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21.
Hiesinger PR Zhai RG Zhou Y Koh TW Mehta SQ Schulze KL Cao Y Verstreken P Clandinin TR Fischbach KF Meinertzhagen IA Bellen HJ 《Current biology : CB》2006,16(18):1835-1843
Specifying synaptic partners and regulating synaptic numbers are at least partly activity-dependent processes during visual map formation in all systems investigated to date . In Drosophila, six photoreceptors that view the same point in visual space have to be sorted into synaptic modules called cartridges in order to form a visuotopically correct map . Synapse numbers per photoreceptor terminal and cartridge are both precisely regulated . However, it is unknown whether an activity-dependent mechanism or a genetically encoded developmental program regulates synapse numbers. We performed a large-scale quantitative ultrastructural analysis of photoreceptor synapses in mutants affecting the generation of electrical potentials (norpA, trp;trpl), neurotransmitter release (hdc, syt), vesicle endocytosis (synj), the trafficking of specific guidance molecules during photoreceptor targeting (sec15), a specific guidance receptor required for visual map formation (Dlar), and 57 other novel synaptic mutants affecting 43 genes. Remarkably, in all these mutants, individual photoreceptors form the correct number of synapses per presynaptic terminal independently of cartridge composition. Hence, our data show that each photoreceptor forms a precise and constant number of afferent synapses independently of neuronal activity and partner accuracy. Our data suggest cell-autonomous control of synapse numbers as part of a developmental program of activity-independent steps that lead to a "hard-wired" visual map in the fly brain. 相似文献
22.
Doile MM Fortunato KA Schmücker IC Schucko SK Silva MA Rodrigues PO 《AAPS PharmSciTech》2008,9(1):314-321
Inclusion complexes between dexamethasone acetate (DMA), a poorly water soluble drug, and β-cyclodextrin (βCD) were obtained
to improve the solubility and dissolution rate of this drug. Phase-solubility profile indicated that the solubility of DMA
was significantly increased in the presence of βCD (33-fold) and was classified as AL-type, indicating the 1:1 stoichiometric inclusion complexes. Solid complexes prepared by different methods (kneading, coevaporation,
freeze drying) and physical mixture were characterized by differential scanning calorimetry, thermogravimetry, infrared absorption
and optical microscopy. Preparation methods influenced the physicochemical properties of the products. The dissolution profiles
of solid complexes were determined and compared with those DMA alone and their physical mixture, in three different mediums:
simulated gastric fluid (pH 1.2), simulated intestinal fluid (pH 7.4) and distilled water. The dissolution studies showed
that in all mediums DMA presented an incomplete dissolution even in four hours. In contrast, the complexes formed presented
a higher dissolution rate in simulated gastric fluid (SGF pH 1.2), which indicate that these have different ionization characteristics.
According to the results, the freeze–dried and kneaded products exhibited higher dissolution rates than the drug alone, in
all the mediums. 相似文献
23.
Grinblat-Huse V Drabek EF Creasy HH Daugherty SC Jones KM Santana-Cruz I Tallon LJ Read TD Hatch TP Bavoil P Myers GS 《Journal of bacteriology》2011,193(15):4039-4040
Chlamydia psittaci is a highly prevalent avian pathogen and the cause of a potentially lethal zoonosis, causing life-threatening pneumonia in humans. We report the genome sequences of C. psittaci 6BC, the prototype strain of the species, and C. psittaci Cal10, a widely used laboratory strain. 相似文献
24.
