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941.
Macrophages (mϕ) from pre-diseased mice of the major murine inbred models of spontaneous autoimmunity (AI), including multiple lupus-prone strains and the type I diabetes-prone NOD (non-obese diabetic) strain, have identical apoptotic target-dependent abnormalities. This characteristic feature of mϕ from AI-prone mice suggests that abnormal signaling events induced within mϕ following their interaction with apoptotic targets may predispose to AI. Such signaling abnormalities would affect predominantly the processing and presentation of self-antigen (i.e., derived from apoptotic targets), while sparing the processing and presentation of foreign antigen (i.e., derived from non-apoptotic sources). Here, we used DNA microarrays to test the hypothesis that mϕ from AI-prone mice (MRL/MpJ [MRL/+] or MRL/MpJ-Tnfrsf6 lpr [MRL/lpr]) differentially express multiple genes in comparison to non-AI mϕ (BALB/c), but do so in a largely apoptotic cell-dependent manner. Mϕ were stimulated with lipopolysaccharide, a potent innate stimulus, in the presence or absence of serum (an experimental surrogate for apoptotic targets). In accord with our hypothesis, the number of genes differentially expressed by MRL mϕ was significantly increased in the presence vs. the absence of serum, the apoptotic target surrogate (n = 401 vs. n = 201). Notably, for genes differentially expressed by MRL mϕ in the presence of serum, serum-free culture normalized their expression to a level statistically indistinguishable from that by non-AI mϕ. Comparisons of mϕ from AI-prone NOD and non-AI C57BL/6 mice corroborated these findings. Together, these data support the hypothesis that mϕ from MRL and other AI-prone mice are characterized by a conditional abnormality elicited by serum lipids or apoptotic targets.  相似文献   
942.
Polycystic ovary syndrome (PCOS) is a variable disorder characterized by a broad spectrum of anomalies, including hyperandrogenemia, insulin resistance, dyslipidemia, body adiposity, low-grade inflammation and increased cardiovascular disease risks. Recently, a new polytherapy consisting of low-dose flutamide, metformin and pioglitazone in combination with an estro-progestagen resulted in the regulation of endocrine clinical markers in young and non-obese PCOS women. However, the metabolic processes involved in this phenotypic amelioration remain unidentified. In this work, we used NMR and MS-based untargeted metabolomics to study serum samples of young non-obese PCOS women prior to and at the end of a 30 months polytherapy receiving low-dose flutamide, metformin and pioglitazone in combination with an estro-progestagen. Our results reveal that the treatment decreased the levels of oxidized LDL particles in serum, as well as downstream metabolic oxidation products of LDL particles such as 9- and 13-HODE, azelaic acid and glutaric acid. In contrast, the radiuses of small dense LDL and large HDL particles were substantially increased after the treatment. Clinical and endocrine-metabolic markers were also monitored, showing that the level of HDL cholesterol was increased after the treatment, whereas the level of androgens and the carotid intima-media thickness were reduced. Significantly, the abundance of azelaic acid and the carotid intima-media thickness resulted in a high degree of correlation. Altogether, our results reveal that this new polytherapy markedly reverts the oxidant status of untreated PCOS women, and potentially improves the pro-atherosclerosis condition in these patients.  相似文献   
943.

Background

Transketolase-like 1 (TKTL1) induces glucose degradation through anaerobic pathways, even in presence of oxygen, favoring the malignant aerobic glycolytic phenotype characteristic of tumor cells. As TKTL1 appears to be a valid biomarker for cancer prognosis, the aim of the current study was to correlate its expression with tumor stage, probability of tumor recurrence and survival, in a series of colorectal cancer patients.

Methodolody/Principal Findings

Tumor tissues from 63 patients diagnosed with colorectal cancer at different stages of progression were analyzed for TKTL1 by immunohistochemistry. Staining was quantified by computational image analysis, and correlations between enzyme expression, local growth, lymph-node involvement and metastasis were assessed. The highest values for TKTL1 expression were detected in the group of stage III tumors, which showed significant differences from the other groups (Kruskal-Wallis test, P = 0.000008). Deeper analyses of T, N and M classifications revealed a weak correlation between local tumor growth and enzyme expression (Mann-Whitney test, P = 0.029), a significant association of the enzyme expression with lymph-node involvement (Mann-Whitney test, P = 0.0014) and a significant decrease in TKTL1 expression associated with metastasis (Mann-Whitney test, P = 0.0004).

