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991.
Lihi Brocke Annie Bendahan Myriam Grunewald Baruch I Kanner 《The Journal of biological chemistry》2002,277(6):3985-3992
Sodium- and potassium-coupled transporters clear the excitatory neurotransmitter glutamate from the synaptic cleft. Their function is essential for effective glutamatergic neurotransmission. Glutamate transporters have an unusual topology, containing eight membrane-spanning domains and two reentrant loops of opposite orientation. We have introduced pairwise cysteine substitutions in several structural elements of the GLT-1 transporter. A complete inhibition of transport by Cu(II)(1,10-phenanthroline)(3) is observed in the double mutants A412C/V427C and A364C/S440C, but not in the corresponding single mutants. No inhibition is observed in more then 20 other double cysteine mutants. The Cu(II)(1,10-phenanthroline)(3) inhibition can be partly prevented by the nontransportable glutamate analogue dihydrokainate. Treatment with dithiothreitol restores much of the transport activity. Moreover, micromolar concentrations of cadmium ions reversibly inhibit transport catalyzed by A412C/V427C and A364C/S440C double mutants, but not by the corresponding single mutants. Inhibition by Cu(II)(1,10-phenanthroline)(3) and by cadmium is only observed when the cysteine pairs are introduced in the same polypeptide. Therefore, in both cases the proximity appears to be intra- rather than intermolecular. Positions 364 and 440 are located on reentrant loop I and II, respectively. Our results suggest that these two loops, previously shown to be essential for glutamate transport, come in close proximity. 相似文献
992.
Venkatesh Sampath Aaron C. Radish Annie L. Eis Katarzyna Broniowska Neil Hogg Girija G. Konduri 《Free radical biology & medicine》2009,46(5):663-671
Pulmonary vascular endothelial injury resulting from lipopolysaccharide (LPS) and oxygen toxicity contributes to vascular simplification seen in the lungs of premature infants with bronchopulmonary dysplasia. Whether the severity of endotoxin-induced endothelial injury is modulated by ambient oxygen tension (hypoxic intrauterine environment vs. hyperoxic postnatal environment) remains unknown. We posited that ovine fetal pulmonary artery endothelial cells (FPAEC) will be more resistant to LPS toxicity under hypoxic conditions (20–25 Torr) mimicking the fetal milieu. LPS (10 μg/ml) inhibited FPAEC proliferation and induced apoptosis under normoxic conditions (21% O2) in vitro. LPS-induced FPAEC apoptosis was attenuated in hypoxia (5% O2) and exacerbated by hyperoxia (55% O2). LPS increased intracellular superoxide formation, as measured by 2-hydroxyethidium (2-HE) formation, in FPAEC in normoxia and hypoxia. 2-HE formation in LPS-treated FPAEC increased in parallel with the severity of LPS-induced apoptosis in FPAEC, increasing from hypoxia to normoxia to hyperoxia. Differences in LPS-induced apoptosis between hypoxia and normoxia were abolished when LPS-treated FPAEC incubated in hypoxia were pretreated with menadione to increase superoxide production. Apocynin decreased 2-HE formation, and attenuated LPS-induced FPAEC apoptosis under normoxic conditions. We conclude that ambient oxygen concentration modulates the severity of LPS-mediated injury in FPAEC by regulating superoxide levels produced in response to LPS. 相似文献
993.
Geneviève Marcelin Catherine Diatloff-Zito Annie Nicole Jean-Jacques Robert 《Mammalian genome》2009,20(3):131-139
The human 6q24 region is involved in growth and development, transient neonatal diabetes (TND), cancer, and metabolic dysfunction.
To further characterize this region, the developmental status of DNA methylation and expression of Zac1 and Stx11 genes located within the mouse 10A1 region ortholog of human 6q24 were determined. In mice, imprinted Zac1 and Stx11 were highly expressed at the end of fetal development but downregulated at 4 and 11 weeks in brain, pancreas, and heart.
Postnatal Zac1 downregulation was independent from promoter methylation of the expressed allele, suggesting the mediation of age-dependent
chromatin remodeling. Stx11 nonpromoter CpG island was methylated de novo from E18 to 1 year with tissue-specific kinetics. The high conservation in
vertebrates of Stx11 CpG2 is suggestive of an important regulatory function in age-related regional epigenetic state and/or chromatin configuration.
