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101.
Squash trypsin inhibitors from Momordica cochinchinensis exhibit an atypical macrocyclic structure 总被引:2,自引:0,他引:2
Hernandez JF Gagnon J Chiche L Nguyen TM Andrieu JP Heitz A Trinh Hong T Pham TT Le Nguyen D 《Biochemistry》2000,39(19):5722-5730
Three trypsin inhibitors (TIs), from the seeds of the squash Momordica cochinchinensis (MCo), have been isolated and purified using gel filtration, ion exchange chromatography, and reverse-phase HPLC. Their sequences could be determined only after proteolytic cleavages. In the case of MCoTI-I and -II, it was shown that their polypeptide backbones are cyclic, a structure that has never been described in squash TIs. They contain 34 amino acid residues with 3 disulfide bridges and measured molecular masses of 3453.0 and 3480.7, respectively. They are the largest known macrocyclic peptides containing disulfide bridges. Their sequences show strong homology to other squash TIs, suggesting a similar three-dimensional structure and an analogous mechanism of action. A model of MCoTI-II was constructed by analogy to the crystal structure of the complex between bovine trypsin and CMTI-I, indicating that the linker connecting the two termini is flexible and does not impose significant geometrical constraints. This flexibility allows an Asp-Gly peptide bond rearrangement to occur in this region, giving rise to two isoforms of MCoTI-II. Although the importance of cyclization is not clear, it might confer increased stability and resistance to proteolysis. A minor species, MCoTI-III, was also characterized as containing 30 amino acid residues with a molecular mass of 3379.6. This component possesses a linear backbone with a blocked N-terminus. MCoTIs represent interesting candidates for drug design, either by changing their specificity of inhibition or by using their structure as natural scaffolds bearing new binding activities. 相似文献
102.
Farlow DN Vansant G Cameron AA Chang J Khoh-Reiter S Pham NL Wu W Sagara Y Nicholls JG Carlo DJ Ill CR 《Journal of cellular biochemistry》2000,80(2):171-180
Gene expression monitoring using gene expression microarrays represents an extremely powerful technology for gene discovery in a variety of systems. We describe the results of seven experiments using Incyte GEM technology to compile a proprietary portfolio of data concerning differential gene expression in six different models of neuronal differentiation and regeneration, and recovery from injury or disease. Our first two experiments cataloged genes significantly up- or down-regulated during two phases of the retinoic acid-induced differentiation of the embryonal carcinoma line Ntera-2. To identify genes involved in neuronal regeneration we performed three GEM experiments, which included changes in gene expression in rat dorsal root ganglia during the healing of experimentally injured sciatic nerve, in regenerating neonatal opossum spinal cord, and during lipopolysaccharide stimulation of primary cultures of rat Schwann cells. Finally we have monitored genes involved in the recovery phase of the inflammatory disease of the rat spinal cord, experimental allergic encephalomyelitis, as well as those responsible for protection from oxidative stress in a glutamate-resistant rat hippocampal cell line. Analysis of the results of the approximately 70,000 data points collected is presented. 相似文献
103.
A kinetic model of overflow metabolism in Saccharomyces cerevisiae was used for simulation of aerobic fed-batch cultivations. An inhibitory effect of ethanol on the maximum respiration of the yeast was observed in the experiments and included in the model. The model predicts respiration, biomass, and ethanol formation and the subsequent ethanol consumption, and was experimentally validated in fed-batch cultivations. Oscillating sugar feed with resulting oscillating carbon dioxide production did not influence the maximum respiration rate, which indicates that the pyruvate dehydrogenase complex is not involved as a bottleneck causing aerobic ethanol formation. 相似文献
104.
Sharmi W. Thor Hieu Nguyen Amanda Balish Anh Nguyen Hoang Kortney M. Gustin Pham Thi Nhung Joyce Jones Ngoc Nguyen Thu William Davis Thao Nguyen Thi Ngoc Yunho Jang Katrina Sleeman Julie Villanueva James Kile Larisa V. Gubareva Stephen Lindstrom Terrence M. Tumpey C. Todd Davis Nguyen Thanh Long 《PloS one》2015,10(8)
Highly pathogenic avian influenza (HPAI) H5N1 is endemic in Vietnamese poultry and has caused sporadic human infection in Vietnam since 2003. Human infections with HPAI H5N1 are of concern due to a high mortality rate and the potential for the emergence of pandemic viruses with sustained human-to-human transmission. Viruses isolated from humans in southern Vietnam have been classified as clade 1 with a single genome constellation (VN3) since their earliest detection in 2003. This is consistent with detection of this clade/genotype in poultry viruses endemic to the Mekong River Delta and surrounding regions. Comparison of H5N1 viruses detected in humans from southern Vietnamese provinces during 2012 and 2013 revealed the emergence of a 2013 reassortant virus with clade 1.1.2 hemagglutinin (HA) and neuraminidase (NA) surface protein genes but internal genes derived from clade 2.3.2.1a viruses (A/Hubei/1/2010-like; VN12). Closer analysis revealed mutations in multiple genes of this novel genotype (referred to as VN49) previously associated with increased virulence in animal models and other markers of adaptation to mammalian hosts. Despite the changes identified between the 2012 and 2013 genotypes analyzed, their virulence in a ferret model was similar. Antigenically, the 2013 viruses were less cross-reactive with ferret antiserum produced to the clade 1 progenitor virus, A/Vietnam/1203/2004, but reacted with antiserum produced against a new clade 1.1.2 WHO candidate vaccine virus (A/Cambodia/W0526301/2012) with comparable hemagglutination inhibition titers as the homologous antigen. Together, these results indicate changes to both surface and internal protein genes of H5N1 viruses circulating in southern Vietnam compared to 2012 and earlier viruses. 相似文献
105.