Conclusions/Significance

To our knowledge, few studies have explored the association between variations in TKTL1 expression in the primary tumor and metastasis formation. Here we report downregulation of enzyme expression when metastasis appears, and a correlation between enzyme expression and regional lymph-node involvement in colon cancer. This finding may improve our understanding of metastasis and lead to new and more efficient therapies against cancer.  相似文献   
944.
Conservation strategies for long-lived vertebrates require accurate estimates of parameters relative to the populations' size, numbers of non-breeding individuals (the "cryptic" fraction of the population) and the age structure. Frequently, visual survey techniques are used to make these estimates but the accuracy of these approaches is questionable, mainly because of the existence of numerous potential biases. Here we compare data on population trends and age structure in a bearded vulture (Gypaetus barbatus) population from visual surveys performed at supplementary feeding stations with data derived from population matrix-modelling approximations. Our results suggest that visual surveys overestimate the number of immature (<2 years old) birds, whereas subadults (3-5 y.o.) and adults (>6 y.o.) were underestimated in comparison with the predictions of a population model using a stable-age distribution. In addition, we found that visual surveys did not provide conclusive information on true variations in the size of the focal population. Our results suggest that although long-term studies (i.e. population matrix modelling based on capture-recapture procedures) are a more time-consuming method, they provide more reliable and robust estimates of population parameters needed in designing and applying conservation strategies. The findings shown here are likely transferable to the management and conservation of other long-lived vertebrate populations that share similar life-history traits and ecological requirements.  相似文献   
945.
Omentin is a novel soluble lectin expressed mainly in the stromal‐vascular cells from visceral adipose tissue with vasodilator effect in isolated blood vessels. To gain insight in the relationship between obesity and cardiovascular risk factors, we aimed to explore the interaction among circulating omentin, metabolic parameters, and endothelial function. Circulating omentin (enzyme‐linked immunosorbent assay) was studied in 248 white men (148 with normal glucose tolerance (NGT) and 100 with impaired glucose tolerance (IGT)). Insulin sensitivity was measured using the frequently sampled intravenous glucose tolerance test. Vascular reactivity was measured by high‐resolution ultrasound of the brachial artery. Circulating omentin concentration was significantly increased in lean compared with overweight and obese subjects (53.7 ± 16.9 vs. 45.2 ± 16.8 and vs. 40.1 ± 15.5 ng/ml, P < 0.0001). Circulating omentin concentration correlated with age, BMI, waist‐to‐hip ratio (WHR), percentage of fat mass, systolic and diastolic blood pressure, endothelium‐dependent and independent vasodilation (EDV and EIV), C‐reactive protein, and interleukin‐6 (IL‐6). In IGT subjects, circulating omentin concentration also correlated with insulin sensitivity, although this association did not remain significant after controlling for BMI. In a multiple linear regression analysis, circulating omentin concentration (P = 0.01), systolic blood pressure (P = 0.04), and BMI (P = 0.04) contributed independently to EDV after controlling for age and C‐reactive protein in IGT subjects. In NGT subjects, only circulating omentin concentration (P = 0.01) was significantly associated with EDV. In conclusion, circulating omentin concentration could be a useful marker of endothelial function.  相似文献   
946.

Background

The sustained clinical activity of the BRAF inhibitor vemurafenib (PLX4032/RG7204) in patients with BRAFV600 mutant melanoma is limited primarily by the development of acquired resistance leading to tumor progression. Clinical trials are in progress using MEK inhibitors following disease progression in patients receiving BRAF inhibitors. However, the PI3K/AKT pathway can also induce resistance to the inhibitors of MAPK pathway.

Methodology/Principal Findings

The sensitivity to vemurafenib or the MEK inhibitor AZD6244 was tested in sensitive and resistant human melanoma cell lines exploring differences in activation-associated phosphorylation levels of major signaling molecules, leading to the testing of co-inhibition of the AKT/mTOR pathway genetically and pharmacologically. There was a high degree of cross-resistance to vemurafenib and AZD6244, except in two vemurafenib-resistant cell lines that acquired a secondary mutation in NRAS. In other cell lines, acquired resistance to both drugs was associated with persistence or increase in activity of AKT pathway. siRNA-mediated gene silencing and combination therapy with an AKT inhibitor or rapamycin partially or completely reversed the resistance.

