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101.
102.
Schalk-Hihi C Schubert C Alexander R Bayoumy S Clemente JC Deckman I DesJarlais RL Dzordzorme KC Flores CM Grasberger B Kranz JK Lewandowski F Liu L Ma H Maguire D Macielag MJ McDonnell ME Mezzasalma Haarlander T Miller R Milligan C Reynolds C Kuo LC 《Protein science : a publication of the Protein Society》2011,20(4):670-683
A high-resolution structure of a ligand-bound, soluble form of human monoglyceride lipase (MGL) is presented. The structure highlights a novel conformation of the regulatory lid-domain present in the lipase family as well as the binding mode of a pharmaceutically relevant reversible inhibitor. Analysis of the structure lacking the inhibitor indicates that the closed conformation can accommodate the native substrate 2-arachidonoyl glycerol. A model is proposed in which MGL undergoes conformational and electrostatic changes during the catalytic cycle ultimately resulting in its dissociation from the membrane upon completion of the cycle. In addition, the study outlines a successful approach to transform membrane associated proteins, which tend to aggregate upon purification, into a monomeric and soluble form. 相似文献
103.
Chen A Aspiotis R Campeau LC Cauchon E Chefson A Ducharme Y Falgueyret JP Gagné S Han Y Houle R Laliberté S Larouche G Lévesque JF McKay D Percival D 《Bioorganic & medicinal chemistry letters》2011,21(24):7399-7404
The discovery and SAR of a novel series of spirocyclic renin inhibitors are described herein. It was found that by restricting the northern aromatic plate to the bioactive conformation through spirocyclization, increase in renin potency and decrease in hERG affinity could both be realized. When early members of this series were found to be potent time-dependent CYP3A4 inhibitors, two distinct strategies to address this liability were explored and this effort culminated in the identification of compound 31 as an optimized renin inhibitor. 相似文献
104.
Nanna M Jensen Trine Dalsgaard Maria Jakobsen Roni R Nielsen Charlotte B Sørensen Lars Bolund Thomas G Jensen 《Journal of biomedical science》2011,18(1):10
Transfer of full-length genes including regulatory elements has been the preferred gene therapy strategy for clinical applications.
However, with significant drawbacks emerging, targeted gene alteration (TGA) has recently become a promising alternative to
this method. By means of TGA, endogenous DNA repair pathways of the cell are activated leading to specific genetic correction
of single-base mutations in the genome. This strategy can be implemented using single-stranded oligodeoxyribonucleotides (ssODNs),
small DNA fragments (SDFs), triplex-forming oligonucleotides (TFOs), adeno-associated virus vectors (AAVs) and zinc-finger
nucleases (ZFNs). Despite difficulties in the use of TGA, including lack of knowledge on the repair mechanisms stimulated
by the individual methods, the field holds great promise for the future. The objective of this review is to summarize and
evaluate the different methods that exist within this particular area of human gene therapy research. 相似文献
105.
Fat embolization (FE), the introduction of bone marrow elements into circulation, is a known complication of bone fractures. Although FE has been described in other animal models, this study represents the first reported cases of FE and bone marrow embolism in nonhuman primates. Histopathologic findings from cynomolgus macaques (Macaca fascicularis) indicated that in all 5 cases, fat and bone marrow embolization occurred subsequent to multiple bone marrow biopsies. In the most severe case, extensive embolization was associated pulmonary damage consistent with acute respiratory distress syndrome. Fat embolism syndrome (FES) is an infrequent clinical outcome of FE and is triggered by systemic biochemical and mechanical responses to fat in circulation. Although clinical criteria diagnostic of FES were not investigated at the time of death, this severe case may represent the fulminant form of FES, which occurs within 12 h after trauma. Bone marrow biopsy as an etiology of FES has been reported only once in humans. In addition, the association of embolization with bone marrow biopsies suggests that nonhuman primates may be a useful animal model of FE. FE and FES represent important research confounders and FES should be considered as a differential diagnosis for clinical complications subsequent to skeletal trauma. 相似文献
106.
Paik J Fierce Y Mai PO Phelps SR McDonald T Treuting P Drivdahl R Brabb T LeBoeuf R O'Brien KD Maggio-Price L 《Comparative medicine》2011,61(4):330-338
Murine norovirus (MNV) is prevalent in rodent facilities in the United States. Because MNV has a tropism for macrophages and dendritic cells, we hypothesized that it may alter phenotypes of murine models of inflammatory diseases, such as obesity and atherosclerosis. We examined whether MNV infection influences phenotypes associated with diet-induced obesity and atherosclerosis by using Ldlr(-/-) mice. Male Ldlr(-/-) mice were maintained on either a diabetogenic or high-fat diet for 16 wk, inoculated with either MNV or vehicle, and monitored for changes in body weight, blood glucose, glucose tolerance, and insulin sensitivity. Influence of MNV on atherosclerosis was analyzed by determining aortic sinus lesion area. Under both dietary regimens, MNV-infected and control mice gained similar amounts of weight and developed similar degrees of insulin resistance. However, MNV infection was associated with significant increases in aortic sinus lesion area and macrophage content in Ldlr(-/-) mice fed a high-fat diet but not those fed a diabetogenic diet. In conclusion, MNV infection exacerbates atherosclerosis in Ldlr(-/-) mice fed a high-fat diet but does not influence obesity- and diabetes-related phenotypes. Increased lesion size was associated with increased macrophages, suggesting that MNV may influence macrophage activation or accumulation in the lesion area. 相似文献
107.
