全文获取类型
收费全文 | 1142篇 |
免费 | 64篇 |
专业分类
1206篇 |
出版年
2024年 | 2篇 |
2023年 | 13篇 |
2022年 | 33篇 |
2021年 | 50篇 |
2020年 | 31篇 |
2019年 | 35篇 |
2018年 | 45篇 |
2017年 | 43篇 |
2016年 | 54篇 |
2015年 | 80篇 |
2014年 | 82篇 |
2013年 | 99篇 |
2012年 | 84篇 |
2011年 | 75篇 |
2010年 | 38篇 |
2009年 | 47篇 |
2008年 | 44篇 |
2007年 | 55篇 |
2006年 | 53篇 |
2005年 | 44篇 |
2004年 | 28篇 |
2003年 | 32篇 |
2002年 | 24篇 |
2001年 | 23篇 |
2000年 | 6篇 |
1999年 | 14篇 |
1998年 | 3篇 |
1997年 | 4篇 |
1996年 | 3篇 |
1994年 | 5篇 |
1993年 | 5篇 |
1992年 | 5篇 |
1990年 | 2篇 |
1989年 | 3篇 |
1988年 | 7篇 |
1987年 | 2篇 |
1986年 | 2篇 |
1982年 | 2篇 |
1980年 | 2篇 |
1979年 | 4篇 |
1978年 | 2篇 |
1976年 | 2篇 |
1975年 | 3篇 |
1974年 | 2篇 |
1972年 | 1篇 |
1971年 | 2篇 |
1965年 | 1篇 |
1941年 | 1篇 |
1940年 | 1篇 |
1903年 | 1篇 |
排序方式: 共有1206条查询结果,搜索用时 12 毫秒
61.
62.
Modern microarray technology is capable of providing data about the expression of thousands of genes, and even of whole genomes. An important question is how this technology can be used most effectively to unravel the workings of cellular machinery. Here, we propose a method to infer genetic networks on the basis of data from appropriately designed microarray experiments. In addition to identifying the genes that affect a specific other gene directly, this method also estimates the strength of such effects. We will discuss both the experimental setup and the theoretical background. 相似文献
63.
The lesion of the rat substantia nigra pars compacta dopaminergic neurons as a model for Parkinson's disease memory disabilities 总被引:6,自引:0,他引:6
Da Cunha C Angelucci ME Canteras NS Wonnacott S Takahashi RN 《Cellular and molecular neurobiology》2002,22(3):227-237
1. In this article we review the studies of memory disabilities in a rat model o Parkinson's disease (PD).2. Intranigral administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to rats causes a partial lesion in the substantia nigra, compact part (SNc) and a specific loss of dopamine and its metabolites in the striatum of rats.3. These animals present learning and memory deficits but no sensorimotor impairments, thus modeling the early phase of PD when cognitive impairments are observed but the motor symptoms of the disease are barely present.4. The cognitive deficits observed in these animals affect memory tasks proposed to model habit learning (the cued version of the water maze task and the two-way active avoidance task) and working memory (a working memory version of the water maze), but spare long-term spatial memory (the spatial reference version of the Morris water maze).5. The treatment of these animals with levodopa in a dose that restores the striatal level of dopamine does not reverse these memory impairments, probably because this treatment promotes a high level of dopamine in extrastriatal brain regions, such as the prefrontal cortex and the hippocampus.6. On the other hand, the adenosine receptor antagonist, caffeine, partly reverse the memory impairment effect of SNc lesion in these rats. This effect may be due to caffeine action on nigrostriatal neurons, since it induces dopamine release and modulates the interaction between adenosine and dopamine receptor activity.7. These results suggest that the MPTP SNc-lesioned rats are a good model to study memory disabilities related to PD and that caffeine and other selective A(2A) adenosine receptor antagonists are promising drugs to treat this symptoms in PD patients. 相似文献
64.
