全文获取类型
收费全文 | 1460篇 |
免费 | 106篇 |
国内免费 | 3篇 |
出版年
2023年 | 5篇 |
2022年 | 11篇 |
2021年 | 21篇 |
2020年 | 10篇 |
2019年 | 8篇 |
2018年 | 14篇 |
2017年 | 17篇 |
2016年 | 35篇 |
2015年 | 50篇 |
2014年 | 62篇 |
2013年 | 84篇 |
2012年 | 112篇 |
2011年 | 107篇 |
2010年 | 69篇 |
2009年 | 54篇 |
2008年 | 83篇 |
2007年 | 86篇 |
2006年 | 92篇 |
2005年 | 89篇 |
2004年 | 97篇 |
2003年 | 73篇 |
2002年 | 56篇 |
2001年 | 9篇 |
2000年 | 5篇 |
1999年 | 13篇 |
1998年 | 15篇 |
1997年 | 12篇 |
1996年 | 10篇 |
1995年 | 12篇 |
1994年 | 15篇 |
1993年 | 11篇 |
1991年 | 8篇 |
1990年 | 9篇 |
1989年 | 9篇 |
1988年 | 8篇 |
1987年 | 5篇 |
1986年 | 11篇 |
1985年 | 7篇 |
1984年 | 7篇 |
1983年 | 5篇 |
1982年 | 9篇 |
1981年 | 12篇 |
1980年 | 12篇 |
1979年 | 7篇 |
1977年 | 6篇 |
1975年 | 7篇 |
1974年 | 8篇 |
1973年 | 6篇 |
1971年 | 7篇 |
1962年 | 5篇 |
排序方式: 共有1569条查询结果,搜索用时 15 毫秒
31.
Anne Chevrel Agnes Mesneau Dyana Sanchez Louisa Celma Sophie Quevillon-Cheruel Andrea Cavagnino Sylvie Nessler Ines Li de la Sierra-Gallay Herman van Tilbeurgh Philippe Minard Marie Valerio-Lepiniec Agathe Urvoas 《Journal of structural biology》2018,201(2):88-99
We have previously described a highly diverse library of artificial repeat proteins based on thermostable HEAT-like repeats, named αRep. αReps binding specifically to proteins difficult to crystallize have been selected and in several examples, they made possible the crystallization of these proteins. To further simplify the production and crystallization experiments we have explored the production of chimeric proteins corresponding to covalent association between the targets and their specific binders strengthened by a linker. Although chimeric proteins with expression partners are classically used to enhance expression, these fusions cannot usually be used for crystallization. With specific expression partners like a cognate αRep this is no longer true, and chimeric proteins can be expressed purified and crystallized. αRep selection by phage display suppose that at least a small amount of the target protein should be produced to be used as a bait for selection and this might, in some cases, be difficult. We have therefore transferred the αRep library in a new construction adapted to selection by protein complementation assay (PCA). This new procedure allows to select specific binders by direct interaction with the target in the cytoplasm of the bacteria and consequently does not require preliminary purification of target protein. αRep binders selected by PCA or by phage display can be used to enhance expression, stability, solubility and crystallogenesis of proteins that are otherwise difficult to express, purify and/or crystallize. 相似文献
32.
Agnes Simonyi Yan He Wenwen Sheng Albert Y. Sun W. Gibson Wood Gary A. Weisman Grace Y. Sun 《Molecular neurobiology》2010,41(2-3):73-86
Alzheimer’s disease (AD) is marked by an increase in the production of extracellular beta amyloid plaques and intracellular neurofibrillary tangles associated with a decline in brain function. Increases in oxidative stress are regarded as an early sign of AD pathophysiology, although the source of reactive oxygen species (ROS) and the mechanism(s) whereby beta amyloid peptides (Aβ) impact oxidative stress have not been adequately investigated. Recent studies provide strong evidence for the involvement of NADPH oxidase and its downstream oxidative signaling pathways in the toxic effects elicited by Aβ. ROS produced by NADPH oxidase activate multiple signaling pathways leading to neuronal excitotoxicity and glial cell-mediated inflammation. This review describes recent studies demonstrating the neurotoxic effects of Aβ in conjunction with ROS produced by NADPH oxidase and the downstream pathways leading to activation of cytosolic phospholipase A2 (PLA2) and secretory PLA2. In addition, this review also describes recent studies using botanical antioxidants to protect against oxidative damage associated with AD. Investigating the metabolic and signaling pathways involving Aβ NADPH oxidase and PLA2 can help understand the mechanisms underlying the neurodegenerative effects of oxidative stress in AD. This information should provide new therapeutic approaches for prevention of this debilitating disease. 相似文献
33.
