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991.
992.
AKT/FOXO signaling enforces reversible differentiation blockade in myeloid leukemias 总被引:2,自引:0,他引:2
Sykes SM Lane SW Bullinger L Kalaitzidis D Yusuf R Saez B Ferraro F Mercier F Singh H Brumme KM Acharya SS Scholl C Schöll C Tothova Z Attar EC Fröhling S DePinho RA Armstrong SA Gilliland DG Scadden DT 《Cell》2011,146(5):697-708
AKT activation is associated with many malignancies, where AKT acts, in part, by inhibiting FOXO tumor suppressors. We show a converse role for AKT/FOXOs in acute myeloid leukemia (AML). Rather than decreased FOXO activity, we observed that FOXOs are active in ~40% of AML patient samples regardless of genetic subtype. We also observe this activity in human MLL-AF9 leukemia allele-induced AML in mice, where either activation of Akt or compound deletion of FoxO1/3/4 reduced leukemic cell growth, with the latter markedly diminishing leukemia-initiating cell (LIC) function in vivo and improving animal survival. FOXO inhibition resulted in myeloid maturation and subsequent AML cell death. FOXO activation inversely correlated with JNK/c-JUN signaling, and leukemic cells resistant to FOXO inhibition responded to JNK inhibition. These data reveal a molecular role for AKT/FOXO and JNK/c-JUN in maintaining a differentiation blockade that can be targeted to inhibit leukemias with a range of genetic lesions. 相似文献
993.
Zanoni I Ostuni R Marek LR Barresi S Barbalat R Barton GM Granucci F Kagan JC 《Cell》2011,147(4):868-880
The transport of Toll-like Receptors (TLRs) to various organelles has emerged as an essential means by which innate immunity is regulated. While most of our knowledge is restricted to regulators that promote the transport of newly synthesized receptors, the regulators that control TLR transport after microbial detection remain unknown. Here, we report that the plasma membrane localized Pattern Recognition Receptor (PRR) CD14 is required for the microbe-induced endocytosis of TLR4. In dendritic cells, this CD14-dependent endocytosis pathway is upregulated upon exposure to inflammatory mediators. We identify the tyrosine kinase Syk and its downstream effector PLCγ2 as important regulators of TLR4 endocytosis and signaling. These data establish that upon microbial detection, an upstream PRR (CD14) controls the trafficking and signaling functions of a downstream PRR (TLR4). This innate immune trafficking cascade illustrates how pathogen detection systems operate to induce both membrane transport and signal transduction. 相似文献
994.
Notomista E Pennacchio F Cafaro V Smaldone G Izzo V Troncone L Varcamonti M Di Donato A 《Microbial ecology》2011,61(3):582-594
Novosphingobium sp. PP1Y, isolated from a surface seawater sample collected from a closed bay in the harbour of Pozzuoli (Naples, Italy),
uses fuels as its sole carbon and energy source. Like some other Sphingomonads, this strain can grow as either planktonic
free cells or sessile-aggregated flocks. In addition, this strain was found to grow as biofilm on several types of solid and
liquid hydrophobic surfaces including polystyrene, polypropylene and diesel oil. Strain PP1Y is not able to grow on pure alkanes
or alkane mixtures but is able to grow on a surprisingly wide range of aromatic compounds including mono, bi, tri and tetracyclic
aromatic hydrocarbons and heterocyclic compounds. During growth on diesel oil, the organic layer is emulsified resulting in
the formation of small biofilm-coated drops, whereas during growth on aromatic hydrocarbons dissolved in paraffin the oil
layer is emulsified but the drops are coated only if the mixtures contain selected aromatic compounds, like pyrene, propylbenzene,
tetrahydronaphthalene and heterocyclic compounds. These peculiar characteristics suggest strain PP1Y has adapted to efficiently
grow at the water/fuel interface using the aromatic fraction of fuels as the sole carbon and energy source. 相似文献
995.
Giacomucci L Bertoncello R Salvadori O Martini I Favaro M Villa F Sorlini C Cappitelli F 《Microbial ecology》2011,62(2):287-298
The Grande Albergo Ausonia &; Hungaria (Venice Lido, Italy) has an Art Nouveau polychrome ceramic coating on its façade, which was restored in 2007. Soon after the conservation treatment, many tiles of the façade decoration showed coloured alterations putatively attributed to the presence of microbial communities. To confirm the presence of the biological deposit and the stratigraphy of the Hungaria tiles, stereomicroscope, optical and environmental scanning electron microscope observations were made. The characterisation of the microbial community was performed using a PCR–DGGE approach. This study reported the first use of a culture-independent approach to identify the total community present in biodeteriorated artistic tiles. The case study examined here reveals that the coloured alterations on the tiles were mainly due to the presence of cryptoendolithic cyanobacteria. In addition, we proved that the microflora present on the tiles was generally greatly influenced by the environment of the Hungaria hotel. We found several microorganisms related to the alkaline environment, which is in the range of the tile pH, and related to the aquatic environment, the presence of the acrylic resin Paraloid B72® used during the 2007 treatment and the pollutants of the Venice lagoon. 相似文献
996.
Forty-eight isolates resistant to at least two antibiotics were selected from 53 antibiotic-resistant enterococci from chicken
and pig meat and faeces and analysed for specific resistance determinants. Of the 48 multidrug-resistant (MDR) strains, 31
were resistant to two antibiotics (29 to erythromycin and tetracycline, 1 to erythromycin and vancomycin, 1 to vancomycin
and tetracycline), 14 to three (erythromycin, tetracycline and vancomycin or ampicillin) and 3 to four (erythromycin, vancomycin,
ampicillin and gentamicin). erm(B), tet(M), vanA and aac (6′)-Ie aph (2′′)-Ia were the antibiotic resistance genes most frequently detected. All 48 MDR enterococci were susceptible to linezolid and daptomycin.