Calvi SA Peraçoli MT Mendes RP Marcondes-Machado J Fecchio D Marques SA Soares AM 《Microbes and infection / Institut Pasteur》2003,5(2):107-113
Peripheral blood monocytes obtained from paracoccidioidomycosis patients and healthy individuals were preactivated with recombinant gamma interferon (IFN-gamma) in different concentrations (250, 500 and 1000 U/ml) and evaluated for fungicidal activity against Paracoccidiodes brasiliensis strain 18 (Pb 18, high-virulence strain) and strain 265 (Pb 265, low-virulence strain) by plating of cocultures and counting of colony-forming units, after 10 d. Monocytes from healthy individuals failed to present fungicidal activity against P. brasiliensis even after IFN-gamma activation at the three concentrations. However, patient monocytes activated with IFN-gamma (1000 U/ml) showed a significant fungicidal activity when compared to that obtained with non-activated or activated cells with other IFN-gamma concentrations (250 and 500 U/ml). Moreover, patient monocytes presented higher fungicidal activity than the control, even before the activation process. These results may be explained by the activation state of patients' cells as a function of the in vivo contact with the fungus, which was confirmed by their higher capacity to release H(2)O(2) in vitro. Unlike the results obtained with Pb 18, patient and control cells presented a significant fungicidal activity against Pb 265, after priming with IFN- gamma. These results are explained by the higher levels of TNF-alpha in supernatants of cultures challenged with Pb 265. Moreover, higher levels of the cytokine were obtained in patient cell supernatants. Taken together, our results suggest that for effective killing of P. brasiliensis by monocytes, an initial activation signal induced by IFN-gamma is necessary to stimulate the cells to produce TNF-alpha. This cytokine may be involved, through an autocrine pathway, in the final phase activation process. The effectiveness of this process seems to depend on the virulence of the fungal strain and the activation state of the challenged cells. 相似文献
65.
Dengue fever is currently the most important arthropod-borne viral disease in Brazil. Mathematical modeling of disease dynamics is a very useful tool for the evaluation of control measures. To be used in decision-making, however, a mathematical model must be carefully parameterized and validated with epidemiological and entomological data. In this work, we developed a simple dengue model to answer three questions: (i) which parameters are worth pursuing in the field in order to develop a dengue transmission model for Brazilian cities; (ii) how vector density spatial heterogeneity influences control efforts; (iii) with a degree of uncertainty, what is the invasion potential of dengue virus type 4 (DEN-4) in Rio de Janeiro city. Our model consists of an expression for the basic reproductive number (R0) that incorporates vector density spatial heterogeneity. To deal with the uncertainty regarding parameter values, we parameterized the model using a priori probability density functions covering a range of plausible values for each parameter. Using the Latin Hypercube Sampling procedure, values for the parameters were generated. We conclude that, even in the presence of vector spatial heterogeneity, the two most important entomological parameters to be estimated in the field are the mortality rate and the extrinsic incubation period. The spatial heterogeneity of the vector population increases the risk of epidemics and makes the control strategies more complex. At last, we conclude that Rio de Janeiro is at risk of a DEN-4 invasion. Finally, we stress the point that epidemiologists, mathematicians, and entomologists need to interact more to find better approaches to the measuring and interpretation of the transmission dynamics of arthropod-borne diseases. 相似文献
66.
Cláudio M. Gomes Alice Faria João C. Carita Joaquim Mendes Manuela Regalla Paula Chicau Harald Huber Karl O. Stetter M. Teixeira 《Journal of biological inorganic chemistry》1998,3(5):499-507
Seven-iron ferredoxins from the thermoacidophilic archaea Acidianus ambivalens, A. infernus, Metalosphaera prunae and Sulfolobus metallicus were extensively characterised, allowing study of their expression under aerobic and anaerobic growth conditions as well
as the putative role in thermal stability of a recently described zinc centre. The archaeon S. metallicus was found to express, under the same growth conditions, two ferredoxins in almost identical amounts, a novelty among Archaea. Most interestingly, these two ferredoxins differ at the N-terminal amino acid sequence in that one has a zinc binding motif
(FdA) and the other does not (FdB); in agreement with these findings, FdA contains a zinc ion and FdB does not. These two
ferredoxins have identical thermal stabilities, indicating that the zinc atom is not determinant in the protein thermostability.
