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81.
Salman A. Rahman Sheila K. West Harran Mkocha Beatriz Munoz Travis C. Porco Jeremy D. Keenan Thomas M. Lietman 《PLoS neglected tropical diseases》2015,9(3)
BackgroundMathematical models predict an exponential distribution of infection prevalence across communities where a disease is disappearing. Trachoma control programs offer an opportunity to test this hypothesis, as the World Health Organization has targeted trachoma for elimination as a public health concern by the year 2020. Local programs may benefit if a single survey could reveal whether infection was headed towards elimination. Using data from a previously-published 2009 survey, we test the hypothesis that Chlamydia trachomatis prevalence across 75 Tanzanian communities where trachoma had been documented to be disappearing is exponentially distributed.Methods/FindingsWe fit multiple continuous distributions to the Tanzanian data and found the exponential gave the best approximation. Model selection by Akaike Information Criteria (AICc) suggested the exponential distribution had the most parsimonious fit to the data. Those distributions which do not include the exponential as a special or limiting case had much lower likelihoods of fitting the observed data. 95% confidence intervals for shape parameter estimates of those distributions which do include the exponential as a special or limiting case were consistent with the exponential. Lastly, goodness-of-fit testing was unable to reject the hypothesis that the prevalence data came from an exponential distribution.ConclusionsModels correctly predict that infection prevalence across communities where a disease is disappearing is best described by an exponential distribution. In Tanzanian communities where local control efforts had reduced the clinical signs of trachoma by 80% over 10 years, an exponential distribution gave the best fit to prevalence data. An exponential distribution has a relatively heavy tail, thus occasional high-prevalence communities are to be expected even when infection is disappearing. A single cross-sectional survey may be able to reveal whether elimination efforts are on-track. 相似文献
82.
83.
Matthew G. Stanton Jed Hubbs David Sloman Christopher Hamblett Paula Andrade Minilik Angagaw Grace Bi Regina M. Black Jamie Crispino Jonathan C. Cruz Eric Fan Georgia Farris Bethany L. Hughes Candia M. Kenific Richard E. Middleton George Nikov Peter Sajonz Sanjiv Shah Nirah Shomer Alexander A. Szewczak Benito Munoz 《Bioorganic & medicinal chemistry letters》2010,20(2):755-758
We report herein a novel series of difluoropiperidine acetic acids as modulators of γ-secretase. Synthesis of 2-aryl-3,3-difluoropiperidine analogs was facilitated by a unique and selective β-difluorination with Selectfluor®. Compounds 1f and 2c were selected for in vivo assessment and demonstrated selective lowering of Aβ42 in a genetically engineered mouse model of APP processing. Moreover, in a 7-day safety study, rats treated orally with compound 1f (250 mg/kg per day, AUC0–24 = 2100 μM h) did not exhibit Notch-related effects. 相似文献
84.
Rojas G Lamdan H Padron S Munoz Y Ayala M Gavilondo JV 《Biochemical and biophysical research communications》2005,336(4):1207-1213
We have constructed a highly useful phage-displayed human antibody repertoire with limited cloning efforts. Our strategy was to maximize diversity during the first steps of library construction through the use of various lymphoid sources from several donors, inclusion of different immunoglobulin isotypes, and performance of multiple separate amplification reactions with all possible combinations within a complex primer set. The resulting variable region collections were cloned to form a moderate size library, composed by 4.25x10(8) single chain antibody fragments. This repertoire was successfully used to retrieve binders to seven model antigens: six proteins and one 12 aa peptide. Binding affinities reached nanomolar and even subnanomolar range. Sequence diversity and V-gene usage variability among binders were proven. Our approach was not focused on absolute library size, but on a high quality sampling of variable regions from the human antibody repertoire. 相似文献
85.
John M. VandenBrooks Elyse E. Munoz Michael D. Weed Colleen F. Ford Michael A. Harrison Jon F. Harrison 《Evolutionary biology》2012,39(1):83-93
Atmospheric oxygen has varied substantially over the Phanerozoic (the last 500 million years) with periods of both hyperoxia
and hypoxia relative to today. Unlike some insect groups, cockroaches have not been reported to exhibit gigantism during the
late Paleozoic period of hyperoxia. Studies with modern insects have shown a diversity of developmental responses to oxygen,
suggesting that evaluation of historical hypotheses should focus on groups most closely related to those present in the Paleozoic.
