全文获取类型
收费全文 | 2537篇 |
免费 | 414篇 |
国内免费 | 42篇 |
专业分类
2993篇 |
出版年
2024年 | 10篇 |
2023年 | 86篇 |
2022年 | 134篇 |
2021年 | 210篇 |
2020年 | 198篇 |
2019年 | 197篇 |
2018年 | 167篇 |
2017年 | 98篇 |
2016年 | 96篇 |
2015年 | 138篇 |
2014年 | 211篇 |
2013年 | 180篇 |
2012年 | 140篇 |
2011年 | 140篇 |
2010年 | 105篇 |
2009年 | 97篇 |
2008年 | 91篇 |
2007年 | 120篇 |
2006年 | 106篇 |
2005年 | 62篇 |
2004年 | 62篇 |
2003年 | 54篇 |
2002年 | 39篇 |
2001年 | 30篇 |
2000年 | 23篇 |
1999年 | 19篇 |
1998年 | 14篇 |
1997年 | 25篇 |
1996年 | 10篇 |
1995年 | 15篇 |
1994年 | 15篇 |
1993年 | 9篇 |
1992年 | 15篇 |
1991年 | 10篇 |
1990年 | 14篇 |
1989年 | 9篇 |
1988年 | 6篇 |
1987年 | 4篇 |
1986年 | 2篇 |
1985年 | 4篇 |
1984年 | 5篇 |
1983年 | 2篇 |
1982年 | 4篇 |
1981年 | 2篇 |
1980年 | 3篇 |
1979年 | 2篇 |
1977年 | 2篇 |
1974年 | 3篇 |
1972年 | 1篇 |
1971年 | 1篇 |
排序方式: 共有2993条查询结果,搜索用时 15 毫秒
1.
《Developmental cell》2022,57(18):2221-2236.e5
- Download : Download high-res image (185KB)
- Download : Download full-size image
2.
Deborah Shaw Ian R. Poxton John R.W. Govan 《FEMS immunology and medical microbiology》1995,11(2):99-106
Abstract Burkholderia cepacia has emerged as an important multiresistant pathogen in cystic fibrosis (CF), associated in 20% of colonised patients with a rapid and fatal decline in lung function. Although knowledge of B. cepacia epidemiology has improved, the mechanisms involved in pathogenesis remain obscure. In this study, B. cepacia lipopolysaccharide (LPS) was assessed for endotoxic potential and the capacity to induce tumour necrosis factor (TNF). LPS preparations from clinical and environmental isolates of B. cepacia and from the closely related species Burkholderia gladioli exhibited a higher endotoxic activity and more pronounced cytokine response in vitro compared to preparations from the major CF pathogen Pseudomonas aeruginosa . This study may help to explain the vicious host immune response observed during pulmonary exacerbations in CF patients colonised by B. cepacia and lead to therapeutic advances in clinical management. 相似文献
3.
《European journal of cell biology》2022,101(3):151234
Patients with idiopathic pulmonary fibrosis (IPF) have a high risk of developing lung cancer compared with the general population. The morbidity of lung cancer in IPF patient ranges from 3% to 22%, and in some cases exceeds 50%, and these patients have a reduced survival time. However, the mechanisms through which IPF increases the morbidity and mortality in lung cancer remain unclear.By carefully analyzing the pathological features of these two diseases, we uncovered that, first, similar to IPF, lung carcinomas are more frequently found in the peripheral area of the lungs and, second, lung cancers tend to develop from the honeycomb areas in IPF. In accordance with the above pathological features, due to the spatial location, the peripheral areas of the lung experience a high stretch force because the average distance between adjacent alveolar cells in this area tends to be larger than that at the central lung when inflated; furthermore, the honeycomb areas, comprised of condensed fibrous tissue, are characterized by increased stiffness. Both of these pathological features of lung cancer and IPF are coincidentally related to abnormal mechanical forces (stretch and tissue stiffness). Therefore, we believe that the aberrant mechanical forces that are generated in the lung with IPF may contribute to the onset and progression of lung cancer.In this review, we discuss the possible effects of mechanical forces that are generated in IPF on the initiation and progression of lung cancer from the perspective of the hallmarks of cancer, including proliferation, metastasis, angiogenesis, cancer stem cells, immunology, epigenetics, and metabolism, so as to advance our understanding of the pathogenesis of IPF-related lung cancer and to harness these concepts for lung cancer mechanotherapies. 相似文献
4.