Further, the presence of the additional zinc centre does not interfere with the redox properties of the iron-sulfur clusters
since their reduction potentials are almost identical. From the other three archaea, independently of the growth mode in respect
to oxygen, only a single zinc-containing ferredoxin was found. EPR studies on the purified proteins, both in the oxidised
and dithionite reduced states, allowed the identification of one [3Fe-4S]1+/0 centre and one [4Fe-4S]2+/1+ centre in all proteins studied. The complete sequence of A. ambivalens ferredoxin is reported. Together with the data gathered in this study, the properties of the seven-iron ferredoxins from
Sulfolobales so far known are re-discussed.
Received: 10 June 1998 / Accepted: 25 June 1998 相似文献
67.
Joana T. de Oliveira Ana L. Santos Catarina Gomes Rita Barros Cláudia Ribeiro Nuno Mendes Augusto J. de Matos M. Helena Vasconcelos Maria José Oliveira Celso A. Reis Fátima G?rtner 《PloS one》2015,10(4)
Oseltamivir phosphate is a widely used anti-influenza sialidase inhibitor. Sialylation, governed by sialyltransferases and sialidases, is strongly implicated in the oncogenesis and progression of breast cancer. In this study we evaluated the biological behavior of canine mammary tumor cells upon oseltamivir phosphate treatment (a sialidase inhibitor) in vitro and in vivo. Our in vitro results showed that oseltamivir phosphate impairs sialidase activity leading to increased sialylation in CMA07 and CMT-U27 canine mammary cancer cells. Surprisingly, oseltamivir phosphate stimulated, CMT-U27 cell migration and invasion capacity in vitro, in a dose-dependent manner. CMT-U27 tumors xenograft of oseltamivir phosphate-treated nude mice showed increased sialylation, namely α2,6 terminal structures and SLe(x) expression. Remarkably, a trend towards increased lung metastases was observed in oseltamivir phosphate-treated nude mice. Taken together, our findings revealed that oseltamivir impairs canine mammary cancer cell sialidase activity, altering the sialylation pattern of canine mammary tumors, and leading, surprisingly, to in vitro and in vivo increased mammary tumor aggressiveness. 相似文献
68.
Fabio A. Mendes Juliana M. Coelho Aguiar Suzana A. Kahn Alice H. Reis Luiz Gustavo Dubois Luciana Ferreira Rom?o Lais S. S. Ferreira Hervé Chneiweiss Vivaldo Moura Neto José G. Abreu 《PloS one》2015,10(8)
Connective-tissue growth factor (CTGF) is a modular secreted protein implicated in multiple cellular events such as chondrogenesis, skeletogenesis, angiogenesis and wound healing. CTGF contains four different structural modules. This modular organization is characteristic of members of the CCN family. The acronym was derived from the first three members discovered, cysteine-rich 61 (CYR61), CTGF and nephroblastoma overexpressed (NOV). CTGF is implicated as a mediator of important cell processes such as adhesion, migration, proliferation and differentiation. Extensive data have shown that CTGF interacts particularly with the TGFβ, WNT and MAPK signaling pathways. The capacity of CTGF to interact with different growth factors lends it an important role during early and late development, especially in the anterior region of the embryo. ctgf knockout mice have several cranio-facial defects, and the skeletal system is also greatly affected due to an impairment of the vascular-system development during chondrogenesis. This study, for the first time, indicated that CTGF is a potent inductor of gliogenesis during development. Our results showed that in vitro addition of recombinant CTGF protein to an embryonic mouse neural precursor cell culture increased the number of GFAP- and GFAP/Nestin-positive cells. Surprisingly, CTGF also increased the number of Sox2-positive cells. Moreover, this induction seemed not to involve cell proliferation. In addition, exogenous CTGF activated p44/42 but not p38 or JNK MAPK signaling, and increased the expression and deposition of the fibronectin extracellular matrix protein. Finally, CTGF was also able to induce GFAP as well as Nestin expression in a human malignant glioma stem cell line, suggesting a possible role in the differentiation process of gliomas. These results implicate ctgf as a key gene for astrogenesis during development, and suggest that its mechanism may involve activation of p44/42 MAPK signaling. Additionally, CTGF-induced differentiation of glioblastoma stem cells into a less-tumorigenic state could increase the chances of successful intervention, since differentiated cells are more vulnerable to cancer treatments. 相似文献
69.
