全文获取类型
收费全文 | 3755篇 |
免费 | 249篇 |
专业分类
4004篇 |
出版年
2023年 | 19篇 |
2022年 | 38篇 |
2021年 | 56篇 |
2020年 | 48篇 |
2019年 | 62篇 |
2018年 | 87篇 |
2017年 | 73篇 |
2016年 | 94篇 |
2015年 | 159篇 |
2014年 | 157篇 |
2013年 | 245篇 |
2012年 | 306篇 |
2011年 | 230篇 |
2010年 | 159篇 |
2009年 | 151篇 |
2008年 | 195篇 |
2007年 | 205篇 |
2006年 | 209篇 |
2005年 | 174篇 |
2004年 | 158篇 |
2003年 | 135篇 |
2002年 | 158篇 |
2001年 | 86篇 |
2000年 | 59篇 |
1999年 | 56篇 |
1998年 | 58篇 |
1997年 | 42篇 |
1996年 | 37篇 |
1995年 | 32篇 |
1994年 | 25篇 |
1993年 | 20篇 |
1992年 | 34篇 |
1991年 | 48篇 |
1990年 | 37篇 |
1989年 | 37篇 |
1988年 | 22篇 |
1987年 | 24篇 |
1986年 | 28篇 |
1985年 | 22篇 |
1984年 | 34篇 |
1983年 | 13篇 |
1982年 | 21篇 |
1981年 | 19篇 |
1980年 | 14篇 |
1979年 | 13篇 |
1978年 | 20篇 |
1977年 | 10篇 |
1976年 | 16篇 |
1975年 | 8篇 |
1974年 | 12篇 |
排序方式: 共有4004条查询结果,搜索用时 0 毫秒
991.
S Benedini L Dalle Carbonare N Albiger M Scanarini F Bilora F Petrobelli S Giannini F Mantero C Scaroni 《Hormones et métabolisme》2006,38(1):16-21
OBJECTIVE: This study examines the effects of growth hormone replacement on body composition, insulin sensitivity, lipid profile, endothelial dysfunction and carotid intima media thickness in patients with adult-onset growth-hormone (GH) deficiency. METHODS: Twelve patients with severe GH deficiency received GH replacement for one year. In all patients, the following parameters were evaluated before and after six and twelve months of therapy: fasting glucose, insulin levels and lipid profile, bone mineral density and body composition. Carotid intima media thickness and brachial flow-mediated dilatation were also evaluated by arterial ultrasonography at basal condition and after one year of therapy. RESULTS: No significant changes were seen in body weight and blood pressure, total fat and lean mass, or bone mineral density after six months of GH replacement. There was an increase in triglycerides (p = 0.05), while total and HDL cholesterol, blood glucose, insulin levels did not change significantly. After twelve months, an increase in lean mass and a decrease in fat mass (p < 0.01 vs. baseline), a decrease in insulin resistance (p < 0.01 vs. six months; p = 0.01 vs. baseline) and a decrease in triglycerides (p < 0.01) were observed. Intima media thickness was greater in GH deficiency than in controls (p = 0.01) before therapy, and was unchanged after twelve months of therapy, whereas the flow-mediated dilatation tended to improve (p = 0.05). CONCLUSIONS: GH replacement is able to reverse typical metabolic and body composition alterations in patients with adult GH deficiency after twelve months, but it is unable to revert the vascular alteration completely. Flow-mediated dilatation seems to be a more precocious marker of the remission of arterial damage. 相似文献
992.
