammatory pathways observed in WNV infection, we hypothesized that WNV-mediated neuroinflammation and cell death occurred through WNV infection of both glia and neurons, which was driven in part by WNV capsid protein expression. Analysis of autopsied neural tissues from humans with WNV encephalomyelitis (WNVE) revealed WNV infection of both neurons and glia. Upregulation of proinflammatory genes, CXCL10, interleukin-1beta, and indolamine-2',3'-deoxygenase with concurrent suppression of the protective astrocyte-specific endoplasmic reticulum stress sensor gene, OASIS (for old astrocyte specifically induced substance), was evident in WNVE patients compared to non-WNVE controls. These findings were supported by increased ex vivo expression of these proinflammatory genes in glia infected by WNV-NY99. WNV infection caused endoplasmic reticulum stress gene induction and apoptosis in neurons but did not affect glial viability. WNV-infected astrocytic cells secreted cytotoxic factors, which caused neuronal apoptosis. The expression of the WNV-NY99 capsid protein in neurons and glia by a Sindbis virus-derived vector (SINrep5-WNVc) caused neuronal death and the release of neurotoxic factors by infected astrocytes, coupled with proinflammatory gene induction and suppression of OASIS. Striatal implantation of SINrep5-WNV(C) induced neuroinflammation in rats, together with the induction of CXCL10 and diminished OASIS expression, compared to controls. Moreover, magnetic resonance neuroimaging showed edema and tissue injury in the vicinity of the SINrep5-WNVc implantation site compared to controls, which was complemented by neurobehavioral abnormalities in the SINrep5-WNVc-implanted animals. These studies underscore the important interactions between the WNV capsid protein and neuroinflammation in the pathogenesis of WNV-induced neurological disorders. 相似文献
75.
Athanasiou A Clarke AB Turner AE Kumaran NM Vakilpour S Smith PA Bagiokou D Bradshaw TD Westwell AD Fang L Lobo DN Constantinescu CS Calabrese V Loesch A Alexander SP Clothier RH Kendall DA Bates TE 《Biochemical and biophysical research communications》2007,364(1):131-137
Time-lapse microscopy of human lung cancer (H460) cells showed that the endogenous cannabinoid anandamide (AEA), the phyto-cannabinoid Δ-9-tetrahydrocannabinol (THC) and a synthetic cannabinoid HU 210 all caused morphological changes characteristic of apoptosis. Janus green assays of H460 cell viability showed that AEA and THC caused significant increases in OD 595 nm at lower concentrations (10-50 μM) and significant decreases at 100 μM, whilst HU 210 caused significant decreases at all concentrations. In rat heart mitochondria, all three ligands caused significant decreases in oxygen consumption and mitochondrial membrane potential. THC and HU 210 caused significant increases in mitochondrial hydrogen peroxide production, whereas AEA was without significant effect. All three ligands induced biphasic changes in either mitochondrial complex I activity and/or mitochondrial complex II-III activity. These data demonstrate that AEA, THC, and HU 210 are all able to cause changes in integrated mitochondrial function, directly, in the absence of cannabinoid receptors. 相似文献
76.
77.
Iron and citrate are essential for the metabolism of most organisms, and regulation of iron and citrate biology at both the
cellular and systemic levels is critical for normal physiology and survival. Mitochondrial and cytosolic aconitases catalyze
the interconversion of citrate and isocitrate, and aconitase activities are affected by iron levels, oxidative stress and
by the status of the Fe–S cluster biogenesis apparatus. Assembly and disassembly of Fe–S clusters is a key process not only
in regulating the enzymatic activity of mitochondrial aconitase in the citric acid cycle, but also in controlling the iron
sensing and RNA binding activities of cytosolic aconitase (also known as iron regulatory protein IRP1). This review discusses
the central role of aconitases in intermediary metabolism and explores how iron homeostasis and Fe–S cluster biogenesis regulate
the Fe–S cluster switch and modulate intracellular citrate flux. 相似文献
78.
