全文获取类型
收费全文 | 1409篇 |
免费 | 89篇 |
国内免费 | 2篇 |
专业分类
1500篇 |
出版年
2023年 | 5篇 |
2022年 | 11篇 |
2021年 | 19篇 |
2020年 | 10篇 |
2019年 | 8篇 |
2018年 | 14篇 |
2017年 | 17篇 |
2016年 | 35篇 |
2015年 | 49篇 |
2014年 | 62篇 |
2013年 | 82篇 |
2012年 | 111篇 |
2011年 | 107篇 |
2010年 | 68篇 |
2009年 | 51篇 |
2008年 | 83篇 |
2007年 | 82篇 |
2006年 | 90篇 |
2005年 | 89篇 |
2004年 | 97篇 |
2003年 | 72篇 |
2002年 | 57篇 |
2001年 | 9篇 |
1999年 | 13篇 |
1998年 | 15篇 |
1997年 | 10篇 |
1996年 | 9篇 |
1995年 | 11篇 |
1994年 | 14篇 |
1993年 | 11篇 |
1991年 | 7篇 |
1990年 | 7篇 |
1989年 | 8篇 |
1988年 | 6篇 |
1987年 | 5篇 |
1986年 | 6篇 |
1985年 | 6篇 |
1984年 | 6篇 |
1982年 | 7篇 |
1981年 | 9篇 |
1980年 | 9篇 |
1979年 | 5篇 |
1978年 | 4篇 |
1977年 | 6篇 |
1975年 | 4篇 |
1974年 | 5篇 |
1971年 | 5篇 |
1962年 | 5篇 |
1935年 | 4篇 |
1912年 | 4篇 |
排序方式: 共有1500条查询结果,搜索用时 15 毫秒
71.
T cell activation-induced mitochondrial hyperpolarization is mediated by Ca2+- and redox-dependent production of nitric oxide 总被引:5,自引:0,他引:5
Activation, proliferation, or programmed cell death of T lymphocytes is regulated by the mitochondrial transmembrane potential (Deltapsi(m)) through controlling ATP synthesis, production of reactive oxygen intermediates (ROI), and release of cell death-inducing factors. Elevation of Deltapsi(m) or mitochondrial hyperpolarization is an early and reversible event associated with both T cell activation and apoptosis. In the present study, T cell activation signals leading to mitochondrial hyperpolarization were investigated. CD3/CD28 costimulation of human PBL elevated cytoplasmic and mitochondrial Ca(2+) levels, ROI production, and NO production, and elicited mitochondrial hyperpolarization. Although T cell activation-induced Ca(2+) release, ROI levels, and NO production were diminished by inositol 1,4,5-triphosphate receptor antagonist 2-aminoethoxydiphenyl borane, superoxide dismutase mimic manganese (III) tetrakis (4-benzoic acid) porphyrin chloride, spin trap 5-diisopropoxyphosphoryl-5-methyl-1-pyrroline-N-oxide, and NO chelator carboxy-2-phenyl-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide, mitochondrial hyperpolarization was selectively inhibited by carboxy-2-phenyl-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide (-85.0 +/- 10.0%; p = 0.008) and, to a lesser extent, by 2-aminoethoxydiphenyl borane. Moreover, NO precursor (Z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate diethylenetriamine elicited NO and ROI production, Ca(2+) release, transient ATP depletion, and robust mitochondrial hyperpolarization (3.5 +/- 0.8-fold; p = 0.002). Western blot analysis revealed expression of Ca-dependent endothelial NO synthase and neuronal NO synthase isoforms and absence of Ca-independent inducible NO synthase in PBL. CD3/CD28 costimulation or H(2)O(2) elicited severalfold elevations of endothelial NO synthase and neuronal NO synthase expression, as compared with beta-actin. H(2)O(2) also led to moderate mitochondrial hyperpolarization; however, Ca(2+) influx by ionomycin or Ca(2+) release from intracellular stores by thapsigargin alone failed to induce NO synthase expression, NO production, or Deltapsi(m) elevation. The results suggest that T cell activation-induced mitochondrial hyperpolarization is mediated by ROI- and Ca(2+)-dependent NO production. 相似文献
72.
73.
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
74.
Madritsch Silvia Bomers Svenja Posekany Alexandra Burg Agnes Birke Rebekka Emerstorfer Florian Turetschek Reinhard Otte Sandra Eigner Herbert Sehr Eva M. 《Plant molecular biology》2020,104(4-5):379-380
Plant Molecular Biology - In the above mentioned publication, part of Fig. 6B was distorted (extra diagonal lines appeared). The original article has been corrected and the proper version... 相似文献
75.
T lymphocyte activation is associated with nitric oxide (NO) production, which plays an essential role in multiple T cell functions. NO acts as a messenger, activating soluble guanyl cyclase and participating in the transduction signaling pathways involving cyclic GMP. NO modulates mitochondrial events that are involved in apoptosis and regulates mitochondrial membrane potential and mitochondrial biogenesis in many cell types, including lymphocytes. Mitochondrial hyperpolarization (MHP), an early and reversible event during both activation and apoptosis of Tlymphocytes, is regulated by NO. Here, we discuss recent evidence that NO-induced MHP represents a molecular switch in multiple T cell signaling pathways. Overproduction of NO in systemic lupus erythematosus induces mitochondrial biogenesis and alters Ca(2+) signaling. Thus, whereas NO plays a physiological role in lymphocyte cell signaling, its overproduction may disturb normal T cell function, contributing to the pathogenesis of autoimmunity. 相似文献
76.