Stx11 alleles were unequally expressed in F1 mice tissues, reflecting the influence of cis-regulatory factors on its expression. These data suggest the presence of a methylation domain and a coordinated gene expression
pattern in multiple tissues. Methylation variation and allelic regulation of expression may underlie genetic diversity and
contribute to disease susceptibility at the 6q24 locus in humans.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
994.
Carrie A. Millward Lindsay C. Burrage Haifeng Shao David S. Sinasac Jean H. Kawasoe Annie E. Hill-Baskin Sheila R. Ernest Aga Gornicka Chang-Wen Hsieh Sorana Pisano Joseph H. Nadeau Colleen M. Croniger 《Mammalian genome》2009,20(2):71-82
Obesity is associated with increased susceptibility to dyslipidemia, insulin resistance, and hypertension, a combination of
traits that comprise the traditional definition of the metabolic syndrome. Recent evidence suggests that obesity is also associated
with the development of nonalcoholic fatty liver disease (NAFLD). Despite the high prevalence of obesity and its related conditions,
their etiologies and pathophysiology remains unknown. Both genetic and environmental factors contribute to the development
of obesity and NAFLD. Previous genetic analysis of high-fat, diet-induced obesity in C57BL/6J (B6) and A/J male mice using
a panel of B6-ChrA/J/NaJ chromosome substitution strains (CSSs) demonstrated that 17 CSSs conferred resistance to high-fat, diet-induced obesity.
One of these CSS strains, CSS-17, which is homosomic for A/J-derived chromosome 17, was analyzed further and found to be resistant
to diet-induced steatosis. In the current study we generated seven congenic strains derived from CCS-17, fed them either a
high-fat, simple-carbohydrate (HFSC) or low-fat, simple-carbohydrate (LFSC) diet for 16 weeks and then analyzed body weight
and related traits. From this study we identified several quantitative trait loci (QTLs). On a HFSC diet, Obrq13 protects against diet-induced obesity, steatosis, and elevated fasting insulin and glucose levels. On the LFSC diet, Obrq13 confers lower hepatic triglycerides, suggesting that this QTL regulates liver triglycerides regardless of diet. Obrq15 protects against diet-induced obesity and steatosis on the HFSC diet, and Obrq14 confers increased final body weight and results in steatosis and insulin resistance on the HFSC diet. In addition, on the
LFSC diet, Obrq 16 confers decreased hepatic triglycerides and Obrq17 confers lower plasma triglycerides on the LFSC diet. These congenic strains provide mouse models to identify genes and metabolic
pathways that are involved in the development of NAFLD and aspects of diet-induced metabolic syndrome.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.
C. A. Millward and L. C. Burrage contributed equally to this work. 相似文献
995.
John M. Louis Rieko Ishima Annie Aniana Jane M. Sayer 《Protein science : a publication of the Protein Society》2009,18(12):2442-2453
Purification and in vitro protein‐folding schemes were developed to produce monodisperse samples of the mature wild‐type HIV‐2 protease (PR2), enabling a comprehensive set of biochemical and biophysical studies to assess the dissociation of the dimeric protease. An E37K substitution in PR2 significantly retards autoproteolytic cleavage during expression. Furthermore, it permits convenient measurement of the dimer dissociation of PR2E37K (elevated Kd ~20 nM) by enzyme kinetics. Differential scanning calorimetry reveals a Tm of 60.5 for PR2 as compared with 65.7°C for HIV‐1 protease (PR1). Consistent with weaker binding of the clinical inhibitor darunavir (DRV) to PR2, the Tm of PR2 increases by 14.8°C in the presence of DRV as compared with 22.4°C for PR1. Dimer interface mutations, such as a T26A substitution in the active site (PR2T26A) or a deletion of the C‐terminal residues 96–99 (PR21–95), drastically increase the Kd (>105‐fold). PR2T26A and PR21–95 consist predominantly of folded monomers, as determined by nuclear magnetic resonance (NMR) and size‐exclusion chromatography coupled with multiangle light scattering and refractive index measurements (SMR), whereas wild‐type PR2 and its active‐site mutant PR2D25N are folded dimers. Addition of twofold excess active‐site inhibitor promotes dimerization of PR2T26A but not of PR21–95, indicating that subunit interactions involving the C‐terminal residues are crucial for dimer formation. Use of SMR and NMR with PR2 facilitates probing for potential inhibitors that restrict protein folding and/or dimerization and, thus, may provide insights for the future design of inhibitors to circumvent drug resistance. 相似文献
996.