Glucagon stimulates exocytosis in mouse and rat pancreatic alpha-cells by binding to glucagon receptors 总被引:2,自引:0,他引:2
Ma X Zhang Y Gromada J Sewing S Berggren PO Buschard K Salehi A Vikman J Rorsman P Eliasson L 《Molecular endocrinology (Baltimore, Md.)》2005,19(1):198-212
Glucagon, secreted by the pancreatic alpha-cells, stimulates insulin secretion from neighboring beta-cells by cAMP- and protein kinase A (PKA)-dependent mechanisms, but it is not known whether glucagon also modulates its own secretion. We have addressed this issue by combining recordings of membrane capacitance (to monitor exocytosis) in individual alpha-cells with biochemical assays of glucagon secretion and cAMP content in intact pancreatic islets, as well as analyses of glucagon receptor expression in pure alpha-cell fractions by RT-PCR. Glucagon stimulated cAMP generation and exocytosis dose dependently with an EC50 of 1.6-1.7 nm. The stimulation of both parameters plateaued at concentrations beyond 10 nm of glucagon where a more than 3-fold enhancement was observed. The actions of glucagon were unaffected by the GLP-1 receptor antagonist exendin-(9-39) but abolished by des-His1-[Glu9]-glucagon-amide, a specific blocker of the glucagon receptor. The effects of glucagon on alpha-cell exocytosis were mimicked by forskolin and the stimulatory actions of glucagon and forskolin on exocytosis were both reproduced by intracellular application of 0.1 mm cAMP. cAMP-potentiated exocytosis involved both PKA-dependent and -independent (resistant to Rp-cAMPS, an Rp-isomer of cAMP) mechanisms. The presence of the cAMP-binding protein cAMP-guanidine nucleotide exchange factor II in alpha-cells was documented by a combination of immunocytochemistry and RT-PCR and 8-(4-chloro-phenylthio)-2'-O-methyl-cAMP, a cAMP-guanidine nucleotide exchange factor II-selective agonist, mimicked the effect of cAMP and augmented rapid exocytosis in a PKA-independent manner. We conclude that glucagon released from the alpha-cells, in addition to its well-documented systemic effects and paracrine actions within the islet, also represents an autocrine regulator of alpha-cell function. 相似文献
25.
Hannah Ryan Patrik G Flammer Rebecca Nicholson Louise Loe Ben Reeves Enid Allison Christopher Guy Ins Lopez Doriga Tony Waldron Don Walker Claas Kirchhelle Greger Larson Adrian L Smith 《PLoS neglected tropical diseases》2022,16(4)
Intestinal helminth parasites (worms) have afflicted humans throughout history and their eggs are readily detected in archaeological deposits including at locations where intestinal parasites are no longer considered endemic (e.g. the UK). Parasites provide valuable archaeological insights into historical health, sanitation, hygiene, dietary and culinary practices, as well as other factors. Differences in the prevalence of helminths over time may help us understand factors that affected the rate of infection of these parasites in past populations. While communal deposits often contain relatively high numbers of parasite eggs, these cannot be used to calculate prevalence rates, which are a key epidemiological measure of infection. The prevalence of intestinal helminths was investigated through time in England, based on analysis of 464 human burials from 17 sites, dating from the Prehistoric to Industrial periods. Eggs from two faecal-oral transmitted nematodes (Ascaris sp. and Trichuris sp.) and the food-derived cestodes (Taenia spp. and Diphyllobothrium latum syn Dibothriocephalus latus) were identified, although only Ascaris was detected at a high frequency. The changing prevalence of nematode infections can be attributed to changes in effective sanitation or other factors that affect these faecal-oral transmitted parasites and the presence of cestode infections reflect dietary and culinary preferences. These results indicate that the impact of helminth infections on past populations varied over time, and that some locations witnessed a dramatic reduction in parasite prevalence during the industrial era (18th-19th century), whereas other locations continued to experience high prevalence levels. The factors underlying these reductions and the variation in prevalence provide a key historical context for modern anthelmintic programs. 相似文献
26.
Johannes Schilling Christian Jost Ioana Mariuca Ilie Joachim Schnabl Oralea Buechi Rohan S. Eapen Rafaela Truffer Amedeo Caflisch Patrik Forrer 《The Journal of biological chemistry》2022,298(1)
Designed ankyrin repeat proteins (DARPins) are antibody mimetics with high and mostly unexplored potential in drug development. By using in silico analysis and a rationally guided Ala scanning, we identified position 17 of the N-terminal capping repeat to play a key role in overall protein thermostability. The melting temperature of a DARPin domain with a single full-consensus internal repeat was increased by 8 °C to 10 °C when Asp17 was replaced by Leu, Val, Ile, Met, Ala, or Thr. We then transferred the Asp17Leu mutation to various backgrounds, including clinically validated DARPin domains, such as the vascular endothelial growth factor-binding domain of the DARPin abicipar pegol. In all cases, these proteins showed improvements in the thermostability on the order of 8 °C to 16 °C, suggesting the replacement of Asp17 could be generically applicable to this drug class. Molecular dynamics simulations showed that the Asp17Leu mutation reduces electrostatic repulsion and improves van-der-Waals packing, rendering the DARPin domain less flexible and more stable. Interestingly, this beneficial Asp17Leu mutation is present in the N-terminal caps of three of the five DARPin domains of ensovibep, a SARS-CoV-2 entry inhibitor currently in clinical development, indicating this mutation could be partly responsible for the very high melting temperature (>90 °C) of this promising anti-COVID-19 drug. Overall, such N-terminal capping repeats with increased thermostability seem to be beneficial for the development of innovative drugs based on DARPins. 相似文献
27.