《Cryobiology》2019
The aim of the study was to investigate the effects of endovascular hypothermia on mitochondrial biogenesis in a pig model of prolonged cardiac arrest (CA). Ventricular fibrillation was electrically induced, and animals were left untreated for 10 min; then after 6min of cardiopulmonary resuscitation (CPR), defibrillation was attempted. 25 animals that were successfully resuscitated were randomized into three groups: Sham group (SG, 5, no CA), normal temperature group (NTG, 5 for 12 h observation and 5 for 24 h observation), and endovascular hypothermia group (EHG, 5 for 12 h observation and 5 for 24 h observation). The core temperatures (Tc) in the EHG were maintained at 34 ± 0.5 °C for 6 h by an endovascular hypothermia device (Coolgard 3000), then actively increased at the speed of 0.5 °C per hour during the next 6 h to achieve a normal body temperature, while Tc were maintained at 37.5 ± 0.5 °C in the NTG. Cardiac and mitochondrial functions, the quantification of myocardial mitochondrial DNA (mtDNA), peroxisome proliferator-activated receptor coactivator-1α (PGC-1α), nuclear respiratory factor (NRF)-1, and NRF-2 were examined. Results showed that myocardial and mitochondrial injury and dysfunction increased significantly at 12 h and 24 h after CA. Endovascular hypothermia offered a method to rapidly achieve the target temperature and provide stable target temperature management (TTM). Cardiac outcomes were improved and myocardial injuries were alleviated with endovascular hypothermia. Compared with NTG, endovascular hypothermia significantly increased mitochondrial activity and biogenesis by amplifying mitochondrial biogenesis factors’ expressions, including PGC-1α, NRF-1, and NRF-2. In conclusions, endovascular hypothermia after CA alleviated myocardial and mitochondrial dysfunction, and was associated with increasing mitochondrial biogenesis. 相似文献
5.
There have been numerous reports in the literature describing the diversity of microbial flora isolated from woodwind and brass instruments, with potential infection risks for players, especially when such instruments are shared. Steam disinfection has become established as a trusted method of decontamination; however, there have been no reports on the employment of this technology to disinfect parts of musical instruments, hence it was the aim of this study to examine the fate of bacterial and yeast pathogens on artificially contaminated trumpet mouthpieces and to evaluate whether such disinfection is an effective method of disinfection for such instrument parts. Trumpet mouthpieces were artificially contaminated with 18 microbial strains (17 bacteria from four genera (Enterococcus, Escherichia, Staphylococcus and Streptococcus) and one yeast (Candida)), each at an inoculum density of approximately 1·5 × 107 colony forming units and subjected to a disinfection cycle. The experiment was repeated including 50% (v/v) sterile sputum as soil. No bacteria or yeast organisms were recovered post disinfection, including following recovery and with nonselective cultural enrichment techniques. 相似文献
6.
Francis G. Spinale Rupak Mukherjee Juozas A. Zavadzkas Christine N. Koval Shenikqua Bouges Robert E. Stroud Lawrence W. Dobrucki Albert J. Sinusas 《The Journal of biological chemistry》2010,285(39):30316-30327
The membrane type-1 matrix metalloproteinase (MT1-MMP) is a unique member of the MMP family, but induction patterns and consequences of MT1-MMP overexpression (MT1-MMPexp), in a left ventricular (LV) remodeling process such as myocardial infarction (MI), have not been explored. MT1-MMP promoter activity (murine luciferase reporter) increased 20-fold at 3 days and 50-fold at 14 days post-MI. MI was then induced in mice with cardiac restricted MT1-MMPexp (n = 58) and wild type (WT, n = 60). Post-MI survival was reduced (67% versus 46%, p < 0.05), and LV ejection fraction was lower in the post-MI MT1-MMPexp mice compared with WT (41 ± 2 versus 32 ± 2%,p < 0.05). In the post-MI MT1-MMPexp mice, LV myocardial MMP activity, as assessed by radiotracer uptake, and MT1-MMP-specific proteolytic activity using a specific fluorogenic assay were both increased by 2-fold. LV collagen content was increased by nearly 2-fold in the post-MI MT1-MMPexp compared with WT. Using a validated fluorogenic construct, it was discovered that MT1-MMP proteolytically processed the pro-fibrotic molecule, latency-associated transforming growth factor-1 binding protein (LTBP-1), and MT1-MMP-specific LTBP-1 proteolytic activity was increased by 4-fold in the post-MI MT1-MMPexp group. Early and persistent MT1-MMP promoter activity occurred post-MI, and increased myocardial MT1-MMP levels resulted in poor survival, worsening of LV function, and significant fibrosis. A molecular mechanism for the adverse LV matrix remodeling with MT1-MMP induction is increased processing of pro-fibrotic signaling molecules. Thus, a proteolytically diverse portfolio exists for MT1-MMP within the myocardium and likely plays a mechanistic role in adverse LV remodeling. 相似文献
7.