In vitro anti-mycobacterial activities of several 5-substituted acyclic pyrimidine nucleosides containing 1-(2-hydroxyethoxy)methyl and 1-[(2-hydroxy-1-(hydroxymethyl) ethoxy)methyl] acyclic moieties are investigated against three mycobacteria viz. Mycobacterium tuberculosis, Mycobacterium bovis, and Mycobacterium avium, which cause serious infections and mortality in healthy people as well as patients with AIDS. 1-(2-Hydroxyethoxy)methyl-5-(1-azido-2-haloethyl or 1-azidovinyl) analogs (4-7), 1-[(2-hydroxy-1-(hydroxymethyl)ethoxy)methyl]-5-decynyluracil (37), and 1-[(2-hydroxy-1-(hydroxymethyl)ethoxy)methyl]-5-dodecynyluracil (38) exhibited significant in vitro anti-tubercular activity against these mycobacteria. 相似文献
79.
Cholinergic anti-inflammatory pathway activity and High Mobility Group Box-1 (HMGB1) serum levels in patients with rheumatoid arthritis 总被引:2,自引:0,他引:2
Goldstein RS Bruchfeld A Yang L Qureshi AR Gallowitsch-Puerta M Patel NB Huston BJ Chavan S Rosas-Ballina M Gregersen PK Czura CJ Sloan RP Sama AE Tracey KJ 《Molecular medicine (Cambridge, Mass.)》2007,13(3-4):210-215
High Mobility Group Box-1 (HMGB1) is a cytokine implicated in the pathogenesis of rheumatoid arthritis (RA) and other inflammatory diseases. The cholinergic anti-inflammatory pathway, a vagus nerve-dependent mechanism, inhibits HMGB1 release in experimental disease models. Here, we examine the relationship between vagus nerve activity and HMGB1 in patients with RA. We compared RR interval variability, an index of cardiac vagal modulation, HMGB1 and hsCRP serum levels, and disease activity scores in thirteen RA patients and eleven age- and sex-matched controls. In RA patients, serum levels of HMGB1 and hsCRP were elevated as compared with controls (HMGB1=71 ng/mL [45-99] vs. 18 ng/mL [0-40], P<0.0001; hsCRP=14.5 mg/L [0.7-59] vs. 1 mg/L [0.4-2.9], P<0.001). RR interval variability in RA patients was significantly decreased as compared with controls (HF=38 msec2 [14-80] vs. 288 msec2 [38-364], P<0.0001; rMSSD=20.9+/-9.79 msec, 52.6+/-35.3 msec, P<0.01). HMGB1 levels and RR interval variability were significantly related (rho=-0.49, P<0.01). HMGB1 serum levels significantly correlated with disease activity scores (DAS-28) in patients with RA (P=0.004). The study design does not enable a determination of causality, but the results are consistent with the hypothesis that decreased cholinergic anti-inflammatory pathway activity is associated with increased HMGB1 levels in patients with RA. 相似文献
80.
RR interval variability is inversely related to inflammatory markers: the CARDIA study 总被引:4,自引:0,他引:4
Sloan RP McCreath H Tracey KJ Sidney S Liu K Seeman T 《Molecular medicine (Cambridge, Mass.)》2007,13(3-4):178-184
Recent evidence reveals that the immune system is under the direct control of the vagus nerve via the "cholinergic anti-inflammatory pathway." Stimulation of vagus nerve activity significantly inhibits cytokine levels in animal models, and cholinergic agents inhibit cytokine release by human macrophages. Moreover, when vagus nerve activity is decreased or absent, cytokines are overproduced. Atherosclerosis is an inflammatory disease characterized by elevated levels of CRP and IL-6, but the relationship between cardiac vagal activity and cytokine levels in healthy humans is not well understood. Here we measured RR interval variability, an index of cardiac vagal modulation, and CRP and IL-6 in 757 subjects participating in a subset of the year 15 data collection in the CARDIA study of the evolution of risk factors in young adults. Univariate analysis revealed that all indices of RRV were strongly and inversely related to IL-6 (log pg/mL b=-0.08 and -0.17 for HF and LF power, P<0.001 respectively) and CRP (log mg/L b=-0.14 and -0.26 for HF and LF power, P<0.001 respectively) levels. In the multivariate model including gender, race, age, smoking, physical activity, SBP, BMI, and disease, the inverse relationship between RRV and inflammatory markers, although slightly attenuated, remained significant. These findings are consistent with the hypothesis that diminished descending vagal anti-inflammatory signals can allow cytokine overproduction in humans. 相似文献