A Comparison of ToxCast Test Results with In Vivo and Other In Vitro Endpoints for Neuro,Endocrine, and Developmental Toxicities: A Case Study Using Endosulfan and Methidathion 下载免费PDF全文
106.
Serena P. Koenig Alexandra Bornstein Karine Severe Elizabeth Fox Jessy G. Dévieux Patrice Severe Patrice Joseph Adias Marcelin Dgndy Alexandre Bright Ngoc Pham Pierre Cremieux Jean William Pape 《PloS one》2015,10(11)
Objective
We assessed the association between gender and mortality on antiretroviral therapy (ART) using identical models with and without sex-specific categories for weight and hemoglobin.Design
Cohort study of adult patients on ART.Setting
GHESKIO Clinic in Port-au-Prince, Haiti.Participants
4,717 ART-naïve adult patients consecutively enrolled on ART at GHESKIO from 2003 to 2008.Main Outcome Measure
Mortality on ART; multivariable analyses were conducted with and without sex-specific categories for weight and hemoglobin.Results
In Haiti, male gender was associated with mortality (OR 1.61; 95% CI: 1.30–2.00) in multivariable analyses with hemoglobin and weight included as control variables, but not when sex-specific interactions with hemoglobin and weight were used.Conclusions
If sex-specific categories are omitted, multivariable analyses indicate a higher risk of mortality for males vs. females of the same weight and hemoglobin. However, because males have higher normal values for weight and hemoglobin, the males in this comparison would generally have poorer health status than the females. This may explain why gender differences in mortality are sometimes observed after controlling for differences in baseline variables when gender-specific interactions with weight and hemoglobin are omitted. 相似文献107.
Cheryl Carson Pichai Raman Jennifer Tullai Lei Xu Martin Henault Emily Thomas Sarita Yeola Jianmin Lao Mark McPate J. Martin Verkuyl George Marsh Jason Sarber Adam Amaral Scott Bailey Danuta Lubicka Helen Pham Nicolette Miranda Jian Ding Hai-Ming Tang Haisong Ju Pamela Tranter Nan Ji Philipp Krastel Rishi K. Jain Andrew M. Schumacher Joseph J. Loureiro Elizabeth George Giuliano Berellini Nathan T. Ross Simon M. Bushell Gül Erdemli Jonathan M. Solomon 《PloS one》2015,10(6)
Englerin A is a structurally unique natural product reported to selectively inhibit growth of renal cell carcinoma cell lines. A large scale phenotypic cell profiling experiment (CLiP) of englerin A on ¬over 500 well characterized cancer cell lines showed that englerin A inhibits growth of a subset of tumor cell lines from many lineages, not just renal cell carcinomas. Expression of the TRPC4 cation channel was the cell line feature that best correlated with sensitivity to englerin A, suggesting the hypothesis that TRPC4 is the efficacy target for englerin A. Genetic experiments demonstrate that TRPC4 expression is both necessary and sufficient for englerin A induced growth inhibition. Englerin A induces calcium influx and membrane depolarization in cells expressing high levels of TRPC4 or its close ortholog TRPC5. Electrophysiology experiments confirmed that englerin A is a TRPC4 agonist. Both the englerin A induced current and the englerin A induced growth inhibition can be blocked by the TRPC4/C5 inhibitor ML204. These experiments confirm that activation of TRPC4/C5 channels inhibits tumor cell line proliferation and confirms the TRPC4 target hypothesis generated by the cell line profiling. In selectivity assays englerin A weakly inhibits TRPA1, TRPV3/V4, and TRPM8 which suggests that englerin A may bind a common feature of TRP ion channels. In vivo experiments show that englerin A is lethal in rodents near doses needed to activate the TRPC4 channel. This toxicity suggests that englerin A itself is probably unsuitable for further drug development. However, since englerin A can be synthesized in the laboratory, it may be a useful chemical starting point to identify novel modulators of other TRP family channels. 相似文献
108.