Background
The functional significance of proenkephalin systems in processing pain remains an open question and indeed is puzzling. For example, a noxious mechanical stimulus does not alter the release of Met-enkephalin-like material (MELM) from segments of the spinal cord related to the stimulated area of the body, but does increase its release from other segments.Methodology/Principal Findings
Here we show that, in the rat, a noxious mechanical stimulus applied to either the right or the left hind paw elicits a marked increase of MELM release during perifusion of either the whole spinal cord or the cervico-trigeminal area. However, these stimulatory effects were not additive and indeed, disappeared completely when the right and left paws were stimulated simultaneously.Conclusion/Significance
We have concluded that in addition to the concept of a diffuse control of the transmission of nociceptive signals through the dorsal horn, there is a diffuse control of the modulation of this transmission. The “freezing” of Met-enkephalinergic functions represents a potential source of central sensitization in the spinal cord, notably in clinical situations involving multiple painful foci, e.g. cancer with metastases, poly-traumatism or rheumatoid arthritis. 相似文献997.
Didier Bompangue Patrick Giraudoux Martine Piarroux Guy Mutombo Rick Shamavu Bertrand Sudre Annie Mutombo Vital Mondonge Renaud Piarroux 《PLoS neglected tropical diseases》2009,3(5)
Background
During the last eight years, North and South Kivu, located in a lake area in Eastern Democratic Republic of Congo, have been the site of a major volcano eruption and of numerous complex emergencies with population displacements. These conditions have been suspected to favour emergence and spread of cholera epidemics.Methodology/Principal Findings
In order to assess the influence of these conditions on outbreaks, reports of cholera cases were collected weekly from each health district of North Kivu (4,667,699 inhabitants) and South Kivu (4,670,121 inhabitants) from 2000 through 2007. A geographic information system was established, and in each health district, the relationships between environmental variables and the number of cholera cases were assessed using regression techniques and time series analysis. We further checked for a link between complex emergencies and cholera outbreaks. Finally, we analysed data collected during an epidemiological survey that was implemented in Goma after Nyiragongo eruption. A total of 73,605 cases and 1,612 deaths of cholera were reported. Time series decomposition showed a greater number of cases during the rainy season in South Kivu but not in North Kivu. Spatial distribution of cholera cases exhibited a higher number of cases in health districts bordering lakes (Odds Ratio 7.0, Confidence Interval range 3.8–12.9). Four epidemic reactivations were observed in the 12-week periods following war events, but simulations indicate that the number of reactivations was not larger than that expected during any random selection of period with no war. Nyiragongo volcanic eruption was followed by a marked decrease of cholera incidence.Conclusion/Significance
Our study points out the crucial role of some towns located in lakeside areas in the persistence of cholera in Kivu. Even if complex emergencies were not systematically followed by cholera epidemics, some of them enabled cholera spreading. 相似文献998.
Helicobacter pylori and Gastric Malignancy 总被引:2,自引:0,他引:2
999.
1000.
Annie S. P. Yang Sash Lopaticki Matthew T. O'Neill Sara M. Erickson Donna N. Douglas Norman M. Kneteman Justin A. Boddey 《Cellular microbiology》2017,19(9)
The malaria sporozoite injected by a mosquito migrates to the liver by traversing host cells. The sporozoite also traverses hepatocytes before invading a terminal hepatocyte and developing into exoerythrocytic forms. Hepatocyte infection is critical for parasite development into merozoites that infect erythrocytes, and the sporozoite is thus an important target for antimalarial intervention. Here, we investigated two abundant sporozoite proteins of the most virulent malaria parasite Plasmodium falciparum and show that they play important roles during cell traversal and invasion of human hepatocytes. Incubation of P. falciparum sporozoites with R1 peptide, an inhibitor of apical merozoite antigen 1 (AMA1) that blocks merozoite invasion of erythrocytes, strongly reduced cell traversal activity. Consistent with its inhibitory effect on merozoites, R1 peptide also reduced sporozoite entry into human hepatocytes. The strong but incomplete inhibition prompted us to study the AMA‐like protein, merozoite apical erythrocyte‐binding ligand (MAEBL). MAEBL‐deficient P. falciparum sporozoites were severely attenuated for cell traversal activity and hepatocyte entry in vitro and for liver infection in humanized chimeric liver mice. This study shows that AMA1 and MAEBL are important for P. falciparum sporozoites to perform typical functions necessary for infection of human hepatocytes. These two proteins therefore have important roles during infection at distinct points in the life cycle, including the blood, mosquito, and liver stages. 相似文献