Crisafulli A Salis E Pittau G Lorrai L Tocco F Melis F Pagliaro P Concu A 《American journal of physiology. Heart and circulatory physiology》2006,291(6):H3035-H3042
Accumulation of metabolic end products within skeletal muscle stimulates sensory nerves, thus evoking a pressor response termed "metaboreflex." The aim of this study was to evaluate changes in hemodynamics occurring during metaboreflex activation obtained by postexercise muscle ischemia (PEMI) after two different exercise intensities. In twelve healthy subjects, the metaboreflex was studied with the PEMI method at the start of recovery from one leg-dynamic knee extension performed at intensities of 30% (PEMI 30%) and 70% (PEMI 70%) of the maximum workload achieved in a preliminary test. Control exercise recovery tests at the same intensities were also conducted. Central hemodynamics were evaluated by means of impedance cardiography. The main findings were that 1) during metaboreflex, exercise conducted against the higher workload caused a more pronounced blood pressure increase than the strain conducted against the lower workload; and 2) during PEMI 70%, this blood pressure response was mainly achieved through enhancement of myocardial contractility that increased stroke volume and, in turn, cardiac output, whereas during PEMI 30%, the blood pressure response was reached predominantly by means of vasoconstriction. Thus a substantial enhancement of myocardial contractility was reached only in the PEMI 70% test. These results suggest that hemodynamic regulation during metaboreflex engagement caused by PEMI in humans is dependent on the intensity of the previous effort. Moreover, the cardiovascular response during metaboreflex is not merely achieved by vasoconstriction alone, but it appears that there is a complex interplay between peripheral vasoconstriction and heart contractility recruitment. 相似文献
993.
Franco SJ Senetar MA Simonson WT Huttenlocher A McCann RO 《Cell motility and the cytoskeleton》2006,63(9):563-581
The cytoskeletal protein Talin1 is a critical link between integrins and the actin cytoskeleton, where it is required for the structural and signaling functions of integrin-containing adhesion complexes. However, the elements in Talin1 that are responsible for localizing it to adhesion complexes are not known. In this report we have used a series of constructs based on the modular structure of Talin1 to determine the structural elements that specify the subcellular localization of Talin1. We show that the conserved actin-binding I/LWEQ module at the C-terminus of Talin1 is necessary and sufficient for targeting to focal adhesion complexes. We also used truncation and site-directed mutagenesis to demonstrate that this novel targeting function correlates with, but is separable from, the actin-binding properties of the Talin1 I/LWEQ module. In addition, we have shown that focal adhesion targeting, unlike actin binding, is not conserved among I/LWEQ module proteins. Finally, we have demonstrated that the subcellular localization of the Talin1 I/LWEQ module is regulated by an intrasteric interaction with an upstream alpha-helix, suggesting that both the actin binding and adhesion-targeting elements are masked in full-length Talin1. Our results define a novel role for the I/LWEQ module as the primary adhesion-complex targeting determinant of Talin1 and suggest that pathways that can relieve inhibition of I/LWEQ module function will be important for regulating the structural and signaling properties of adhesion complexes. 相似文献
994.
Bordetella pertussis, the causative agent of whooping cough, produces a complex hetero-oligomeric exotoxin, named pertussis toxin (PTX), which is responsible for several of the clinical manifestations associated with whooping cough. The toxin is composed of five dissimilar subunits, named S1 through S5 and arranged in a hexameric structure with a 1S1:1S2:1S3:2S4:1S5 stoichiometry. Although S2 and S3 share 70% amino acid identity, these two subunits were previously thought not to be able to substitute for each other in toxin assembly/secretion and the biological activities of PTX. Here, we show that toxin analogues containing two S3 subunits and lacking S2 (PTXdeltaS2), or containing two S2 subunits and lacking S3 (PTXdeltaS3), can be produced, assembled and secreted by B. pertussis strains, in which the S2-encoding cistron or the S3-coding cistrons have been inactivated by internal in-frame deletions that avoid downstream effects. In fact, PTXdeltaS3 was produced in higher amounts in the bacterial culture supernatants than natural PTX, whereas PTXdeltaS2 was produced in lower amounts than PTX. The action of the toxin analogues on the clustering of Chinese Hamster Ovary cells was also affected differentially by the S2-S3 substitution. These toxin analogues constitute thus interesting probes for the study of cellular functions, in particular immune cell functions, for which natural PTX has already shown its usefulness. 相似文献
995.
Chimenti F Secci D Bolasco A Chimenti P Granese A Carradori S Befani O Turini P Alcaro S Ortuso F 《Bioorganic & medicinal chemistry letters》2006,16(15):4135-4140
A novel series of N,N'-bis[2-oxo-2H-1-benzopyran]-3-carboxamide derivatives have been synthesized and investigated for the ability to inhibit the activity of the A and B isoforms of monoamine oxidase (MAO). Some of the synthesized compounds show good selective inhibitory activity against the MAO-A isoform. Both the MAO-A and -B isoforms, deposited in the Protein Data Bank as the 2BXR and 1GOS models, respectively, were considered in a computational study performed with docking techniques on the most active and selective inhibitors. 相似文献
996.