Enterococcus faecalis (16), Enterococcus faecium (8), Enterococcus mundtii (2) and Enterococcus gallinarum (1) were identified in meat, and E. faecium (13) and Enterococcus durans (13) in faeces. Clonal spread was not detected, suggesting a large role of gene transfer in the dissemination of antibiotic
resistance. Conjugative transfer of resistance genes was more successful when donors were enterococcal strains isolated from
faeces; co-transfer of vanA and erm(B) to a human E. faecium occurred from both E. faecium and E. durans pig faecal strains. These data show that multidrug resistance can be found in food and animal species other than E. faecium and E. faecalis, and that these species can efficiently transfer antibiotic resistance to human strains in inter-specific matings. In particular,
the occurrence of MDR E. durans in the animal reservoir could have a role in the emergence of human enterococcal infections difficult to eradicate with antibiotics. 相似文献
997.
Baracchi F Ingiosi AM Raymond RM Opp MR 《American journal of physiology. Regulatory, integrative and comparative physiology》2011,301(5):R1467-R1478
Sepsis is a systemic immune response to infection that may result in multiple organ failure and death. Polymicrobial infections remain a serious clinical problem, and in the hospital, sepsis is the number-one noncardiac killer. Although the central nervous system may be one of the first systems affected, relatively little effort has been made to determine the impact of sepsis on the brain. In this study, we used the cecal ligation and puncture (CLP) model to determine the extent to which sepsis alters sleep, the EEG, and brain temperature (Tbr) of rats. Sepsis increases the amount of time rats spend in non-rapid eye movement sleep (NREMS) during the dark period, but not during the light period. Rapid eye movements sleep (REMS) of septic rats is suppressed for about 24 h following CLP surgery, after which REMS increases during dark periods for at least three nights. The EEG is dramatically altered shortly after sepsis induction, as evidenced by reductions in slow-frequency components. Furthermore, sleep is fragmented, indicating that the quality of sleep is diminished. Effects on sleep, the EEG, and Tbr persist for at least 84 h after sepsis induction, the duration of our recording period. Immunohistochemical assays focused on brain stem mechanisms responsible for alterations in REMS, as little information is available concerning infection-induced suppression of this sleep stage. Our immunohistochemical data suggest that REMS suppression after sepsis onset may be mediated, in part, by the brain stem GABAergic system. This study demonstrates for the first time that sleep and EEG patterns are altered during CLP-induced sepsis. These data suggest that the EEG may serve as a biomarker for sepsis onset. These data also contribute to our knowledge of potential mechanisms, whereby infections alter sleep and other central nervous system functions. 相似文献
998.
Detecting common copy number variants in high-throughput sequencing data by using JointSLM algorithm
The discovery of genomic structural variants (SVs), such as copy number variants (CNVs), is essential to understand genetic variation of human populations and complex diseases. Over recent years, the advent of new high-throughput sequencing (HTS) platforms has opened many opportunities for SVs discovery, and a very promising approach consists in measuring the depth of coverage (DOC) of reads aligned to the human reference genome. At present, few computational methods have been developed for the analysis of DOC data and all of these methods allow to analyse only one sample at time. For these reasons, we developed a novel algorithm (JointSLM) that allows to detect common CNVs among individuals by analysing DOC data from multiple samples simultaneously. We test JointSLM performance on synthetic and real data and we show its unprecedented resolution that enables the detection of recurrent CNV regions as small as 500 bp in size. When we apply JointSLM to analyse chromosome one of eight genomes with different ancestry, we identify 3000 regions with recurrent CNVs of different frequency and size: hierarchical clustering on these regions segregates the eight individuals in two groups that reflect their ancestry, demonstrating the potential utility of JointSLM for population genetics studies. 相似文献
999.
Plummer PN Colson NJ Lewohl JM MacKay RK Fernandez F Haupt LM Griffiths LR 《Gene》2011,490(1-2):32-36
Migraine is a debilitating neurovascular disorder, with a substantial genetic component. The exact cause of a migraine attack is unknown; however cortical hyperexcitability is thought to play a role. As Gamma-aminobutyric Acid (GABA) is the major inhibitory neurotransmitter in the brain, malfunctioning of this system may be a cause of the hyperexcitability. To date, there has been limited research examining the gene expression or genetics of GABA receptors in relation to migraine. The aim of our study was to determine if GABA receptors play a role in migraine by investigating their gene expression using profile in migraine affected individuals and non-affected controls by Q-PCR. Gene expression of GABA(A) receptor subunit isoforms (GABRA3, GABRB3, GABRQ) and GABA(B) receptor 2 (GABBR2) was quantified in mRNA obtained from peripheral blood leukocytes from 28 migraine subjects and 22 healthy control subjects. Analysis of results showed that two of the tested genes, GABRA3 and GABBR2, were significantly down regulated in migraineurs (P=0.018; P=0.017), compared to controls. Results from the other tested genes did not show significant gene expression variation. The results indicate that there may be specific GABA receptor gene expression variation in migraine, particularly involving the GABRA3 and GABBR2 genes. This study also identifies GABRA3 and GABBR2 as potential biomarkers to select migraineurs that may be more responsive to GABA agonists with future investigations in this area warranted. 相似文献
1000.