Here we investigated the impacts of Paleozoic oxygen levels (12–31%) on the development of Blatella germanica cockroaches. Body size decreased strongly in hypoxia, but was only mildly affected by hyperoxia. Development time, growth
rate and fecundity were negatively impacted by both hypoxia and hyperoxia. Tracheal volumes were inversely proportional to
rearing oxygen, suggesting developmental responses aimed at regulating internal oxygen level. The results of these experiments
on a modern species are consistent with the fossil record and suggest that changes in atmospheric oxygen would be challenging
for many insects, despite plastic compensatory responses in the tracheal system. 相似文献
86.
Youngsaye W Dockendorff C Vincent B Hartland CL Bittker JA Dandapani S Palmer M Whitesell L Lindquist S Schreiber SL Munoz B 《Bioorganic & medicinal chemistry letters》2012,22(9):3362-3365
Continuing efforts to discover novel means of combating fluconazole resistance in Candida albicans have identified an indole derivative that sensitizes strains demonstrating resistance to fluconazole. This tetracycle (3, ML229) does not appear to act through established Hsp90 or calcineurin pathways to chemosensitize C. albicans, as determined in Saccharomyces cerevisiae models, and may be a useful probe to uncover alternative resistance pathways. 相似文献
87.
Gower EW West SK Cassard SD Munoz BE Harding JC Merbs SL 《PLoS neglected tropical diseases》2012,6(6):e1713
Background
Clear definitions of outcomes following trichiasis surgery are critical for planning program evaluations and for identifying ways to improve trichiasis surgery. Eyelid contour abnormality is an important adverse outcome of surgery; however, no standard method has been described to categorize eyelid contour abnormalities.Methodology/Principal Findings
A classification system for eyelid contour abnormalities following surgery for trachomatous trichiasis was developed. To determine whether the grading was reproducible using the classification system, six-week postoperative photographs were reviewed by two senior graders to characterize severity of contour abnormalities. Sample photographs defining each contour abnormality category were compiled and used to train four new graders. All six graders independently graded a Standardization Set of 75 eyelids, which included a roughly equal distribution across the severity scale, and weighted kappa scores were calculated. Two hundred forty six-week postoperative photographs from an ongoing clinical trial were randomly selected for evaluating agreement across graders. Two months after initial grading, one grader regraded a subset of the 240 photographs to measure longer-term intra-observer agreement. The weighted kappa for agreement between the two senior graders was 0.80 (95% CI: 0.71–0.89). Among the Standardization Set, agreement between the senior graders and the 4 new graders showed weighted kappa scores ranging from 0.60–0.80. Among 240 eyes comprising the clinical trial dataset, agreement ranged from weighted kappa 0.70–0.71. Longer-term intra-observer agreement was weighted kappa 0.86 (95% CI: 0.80–0.92).Conclusions/Significance
The standard eyelid contour grading system we developed reproducibly delineates differing levels of contour abnormality. This grading system could be useful both for helping to evaluate trichiasis surgery outcomes in clinical trials and for evaluating trichiasis surgery programs. 相似文献88.
Herrera FE Chesi A Paleologou KE Schmid A Munoz A Vendruscolo M Gustincich S Lashuel HA Carloni P 《PloS one》2008,3(10):e3394
The interplay between dopamine and alpha-synuclein (AS) plays a central role in Parkinson's disease (PD). PD results primarily from a severe and selective devastation of dopaminergic neurons in substantia nigra pars compacta. The neuropathological hallmark of the disease is the presence of intraneuronal proteinaceous inclusions known as Lewy bodies within the surviving neurons, enriched in filamentous AS. In vitro, dopamine inhibits AS fibril formation, but the molecular determinants of this inhibition remain obscure. Here we use molecular dynamic (MD) simulations to investigate the binding of dopamine and several of its derivatives onto conformers representative of an NMR ensemble of AS structures in aqueous solution. Within the limitations inherent to MD simulations of unstructured proteins, our calculations suggest that the ligands bind to the (125)YEMPS(129) region, consistent with experimental findings. The ligands are further stabilized by long-range electrostatic interactions with glutamate 83 (E83) in the NAC region. These results suggest that by forming these interactions with AS, dopamine may affect AS aggregation and fibrillization properties. To test this hypothesis, we investigated in vitro the effects of dopamine on the aggregation of mutants designed to alter or abolish these interactions. We found that point mutations in the (125)YEMPS(129) region do not affect AS aggregation, which is consistent with the fact that dopamine interacts non-specifically with this region. In contrast, and consistent with our modeling studies, the replacement of glutamate by alanine at position 83 (E83A) abolishes the ability of dopamine to inhibit AS fibrillization. 相似文献
89.