Yasmin Silva Rizk Alice Fischer Marillin de Castro Cunha Patrik Oening Rodrigues Maria Carolina Silva Marques Maria de Fátima Cepa Matos M?nica Cristina Toffoli Kadri Carlos Alexandre Carollo Carla Cardozo Pinto de Arruda 《Memórias do Instituto Oswaldo Cruz》2014,109(8):1050-1056
This study is the first phytochemical investigation of Selaginella sellowii
and demonstrates the antileishmanial activity of the hydroethanolic extract
from this plant (SSHE), as well as of the biflavonoids amentoflavone and
robustaflavone, isolated from this species. The effects of these substances were
evaluated on intracellular amastigotes of Leishmania (Leishmania)
amazonensis, an aetiological agent of American cutaneous leishmaniasis.
SSHE was highly active against intracellular amastigotes [the half maximum inhibitory
concentration (IC50) = 20.2 µg/mL]. Fractionation of the extract led to the isolation
of the two bioflavonoids with the highest activity: amentoflavone, which was about
200 times more active (IC50 = 0.1 μg/mL) and less cytotoxic than SSHE (IC50 = 2.2 and
3 μg/mL, respectively on NIH/3T3 and J774.A1 cells), with a high selectivity index
(SI) (22 and 30), robustaflavone, which was also active against L.
amazonensis (IC50 = 2.8 µg/mL), but more cytotoxic, with IC50 = 25.5
µg/mL (SI = 9.1) on NIH/3T3 cells and IC50 = 3.1 µg/mL (SI = 1.1) on J774.A1 cells.
The production of nitric oxide (NO) was lower in cells treated with amentoflavone
(suggesting that NO does not contribute to the leishmanicidal mechanism in this
case), while NO release was higher after treatment with robustaflavone. S.
sellowii may be a potential source of biflavonoids that could provide
promising compounds for the treatment of cutaneous leishmaniasis. 相似文献
28.
29.
Plett JM Gibon J Kohler A Duffy K Hoegger PJ Velagapudi R Han J Kües U Grigoriev IV Martin F 《Fungal genetics and biology : FG & B》2012,49(3):199-209
Hydrophobins are morphogenetic, small secreted hydrophobic fungal proteins produced in response to changing development and environmental conditions. These proteins are important in the interaction between certain fungi and their hosts. In mutualistic ectomycorrhizal fungi several hydrophobins form a subclass of mycorrhizal-induced small secreted proteins that are likely to be critical in the formation of the symbiotic interface with host root cells. In this study, two genomes of the ectomycorrhizal basidiomycete Laccaria bicolor strains S238N-H82 (from North America) and 81306 (from Europe) were surveyed to construct a comprehensive genome-wide inventory of hydrophobins and to explore their characteristics and roles during host colonization. The S238N-H82 L. bicolor hydrophobin gene family is composed of 12 genes while the 81306 strain encodes nine hydrophobins, all corresponding to class I hydrophobins. The three extra hydrophobin genes encoded by the S238N-H82 genome likely arose via gene duplication and are bordered by transposon rich regions. Expression profiles of the hydrophobin genes of L. bicolor varied greatly depending on life stage (e.g. free living mycelium vs. root colonization) and on the host root environment. We conclude from this study that the complex diversity and range of expression profiles of the Laccaria hydrophobin multi-gene family have likely been a selective advantage for this mutualist in colonizing a wide range of host plants. 相似文献
30.