McClure KF Letavic MA Kalgutkar AS Gabel CA Audoly L Barberia JT Braganza JF Carter D Carty TJ Cortina SR Dombroski MA Donahue KM Elliott NC Gibbons CP Jordan CK Kuperman AV Labasi JM Laliberte RE McCoy JM Naiman BM Nelson KL Nguyen HT Peese KM Sweeney FJ Taylor TJ Trebino CE Abramov YA Laird ER Volberg WA Zhou J Bach J Lombardo F 《Bioorganic & medicinal chemistry letters》2006,16(16):4339-4344
The synthesis, structure-activity relationship, in vivo activity, and metabolic profile for a series of triazolopyridine-oxazole based p38 inhibitors are described. The deficiencies of the lead structure in the series, CP-808844, were overcome by changes to the C4 aryl group and the triazole side-chain culminating in the identification of several potential clinical candidates. 相似文献
997.
De Angeli A Monachello D Ephritikhine G Frachisse JM Thomine S Gambale F Barbier-Brygoo H 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2009,364(1514):195-201
Plants need nitrate for growth and store the major part of it in the central vacuole of cells from root and shoot tissues. Based on few studies on the two model plants Arabidopsis thaliana and rice, members of the large ChLoride Channel (CLC) family have been proposed to encode anion channels/transporters involved in nitrate homeostasis. Proteins from the Arabidopsis CLC family (AtClC, comprising seven members) are present in various membrane compartments including the vacuolar membrane (AtClCa), Golgi vesicles (AtClCd and AtClCf) or chloroplast membranes (AtClCe). Through a combination of electrophysiological and genetic approaches, AtClCa was shown to function as a 2NO3-/1H+ exchanger that is able to accumulate specifically nitrate into the vacuole, in agreement with the main phenotypic trait of knockout mutant plants that accumulate 50 per cent less nitrate than their wild-type counterparts. The set-up of a functional complementation assay relying on transient expression of AtClCa cDNA in the mutant background opens the way for studies on structure-function relationships of the AtClCa nitrate transporter. Such studies will reveal whether important structural determinants identified in bacterial or mammalian CLCs are also crucial for AtClCa transport activity and regulation. 相似文献
998.
Ana Carolina C. Asbahr Luzia Franco Andersson Barison Caroline W.P. Silva Humberto G. Ferraz Letícia N.C. Rodrigues 《Bioorganic & medicinal chemistry》2009,17(7):2718-2723
The aim of this study was to determine whether inclusion complexes between 2-hydroxypropyl-β-cyclodextrin (HPβCD) and finasteride (FIN) are formed, and to characterize these. Equimolar FIN/HPβCD solid systems in the presence or absence of 0.1% (w/v) of polyvinylpyrrolidone K30 (PVP K30) or 0.3% of chitosan were prepared by coevaporation and freeze-drying methods. The systems were characterized by phase solubility, NMR, DSC, and XRD analysis. The results suggest that true binary and ternary inclusion complexes were formed. 相似文献
999.
Nicoletta Bodrato Luisa Franco Chiara Fresia Lucrezia Guida Cesare Usai Annalisa Salis Iliana Moreschi Chiara Ferraris Claudia Verderio Giovanna Basile Santina Bruzzone Sonia Scarf�� Antonio De Flora Elena Zocchi 《The Journal of biological chemistry》2009,284(22):14777-14787
Abscisic acid (ABA) is a phytohormone regulating important functions in
higher plants, notably responses to abiotic stress. Recently, chemical or
physical stimulation of human granulocytes was shown to induce production and
release of endogenous ABA, which activates specific cell functions. Here we
provide evidence that ABA stimulates several functional activities of the
murine microglial cell line N9 (NO and tumor necrosis factor-α
production, cell migration) through the second messenger cyclic ADP-ribose and
an increase of intracellular calcium. ABA production and release occur in N9
cells stimulated with bacterial lipopolysaccharide, phorbol myristate acetate,
the chemoattractant peptide f-MLP, or β-amyloid, the primary plaque
component in Alzheimer disease. Finally, ABA priming stimulates N9 cell
migration toward β-amyloid. These results indicate that ABA is a
pro-inflammatory hormone inducing autocrine microglial activation, potentially
representing a new target for anti-inflammatory therapies aimed at limiting
microglia-induced tissue damage in the central nervous system.Microglial cells are the monocyte/macrophage equivalent of the central
nervous system and represent the first line of defense in the brain, by
removing infectious agents and damaged cells
(1). Microglia can also release
a variety of trophic factors and cytokines able to regulate the communication
between neuronal and other glial cells and can contribute to tissue repair and
neuroprotection
(2–4).