Ecological Risk Assessment of a Metal-Contaminated Area in the Tropics. Tier II: Detailed Assessment
Júlia Carina Niemeyer Matilde Moreira-Santos Rui Ribeiro Michiel Rutgers Marco Antonio Nogueira Eduardo Mendes da Silva José Paulo Sousa 《PloS one》2015,10(11)
This study presents data on the detailed evaluation (tier 2) of a site-specific ecological risk assessment (ssERA) in a former smelter area contaminated with metals (Santo Amaro, Bahia, Brazil). Combining information from three lines of evidence (LoE), chemical (ChemLoE), ecotoxicological (EcotoxLoE) and ecological (EcoLoE), in the Triad approach, integrated risk values were calculated to rank sites and confirm the potential risk disclosed with tier 1. Risk values were calculated for the habitat and for the retention functions in each sampling point. Habitat function included the ChemLoE calculated from total metal concentrations. The EcotoxLoE was based on reproduction tests with terrestrial invertebrates (Folsomia candida, Enchytraeus crypticus, Eisenia andrei), shoot length and plant biomass (Avena sativa, Brassica rapa). For the EcoLoE, ecological parameters (microbial parameters, soil invertebrate community, litter breakdown) were used to derive risk values. Retention function included the ChemLoE, calculated from extractable metal concentrations, and the EcotoxLoE based on eluate tests with aquatic organisms (Daphnia magna reproduction and Pseudokirchneriella subcapitata growth). Results related to the habitat function indicated that the metal residues are sufficient to cause risk to biota, while the low metal levels in extracts and the general lack of toxicity in aquatic tests indicated a high soil retention capacity in most sampling points. Integrated risk of tier 2 showed the same trend of tier 1, suggesting the need to proceed with remediation actions. The high risk levels were related to direct toxicity to organisms and indirect effects, such as failure in the establishment of vegetation and the consequent loss of habitat quality for microorganisms and soil fauna. This study shed some light on the selection of tools for the tier 2 of an ssERA in tropical metal-contaminated sites, focusing on ecological receptors at risk and using available chemical methods, ecological surveys and ecotoxicity tests. 相似文献
70.
Mapping Soil Properties of Africa at 250 m Resolution: Random Forests Significantly Improve Current Predictions 总被引:3,自引:0,他引:3
Tomislav Hengl Gerard B. M. Heuvelink Bas Kempen Johan G. B. Leenaars Markus G. Walsh Keith D. Shepherd Andrew Sila Robert A. MacMillan Jorge Mendes de Jesus Lulseged Tamene Jér?me E. Tondoh 《PloS one》2015,10(6)
80% of arable land in Africa has low soil fertility and suffers from physical soil problems. Additionally, significant amounts of nutrients are lost every year due to unsustainable soil management practices. This is partially the result of insufficient use of soil management knowledge. To help bridge the soil information gap in Africa, the Africa Soil Information Service (AfSIS) project was established in 2008. Over the period 2008–2014, the AfSIS project compiled two point data sets: the Africa Soil Profiles (legacy) database and the AfSIS Sentinel Site database. These data sets contain over 28 thousand sampling locations and represent the most comprehensive soil sample data sets of the African continent to date. Utilizing these point data sets in combination with a large number of covariates, we have generated a series of spatial predictions of soil properties relevant to the agricultural management—organic carbon, pH, sand, silt and clay fractions, bulk density, cation-exchange capacity, total nitrogen, exchangeable acidity, Al content and exchangeable bases (Ca, K, Mg, Na). We specifically investigate differences between two predictive approaches: random forests and linear regression. Results of 5-fold cross-validation demonstrate that the random forests algorithm consistently outperforms the linear regression algorithm, with average decreases of 15–75% in Root Mean Squared Error (RMSE) across soil properties and depths. Fitting and running random forests models takes an order of magnitude more time and the modelling success is sensitive to artifacts in the input data, but as long as quality-controlled point data are provided, an increase in soil mapping accuracy can be expected. Results also indicate that globally predicted soil classes (USDA Soil Taxonomy, especially Alfisols and Mollisols) help improve continental scale soil property mapping, and are among the most important predictors. This indicates a promising potential for transferring pedological knowledge from data rich countries to countries with limited soil data. 相似文献