Conclusions/Significance

Primary and acquired resistance to vemurafenib in these in vitro models results in frequent cross resistance to MEK inhibitors, except when the resistance is the result of a secondary NRAS mutation. Resistance to BRAF or MEK inhibitors is associated with the induction or persistence of activity within the AKT pathway in the presence of these drugs. This resistance can be potentially reversed by the combination of a RAF or MEK inhibitor with an AKT or mTOR inhibitor. These combinations should be available for clinical testing in patients progressing on BRAF inhibitors.  相似文献   
947.
Caspase malfunction in stem cells often precedes the appearance and progression of multiple types of cancer, including human colorectal cancer. However, the caspase‐dependent regulation of intestinal stem cell properties remains poorly understood. Here, we demonstrate that Dronc, the Drosophila ortholog of caspase‐9/2 in mammals, limits the number of intestinal progenitor cells and their entry into the enterocyte differentiation programme. Strikingly, these unexpected roles for Dronc are non‐apoptotic and have been uncovered under experimental conditions without epithelial replenishment. Supporting the non‐apoptotic nature of these functions, we show that they require the enzymatic activity of Dronc, but are largely independent of the apoptotic pathway. Alternatively, our genetic and functional data suggest that they are linked to the caspase‐mediated regulation of Notch signalling. Our findings provide novel insights into the non‐apoptotic, caspase‐dependent modulation of stem cell properties that could improve our understanding of the origin of intestinal malignancies.  相似文献   
948.

Colostral proline-rich polypeptide complex (PRP) with immunoregulatory and procognitive activities shows beneficial effects in Alzheimer’s disease (AD). As the laboratory method of isolating PRP is expensive, laborious, and time consuming, a new large-scale methanol method of PRP isolation was developed. The proline-rich polypeptide complex obtained by this new method (named methanol PRP–MPRP) from both ovine or bovine colostra shows psychotropic activity and inhibitory effect on amyloid β aggregation similar to those produced by the laboratory-scale method. The comparative study of the antioxidant properties, cytokine-inducing activity, and nitric oxide release of PRP and MPRP showed that preparations are biologically active, moreover MPRP should be used at concentration higher than 100 µg/ml to obtain results comparable to PRP.

  相似文献   
949.
A significant barrier to effective immune clearance of cancer is loss of antitumor cytotoxic T cell activity. Antibodies to block pro-apoptotic/downmodulatory signals to T cells are currently being tested. Because invariant natural killer T cells (iNKT) can regulate the balance of Th1/Th2 cellular immune responses, we characterized the frequencies of circulating iNKT cell subsets in 21 patients with melanoma who received the anti-CTLA4 monoclonal antibody tremelimumab alone and 8 patients who received the antibody in combination with MART-126–35 peptide-pulsed dendritic cells (MART-1/DC). Blood T cell phenotypes and functionality were characterized by flow cytometry before and after treatment. iNKT cells exhibited the central memory phenotype and showed polyfunctional cytokine production. In the combination treatment group, high frequencies of pro-inflammatory Th1 iNKT CD8+ cells correlated with positive clinical responses. These results indicate that iNKT cells play a critical role in regulating effective antitumor T cell activity.  相似文献   
950.

Background

Despite empirical support for an increase in ecosystem productivity with species diversity in synthetic systems, there is ample evidence that this relationship is dependent on environmental characteristics, especially in structurally more complex natural systems. Empirical support for this relationship in forests is urgently needed, as these ecosystems play an important role in carbon sequestration.

Methodology/Principal Findings

We tested whether tree wood production is positively related to tree species richness while controlling for climatic factors, by analyzing 55265 forest inventory plots in 11 forest types across five European countries. On average, wood production was 24% higher in mixed than in monospecific forests. Taken alone, wood production was enhanced with increasing tree species richness in almost all forest types. In some forests, wood production was also greater with increasing numbers of tree types. Structural Equation Modeling indicated that the increase in wood production with tree species richness was largely mediated by a positive association between stand basal area and tree species richness. Mean annual temperature and mean annual precipitation affected wood production and species richness directly. However, the direction and magnitude of the influence of climatic variables on wood production and species richness was not consistent, and vary dependent on forest type.

Conclusions

Our analysis is the first to find a local scale positive relationship between tree species richness and tree wood production occurring across a continent. Our results strongly support incorporating the role of biodiversity in management and policy plans for forest carbon sequestration.  相似文献   
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