Marcela Parra Xia Liu Steven C. Derrick Amy Yang Alvaro Molina-Cruz Carolina Barillas-Mury Hong Zheng Phuong Thao Pham Martha Sedegah Arnel Belmonte Dianne D. Litilit Thomas A. Waldmann Sanjai Kumar Sheldon L. Morris Liyanage P. Perera 《PloS one》2015,10(10)
Malaria remains a major global public health problem with an estimated 200 million cases detected in 2012. Although the most advanced candidate malaria vaccine (RTS,S) has shown promise in clinical trials, its modest efficacy and durability have created uncertainty about the impact of RTS,S immunization (when used alone) on global malaria transmission. Here we describe the development and characterization of a novel modified vaccinia virus Ankara (MVA)–based malaria vaccine which co-expresses the Plasmodium yoelii circumsporozoite protein (CSP) and IL-15. Vaccination/challenge studies showed that C57BL/6 mice immunized with the MVA-CSP/IL15 vaccine were protected significantly better against a P. yoelii 17XNL sporozoite challenge than either mice immunized with an MVA vaccine expressing only CSP or naïve controls. Importantly, the levels of total anti-CSP IgG were elevated about 100-fold for the MVA-CSP/IL15 immunized group compared to mice immunized with the MVA-CSP construct that does not express IL-15. Among the IgG subtypes, the IL-15 expressing MVA-CSP vaccine induced levels of IgG1 (8 fold) and IgG2b (80 fold) higher than the MVA-CSP construct. The significantly enhanced humoral responses and protection detected after immunization with the MVA-CSP/IL15 vaccine suggest that this IL-15 expressing MVA construct could be considered in the development of future malaria immunization strategies. 相似文献
109.
A. Heckel M. Weiler A. Xia M. Ruetters M. Pham M. Bendszus S. Heiland P. Baeumer 《PloS one》2015,10(6)
Purpose
To investigate the potential of diffusion tensor imaging (DTI) parameters as in-vivo biomarkers of axon and myelin sheath integrity of the median nerve in the carpal tunnel as validated by correlation with electrophysiology.Methods
MRI examinations at 3T including DTI were conducted on wrists in 30 healthy subjects. After manual segmentation of the median nerve quantitative analysis of fractional anisotropy (FA) as well as axial, radial and mean diffusivity (AD, RD, and MD) was carried out. Pairwise Pearson correlations with electrophysiological parameters comprising sensory nerve action potential (SNAP) and compound muscle action potential (CMAP) as markers of axon integrity, and distal motor latency (dml) and sensory nerve conduction velocity (sNCV) as markers of myelin sheath integrity were computed. The significance criterion was set at P=0.05, Bonferroni corrected for multiple comparisons.Results
DTI parameters showed a distinct proximal-to-distal profile with FA, MD, and RD extrema coinciding in the center of the carpal tunnel. AD correlated with CMAP (r=0.50, p=0.04, Bonf. corr.) but not with markers of myelin sheath integrity. RD correlated with sNCV (r=-0.53, p=0.02, Bonf. corr.) but not with markers of axon integrity. FA correlated with dml (r=-0.63, p=0.002, Bonf. corr.) and sNCV (r=0.68, p=0.001, Bonf. corr.) but not with markers of axon integrity.Conclusion
AD reflects axon integrity, while RD (and FA) reflect myelin sheath integrity as validated by correlation with electrophysiology. DTI parameters consistently indicate a slight decrease of structural integrity in the carpal tunnel as a physiological site of median nerve entrapment. DTI is particularly sensitive, since these findings are observed in healthy participants. Our results encourage future studies to evaluate the potential of DTI in differentiating axon from myelin sheath injury in patients with manifest peripheral neuropathies. 相似文献110.
Agata Rekas Robert B. Knott Anna Sokolova Kevin J. Barnham Keyla A. Perez Colin L. Masters Simon C. Drew Roberto Cappai Cyril C. Curtain Chi L. L. Pham 《European biophysics journal : EBJ》2010,39(10):1407-1419
Inclusions of aggregated α-synuclein (α-syn) in dopaminergic neurons are a characteristic histological marker of Parkinson’s
disease (PD). In vitro, α-syn in the presence of dopamine (DA) at physiological pH forms SDS-resistant non-amyloidogenic oligomers.
We used a combination of biophysical techniques, including sedimentation velocity analysis, small angle X-ray scattering (SAXS)
and circular dichroism spectroscopy to study the characteristics of α-syn oligomers formed in the presence of DA. Our SAXS
data show that the trimers formed by the action of DA on α-syn consist of overlapping worm-like monomers, with no end-to-end
associations. This lack of structure contrasts with the well-established, extensive β-sheet structure of the amyloid fibril
form of the protein and its pre-fibrillar oligomers. We propose on the basis of these and earlier data that oxidation of the
four methionine residues at the C- and N-terminal ends of α-syn molecules prevents their end-to-end association and stabilises
oligomers formed by cross linking with DA-quinone/DA-melanin, which are formed as a result of the redox process, thus inhibiting
formation of the β-sheet structure found in other pre-fibrillar forms of α-syn. 相似文献