Pathologic microglial activation, however, confers neurotoxic properties to
these cells, thereby causing neuronal degeneration
(5). Excessive activation of
microglia, under conditions of chronic inflammation, can contribute to the
pathogenesis of neurodegenerative diseases, such as multiple sclerosis and
Alzheimer and Parkinson diseases, by producing and releasing a number of
potentially cytotoxic substances, including pro-inflammatory cytokines and NO
(4,
6–8).
Therefore, identification of the molecular mechanisms underlying microglial
activation might lead to the development of new anti-inflammatory drugs for
the treatment of these diseases.Abscisic acid
(ABA)2 is a plant
hormone regulating important biological functions in higher plants, including
response to abiotic stress, control of stomatal closure, regulation of seed
dormancy, and germination (9).
Recently, ABA was shown to behave as an endogenous pro-inflammatory hormone in
human granulocytes (10),
stimulating several functional activities of these cells (migration,
phagocytosis, reactive oxygen species, and NO production) through a signaling
cascade that involves a protein kinase A-mediated ADP-ribosyl cyclase
phosphorylation and consequent overproduction of the universal Ca2+
mobilizer cyclic ADP-ribose (cADPR)
(11). This mechanism leads to
an increase of the intracellular Ca2+ concentration, which is
ultimately responsible for granulocyte activation
(10).The facts that microglial cells play a defensive role in the central
nervous system similar to that of granulocytes in other tissues and that cADPR
has been described as the second messenger involved in the activation of
microglia induced by lipopolysaccharide (LPS)
(12) prompted us to
investigate the effect of ABA in these cells.Indeed, exogenous ABA, at concentrations ranging from 250 nm to
20 μm, elicits functional activation of murine N9 cells,
stimulating TNF-α release and cell migration through activation of the
ADP-ribosyl cyclase CD38 and overproduction of cADPR. Moreover, N9 cells
produce and release ABA when stimulated with LPS, amyloid β-peptide
(βA), phorbol myristate acetate (PMA), or the chemoattractant peptide
f-MLP. These results indicate that ABA behaves as an endogenous,
pro-inflammatory hormone in murine microglia and provide a new target for
future investigations into the role of this hormone in inflammatory and
degenerative diseases of the central nervous system accompanied by microglial
activation. 相似文献
1000.
Shira Corem Armando Carpaneto Paolo Soliani Laura Cornara Franco Gambale Joachim Scholz-Starke 《European biophysics journal : EBJ》2009,38(4):495-501
We applied the patch-clamp technique to investigate the transport properties of the Slow Vacuolar (SV) channel identified
in leaf vacuoles of Alyssum bertolonii Desv., a nickel hyperaccumulator plant growing in serpentine soil of the northern Apennines (Italy). SV currents recorded
in vacuoles from adult plants collected in their natural habitat showed high sensitivity towards cytosolic nickel. Dose-response
analyses indicated half-maximal current inhibition at submicromolar concentrations, i.e. up to three orders of magnitude lower
than previously reported values from other plant species. The voltage-dependent increase of residual currents at saturating
nickel concentrations could be interpreted as relief of channel block by nickel permeation at high positive membrane potentials.
Including young plants of A. bertolonii into the study, we found that SV channels from these plants did not display elevated nickel sensitivity. This difference
may be related to age-dependent changes in nickel hyperaccumulation of A. bertolonii leaf cells. 相似文献