Comtois P Sakabe M Vigmond EJ Munoz M Texier A Shiroshita-Takeshita A Nattel S 《American journal of physiology. Heart and circulatory physiology》2008,295(4):H1489-H1504
Atrial fibrillation (AF) is the most common sustained clinical arrhythmia and is a problem of growing proportions. Recent studies have increased interest in fast-unbinding Na(+) channel blockers like vernakalant (RSD1235) and ranolazine for AF therapy, but the mechanism of efficacy is poorly understood. To study how fast-unbinding I(Na) blockers affect AF, we developed realistic mathematical models of state-dependent Na(+) channel block, using a lidocaine model as a prototype, and studied the effects on simulated cholinergic AF in two- and three-dimensional atrial substrates. We then compared the results with in vivo effects of lidocaine on vagotonic AF in dogs. Lidocaine action was modeled with the Hondeghem-Katzung modulated-receptor theory and maximum affinity for activated Na(+) channels. Lidocaine produced frequency-dependent Na(+) channel blocking and conduction slowing effects and terminated AF in both two- and three-dimensional models with concentration-dependent efficacy (maximum approximately 89% at 60 microM). AF termination was not related to increases in wavelength, which tended to decrease with the drug, but rather to decreased source Na(+) current in the face of large ACh-sensitive K(+) current-related sinks, leading to the destabilization of primary generator rotors and a great reduction in wavebreak, which caused primary rotor annihilations in the absence of secondary rotors to resume generator activity. Lidocaine also reduced the variability and maximum values of the dominant frequency distribution during AF. Qualitatively similar results were obtained in vivo for lidocaine effects on vagal AF in dogs, with an efficacy of 86% at 2 mg/kg iv, as well as with simulations using the guarded-receptor model of lidocaine action. These results provide new insights into the mechanisms by which rapidly unbinding class I antiarrhythmic agents, a class including several novel compounds of considerable promise, terminate AF. 相似文献
90.
Localization of eukaryotic initiation factor 2 in neuron primary cultures and established cell lines
Maria V. T. Lobo F. Javier M. Alonso Susana Rodriguez Alberto Alcazar Elena Martin Francisco Munoz Rafael G-Santander Matilde Salinas Juan L. Fando 《The Histochemical journal》1997,29(6):453-468
Eukaryotic initiation factor 2 (eIF-2) is a heterotrimeric protein with subunits α, β and γ that forms a ternary complex with
Met-tRNA and GTP. It promotes the binding of Met-tRNA to ribosomes and controls translational rates via phosphorylation/dephosphorylation
mechanisms. By means of immunofluorescence and post-embedding immunocytochemistry of intact cells and quantitative immunoblotting
of cell extracts, the cellular distribution of the initiation factor has been examined in primary neuronal cultures as well
as in two established cell lines: PC12 phaeochromocytoma cells and rat pituitary GH4C1 cells. Our results indicated that the
initiation factor is located not only in the cytoplasm but also in the nuclei of the cultured neurons and cell lines. In the
cytoplasm, immunocytochemical studies reveal that the factor is present mainly in those areas that are rich in ribosomes.
In the nucleus, the immunolabelling of eukaryotic initiation factor 2 verified the presence of gold particles in both nucleolar
and extranucleolar areas. The specific distribution of this factor on both sides of the nuclear envelope suggests that it
might have some nuclear-related function(s) besides its already known role in the control of translation 相似文献