Rønnest NP Stocks SM Eliasson Lantz A Gernaey KV 《Journal of industrial microbiology & biotechnology》2011,38(10):1679-1690
The recent process analytical technology (PAT) initiative has put an increased focus on online sensors to generate process-relevant
information in real time. Specifically for fermentation, however, introduction of online sensors is often far from straightforward,
and online measurement of biomass is one of the best examples. The purpose of this study was therefore to compare the performance
of various online biomass sensors, and secondly to demonstrate their use in early development of a filamentous cultivation
process. Eight Streptomyces coelicolor fed-batch cultivations were run as part of process development in which the pH, the feeding strategy, and the medium composition
were varied. The cultivations were monitored in situ using multi-wavelength fluorescence (MWF) spectroscopy, scanning dielectric
(DE) spectroscopy, and turbidity measurements. In addition, we logged all of the classical cultivation data, such as the carbon
dioxide evolution rate (CER) and the concentration of dissolved oxygen. Prediction models for the biomass concentrations were
estimated on the basis of the individual sensors and on combinations of the sensors. The results showed that the more advanced
sensors based on MWF and scanning DE spectroscopy did not offer any advantages over the simpler sensors based on dual frequency
DE spectroscopy, turbidity, and CER measurements for prediction of biomass concentration. By combining CER, DE spectroscopy,
and turbidity measurements, the prediction error was reduced to 1.5 g/l, corresponding to 6% of the covered biomass range.
Moreover, by using multiple sensors it was possible to check the quality of the individual predictions and switch between
the sensors in real time. 相似文献
108.
109.
Delgado S Castillo Neyra R Quispe Machaca VR Ancca Juárez J Chou Chu L Verastegui MR Moscoso Apaza GM Bocángel CD Tustin AW Sterling CR Comrie AC Náquira C Cornejo del Carpio JG Gilman RH Bern C Levy MZ 《PLoS neglected tropical diseases》2011,5(2):e970
Background
The history of Chagas disease control in Peru and many other nations is marked by scattered and poorly documented vector control campaigns. The complexities of human migration and sporadic control campaigns complicate evaluation of the burden of Chagas disease and dynamics of Trypanosoma cruzi transmission.Methodology/Principal Findings
We conducted a cross-sectional serological and entomological study to evaluate temporal and spatial patterns of T. cruzi transmission in a peri-rural region of La Joya, Peru. We use a multivariate catalytic model and Bayesian methods to estimate incidence of infection over time and thereby elucidate the complex history of transmission in the area. Of 1,333 study participants, 101 (7.6%; 95% CI: 6.2–9.0%) were confirmed T. cruzi seropositive. Spatial clustering of parasitic infection was found in vector insects, but not in human cases. Expanded catalytic models suggest that transmission was interrupted in the study area in 1996 (95% credible interval: 1991–2000), with a resultant decline in the average annual incidence of infection from 0.9% (95% credible interval: 0.6–1.3%) to 0.1% (95% credible interval: 0.005–0.3%). Through a search of archival newspaper reports, we uncovered documentation of a 1995 vector control campaign, and thereby independently validated the model estimates.Conclusions/Significance
High levels of T. cruzi transmission had been ongoing in peri-rural La Joya prior to interruption of parasite transmission through a little-documented vector control campaign in 1995. Despite the efficacy of the 1995 control campaign, T. cruzi was rapidly reemerging in vector populations in La Joya, emphasizing the need for continuing surveillance and control at the rural-urban interface. 相似文献110.
Deep‐UV resonance Raman (UVRR) spectroscopy and circular dichroism (CD) were employed to study the secondary structure of Aβ(1–42) in fresh samples with increasing fractions of oligomeric peptide. A feature with a minimum at ~217 nm appeared in CD spectra of samples containing oligomeric Aβ(1–42). UVRR spectra more closely resembled those of disordered proteins. The primary difference between UVRR spectra was the ratio of the 1236 cm–1 to 1260 cm–1 amide III peak intensities, which shifted in favor of the 1236 cm–1 band as the fraction of oligomeric peptide increased. (© 2011 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim) 相似文献