Méreau A Le Sommer C Lerivray H Lesimple M Hardy S 《Biology of the cell / under the auspices of the European Cell Biology Organization》2007,99(1):55-65
An increasing number of genes are being identified for which the corresponding mRNAs contain different combinations of the encoded exons. This highly regulated exon choice, or alternative splicing, is often tissue-specific and potentially could differentially affect cellular functions. Alternative splicing is therefore not only a means to increase the coding capacity of the genome, but also to regulate gene expression during differentiation or development. To both evaluate the importance for cellular functions and define the regulatory pathways of alternative splicing, it is necessary to progress from the in vitro or ex vivo experimental models actually used towards in vivo whole-animal studies. We present here the amphibian, Xenopus, as an experimental model highly amenable for such studies. The various experimental approaches that can be used with Xenopus oocytes and embryos to characterize regulatory sequence elements and factors are presented and the advantages and drawbacks of these approaches are discussed. Finally, the real possibilities for large-scale identification of mRNAs containing alternatively spliced exons, the tissue-specific patterns of exon usage and the way in which these patterns are modified by perturbing the relative amount of splicing factors are discussed. 相似文献
77.
Stumvoll S Lidholm J Thunberg R DeWitt AM Eibensteiner P Swoboda I Bugajska-Schretter A Spitzauer S Vangelista L Kazemi-Shirazi L Sperr WR Valent P Kraft D Valenta R 《Biological chemistry》2002,383(9):1383-1396
Almost 500 million people worldwide suffer from Type I allergy, a genetically determined immunodisorder which is based on the production of IgE antibodies against per se harmless antigens (allergens). Due to their worldwide distribution and heavy pollen production, grasses represent a major allergen source for approximately 40% of allergic patients. We purified Phl p 4, a major timothy grass (Phleum pratense) pollen allergen with a molecular mass of 61.3 kDa and a pl of 9.6 to homogeneity. Circular dichroism spectroscopical analysis indicates that Phl p 4 contains a mixed alpha-helical/beta-pleated secondary structure and, unlike many other allergens, showed no reversible unfolding after thermal denaturation. We show that Phl p 4 is a major allergen which reacts with IgE antibodies of 75% of grass pollen allergic patients (n=150) and induces basophil histamine release as well as immediate type skin reactions in sensitized individuals. Phl p 4-specific IgE from three patients as well as two rabbit-anti Phl p 4 antisera cross-reacted with allergens present in pollen of trees, grasses, weeds as well as plant-derived food. Rabbit antibodies raised against Phl p 4 also inhibited the binding of allergic patients IgE to Phl p 4. Phl p 4 may thus be used for diagnosis and treatment of sensitized allergic patients. 相似文献
78.
Cytochrome oxidase in health and disease 总被引:19,自引:0,他引:19
Yeast and bovine cytochrome c oxidases (COX) are composed of 12 and 13 different polypeptides, respectively. In both cases, the three subunits constituting the catalytic core are encoded by mitochondrial DNA. The other subunits are all products of nuclear genes that are translated on cytoplasmic ribosomes and imported through different transport routes into mitochondria. Biogenesis of the functional complex depends on the expression of all the structural and more than two dozen COX-specific genes. The latter impinge on all aspects of the biogenesis process. Here we review the current state of information about the functions of the COX-specific gene products and of their relationship to human COX deficiencies. 相似文献
79.
80.
Houman H Hamzaoui A Ben Ghorbal I Khanfir MS Feki M Hamzaoui K 《Mediators of inflammation》2004,13(4):247-253
BACKGROUND: Peripheral blood CD8+ T cells expressing interferon gamma and interleukin-4 (IL-4), and lacking CD28 molecules, were responsible for the dynamic interplay between peripheral blood and inflammatory sites. INTRODUCTION: The aim of the current study was to define in Behçet''s disease (BD), CD8+ T-cell subsets using CD28 and CD11b monoclonal antibodies, and the characterization of the Tc1/Tc2 ratio and perforin expression. METHODS: Flow cytometry was used for intracytoplasmic cytokines and perforin expression. Effector cells were investigated by adhesion of CD8+ T cells to human microvascular endothelial cells and by chemotaxis using beta-chemokine. RESULTS: Interferon-gamma-producing CD8+ T cells in active and remission BD patients were increased, which induce a significant increase of the Tc1:Tc2 ratio in BD. CD8(+)CD28(-)CD11b+ T cells were found to be more expanded in BD patients than in age-matched healthy controls. The expression of CD11b molecules in active BD allowed to CD8(+)CD28+/CD8(+)CD28- subsets to adhere to human microvascular endothelial cells, with more efficiency in BD. Using MIP-1alpha, we observed that the migratory process of CD28(-)CD11b(+) is more important in BD. CD28(-)CD11b+ exhibited an increased perforin expression in BD patients. CONCLUSION: Taken together these results suggest the presence of immune activation, probably in response to a profound inflammation affecting BD patients. The physiopathological significance of these results were toward autoimmune diseases and/or infectious process. 相似文献