The pathophysiology of Alzheimer's disease (AD) is comprised of complex metabolic abnormalities in different cell types in the brain. To date, there are not yet effective drugs that can completely inhibit the pathophysiological event, and efforts have been devoted to prevent or minimize the progression of this disease. Much attention has focused on studies to understand aberrant functions of the ionotropic glutamate receptors, perturbation of calcium homeostasis, and toxic effects of oligomeric amyloid beta peptides (Aβ) which results in production of reactive oxygen and nitrogen species and signaling pathways, leading to mitochondrial dysfunction and synaptic impairments. Aberrant phospholipase A(2) (PLA(2)) activity has been implicated to play a role in the pathogenesis of many neurodegenerative diseases, including AD. However, mechanisms for their modes of action and their roles in the oxidative and nitrosative signaling pathways have not been firmly established. In this article, we review recent studies providing a metabolic link between cytosolic PLA(2) (cPLA(2)) and neuronal excitation due to stimulation of ionotropic glutamate receptors and toxic Aβ peptides. The requirements for Ca(2+) binding together with its posttranslational modifications by protein kinases and possible by the redox-based S-nitrosylation, provide strong support for a dynamic role of cPLA(2) in serving multiple functions to neurons and glial cells under abnormal physiological and pathological conditions. Therefore, understanding mechanisms for cPLA(2) in the oxidative and nitrosative pathways in neurons will allow the development of novel therapeutic targets to mitigate the detrimental effects of AD. 相似文献
34.
McGinty D Metes A Alam MN Megirian D Stewart D Szymusiak R 《American journal of physiology. Regulatory, integrative and comparative physiology》2004,286(6):R1129-R1137
Upper airway dilator activity during sleep appears to be diminished under conditions of enhanced sleep propensity, such as after sleep deprivation, leading to worsening of obstructive sleep apnea (OSA). Non-rapid eye movement (NREM) sleep propensity originates in sleep-active neurons of the preoptic area (POA) of the hypothalamus and is facilitated by activation of POA warm-sensitive neurons (WSNs). We hypothesized that activation of WSNs by local POA warming would inhibit activity of the posterior cricoarytenoid (PCA) muscle, an airway dilator, during NREM sleep. In chronically prepared unrestrained cats, the PCA exhibited inspiratory bursts in approximate synchrony with inspiratory diaphragmatic activity during waking, NREM, and REM. Integrated inspiratory PCA activity (IA), peak activity (PA), and the lead time (LT) of the onset of inspiratory activity in PCA relative to diaphragm were significantly reduced in NREM sleep and further reduced during REM sleep compared with waking. Mild bilateral local POA warming (0.5-1.2 degrees C) significantly reduced IA, PA, and LT during NREM sleep compared with a prewarming NREM baseline. In some animals, effects of POA warming on PCA activity were found during waking or REM. Because POA WSN activity is increased during spontaneous NREM sleep and regulates sleep propensity, we hypothesize that this activation contributes to reduction of airway dilator activity in patients with OSA. 相似文献
35.
Stockton JC Howson JM Awomoyi AA McAdam KP Blackwell JM Newport MJ 《FEMS immunology and medical microbiology》2004,41(2):157-160
The nucleotide oligomerization binding domain 2 gene (NOD2) encodes an intracellular receptor for bacterial components, which is expressed in monocytes and is associated with Crohn's Disease (CD). This finding, along with epidemiological evidence, supports a role for infection in the pathogenesis of CD. Speculation that mycobacteria are involved in CD led us to investigate NOD2 in susceptibility to tuberculosis (TB), a global public health problem caused by Mycobacterium tuberculosis. CD-associated NOD2 variants were absent in a case-control study of 640 Gambians, where CD is rare. Novel NOD2 promoter polymorphisms were identified but showed no association with TB in this African population sample. 相似文献
36.
Conlon JM Al-Ghaferi N Abraham B Sonnevend A Coquet L Leprince J Jouenne T Vaudry H Iwamuro S 《Comparative biochemistry and physiology. Toxicology & pharmacology : CBP》2006,143(1):42-49
The Tsushima brown frog Rana tsushimensis Stejneger, 1907 exists in reproductive isolation on the island of Tsushima, Japan. Six peptides with antimicrobial activity were isolated in pure form from an extract of the skin of this species and their amino acid sequences identified them as members of the brevinin-1 (one peptide), brevinin-2 (one peptide) and temporin (four peptides) families. The C-terminally alpha-amidated brevinin-1 peptide (FLGSIVGALASALPSLISKIRN.NH2) lacks the cyclic heptapeptide domain Cys18-(Xaa)4-Lys-Cys24 at the COOH-terminus of the molecule that characterizes other members of that family. A structurally similar brevinin-1 peptide, also lacking the cyclic domain, was previously isolated from the skin of the Ryukyu brown frog Rana okinavana, indicative of a close phylogenetic relationship between the species. Brevinin-2TSa (GIMSLFKGVLKTAGKHVAGSLVDQLKCKITGGC) showed broad-spectrum growth inhibitory activity against a range of Gram-negative and Gram-positive bacteria (including methicillin-resistant Staphylococcus aureus) (minimum inhibitory concentrations< or =25 microM) and relatively low hemolytic activity against human erythrocytes (LD50=100 microM). The peptide therefore represents a candidate for drug development. 相似文献
37.