L. Hove-Madsen H. Gesser 《Journal of comparative physiology. B, Biochemical, systemic, and environmental physiology》1989,159(1):61-69
Summary Isolated heart ventricular preparations from rainbow trout were electrically stimulated to contraction. Following a temporary change in stimulation rate from 0.2 Hz to a higher value, the force fell to a minimum after which it increased and levelled off. Upon the return to 0.2 Hz a further transient increase in force appeared. The latter two responses were stimulated by an increased extracellular K+, which is known to inactivate the Na+ channel. The initial negative inotropic effect, in contrast to the two subsequent positive effects, was associated with a parallel decrease in amplitude of the action potential measured in 15 mM K+, used as an index of the Ca2+ influx. One micromolar (1 M) ryanodine did not affect either the negative or the positive responses due to an increase in stimulation rate, but depressed the force developed after prolonged periods of rest. Ten micromolar (10 M) adrenaline strongly inhibited the positive effects of an elevation of frequency. An elevation of extracellular Na+ from 141 to 166 mM had a similar effect. In conclusion, the positive effects occurring in 15 mM K+ do not seem to depend on the initial Na+ current. They may nevertheless depend on changes of the cellular Na+ balance as suggested by the effects of adrenaline, K+ and Na+. The functional role of the sarcoplasmic reticulum is unclear. 相似文献
8.
9.
A biochemical link is proposed between recent observations on defective regulation of Cl– transport in CF respiratory epithelial cells and studies showing altered biological activity of calmodulin in exocrine glands from CF patients. A consensus is emerging that defective -adrenergic secretory responsiveness in CF cells is caused by a defect in a regulator protein at a site distal to cyclic AMP formation. Our results indicate that this protein might be a specific calmodulin acceptor protein which modifies the activity of calmodulin in epithelial cells. Alteration in Ca2+/calmodulin dependent regulation of Cl– transport and protein secretion could explain (i) alterations in Ca2+ homeostasis seen in CF, (ii) defective -adrenergic responses of CF cells, and (iii) the observed inability of cyclic AMP (acting via its specific protein kinase, A-kinase) to open apical membrane Cl– channels in CF epithelial cells. Most of the physiological abnormalities of CF including elevated sweat electrolytes and hyperviscous mucus can be explained on this basis.Abbreviations -adrenergic agonist acting at its receptor cAMP
cyclic AMP
- PDE
phosphodiesterase
- CaM
calmodulin
- Pase
phosphatase 相似文献
10.
Peter W. Achterberg Peter P. de Tombe Eef Harmsen Jan Willem de Jong 《Biochimica et Biophysica Acta (BBA)/General Subjects》1985,840(3):393-400
(1) The coronary vasodilator adenosine can be formed in the heart by breakdown of AMP or S-adenosylhomocysteine (SAdoHcy). The purpose of this study was to get insight into the relative importance of these routes of adenosine formation in both the normoxic and the ischemic heart. (2) A novel HPLC method was used to determine myocardial adenosine and SAdoHcy. Accumulation of SAdoHcy was induced in isolated rat hearts by perfusion with L-homocysteine thiolactone or L-homocysteine. The release of adenosine, inosine, hypoxanthine, xanthine and uric acid was determined. Additional in vitro experiments were performed to determine the kinteic parameters of S-adenosylhomocysteine hydrolase. (3) During normoxia the thiolactone caused a concentration-dependent increase in SAdoHcy. At 2000 μM of the thiolactone an SAdoHcy accumulation of 0.49 nmol/min per g wet weight was found during normoxia. L-Homocysteine (200 μM) caused an increased of 0.37 and 4.17 nmol SAdony/soc per g wet weight during normaxia and ischemia, respectively. (4) The adenosine concentration in ischemic hearts was significantly lower when homocysteine was infused (6.2 vs. 115 nmol/g; P < 0.05). Purine release was increased 4-fold during ischemia. (5) The Km for hydrolysis of SAdoHcy was about 12 μM. At in vitro conditions favoring near-maximal SAdoHcy synthesis (72 μM adenosine, 1.8 mM homocysteine), the synthesis rate in homogenates was 10 nmol/min per g wet weight. (6) From the combined in vitro and perfusion studies, we comclude that S-adenosylhomocysteine hydrolase can contribute significantly to adenosine production in normoxic rat heart, but not during ischemia. 相似文献