Akunyili AA Alfatlawi M Upadhyaya B Rhoads LS Eichelberger H Van Bell CT 《The Journal of eukaryotic microbiology》2008,55(3):207-213
Tetrahymena has been shown to ingest and inactivate bacteriophages, such as T4, in co-incubation experiments. In this study, Tetrahymena thermophila failed to inactivate phages PhiX174 and MS2 in co-incubations, although PhiX174 were ingested by T. thermophila, as demonstrated by: (1) recovery at defecation in a pulse-chase experiment, (2) recovery from Tetrahymena by detergent lysis, and (3) transmission electron microscopy. We conclude, therefore, that the phages must be digestion-resistant. Internalized PhiX174 were further shown to be partially protected from lethal damage by ultraviolet (UV) C and UVB irradiation. Finally, ingested PhiX174 were shown to be rapidly transported through buffer in a horizontal swimming, race tube-like assay. The transport and protection of phages may confer evolutionary advantages that explain the acquisition of digestion-resistance by some phages. 相似文献
38.
39.
40.
Tazeen Hasan Jafar Ngiap Chuan Tan Rupesh Madhukar Shirore John Carson Allen Eric Andrew Finkelstein Siew Wai Hwang Agnes Ying Leng Koong Peter Kirm Seng Moey Gary Chun-Yun Kang Chris Wan Teng Goh Reena Chandhini Subramanian Anandan Gerard Thiagarajah Chandrika Ramakrishnan Ching Wee Lim Jianying Liu for SingHypertension Study Group 《PLoS medicine》2022,19(6)
BackgroundDespite availability of clinical practice guidelines for hypertension management, blood pressure (BP) control remains sub-optimal (<30%) even in high-income countries. This study aims to assess the effectiveness of a potentially scalable multicomponent intervention integrated into primary care system compared to usual care on BP control.Methods and findingsA cluster-randomized controlled trial was conducted in 8 government clinics in Singapore. The trial enrolled 916 patients aged ≥40 years with uncontrolled hypertension (systolic BP (SBP) ≥140 mmHg or diastolic BP (DBP) ≥90 mmHg).Multicomponent intervention consisted of physician training in risk-based treatment of hypertension, subsidized losartan-HCTZ single-pill combination (SPC) medications, nurse training in motivational conversations (MCs), and telephone follow-ups. Usual care (controls) comprised of routine care in the clinics, no MC or telephone follow-ups, and no subsidy on SPCs. The primary outcome was mean SBP at 24 months’ post-baseline. Four clinics (447 patients) were randomized to intervention and 4 (469) to usual care. Patient enrolment commenced in January 2017, and follow-up was during December 2018 to September 2020. Analysis used intention-to-treat principles. The primary outcome was SBP at 24 months. BP at baseline, 12 and 24 months was modeled at the patient level in a likelihood-based, linear mixed model repeated measures analysis with treatment group, follow-up, treatment group × follow-up interaction as fixed effects, and random cluster (clinic) effects.A total of 766 (83.6%) patients completed 2-year follow-up. A total of 63 (14.1%) and 87 (18.6%) patients in intervention and in usual care, respectively, were lost to follow-up. At 24 months, the adjusted mean SBP was significantly lower in the intervention group compared to usual care (−3.3 mmHg; 95% CI: −6.34, −0.32; p = 0.03). The intervention led to higher BP control (odds ratio 1.51; 95% CI: 1.10, 2.09; p = 0.01), lower odds of high (>20%) 10-year cardiovascular risk score (OR 0.67; 95% CI: 0.47, 0.97; p = 0.03), and lower mean log albuminuria (−0.22; 95% CI: −0.41, −0.02; p = 0.03). Mean DBP, mortality rates, and serious adverse events including hospitalizations were not different between groups. The main limitation was no masking in the trial.ConclusionsA multicomponent intervention consisting of physicians trained in risk-based treatment, subsidized SPC medications, nurse-delivered motivational conversation, and telephone follow-ups improved BP control and lowered cardiovascular risk. Wide-scale implementation of a multicomponent intervention such as the one in our trial is likely to reduce hypertension-related morbidity and mortality globally.Trial registrationTrial Registration: Clinicaltrials.gov .Tazeen H Jafar and colleagues present findings from a cluster-randomized controlled trial conducted to evaluate the effectiveness of an intervention designed to manage hypertension. NCT02972619相似文献