全文获取类型
收费全文 | 553篇 |
免费 | 45篇 |
出版年
2022年 | 3篇 |
2021年 | 8篇 |
2020年 | 3篇 |
2019年 | 6篇 |
2018年 | 8篇 |
2017年 | 9篇 |
2016年 | 17篇 |
2015年 | 29篇 |
2014年 | 27篇 |
2013年 | 24篇 |
2012年 | 27篇 |
2011年 | 31篇 |
2010年 | 22篇 |
2009年 | 15篇 |
2008年 | 25篇 |
2007年 | 26篇 |
2006年 | 30篇 |
2005年 | 26篇 |
2004年 | 32篇 |
2003年 | 17篇 |
2002年 | 24篇 |
2001年 | 12篇 |
2000年 | 6篇 |
1999年 | 10篇 |
1998年 | 10篇 |
1997年 | 12篇 |
1996年 | 10篇 |
1995年 | 9篇 |
1994年 | 11篇 |
1993年 | 6篇 |
1992年 | 11篇 |
1991年 | 7篇 |
1990年 | 4篇 |
1989年 | 6篇 |
1988年 | 9篇 |
1987年 | 5篇 |
1985年 | 4篇 |
1984年 | 3篇 |
1983年 | 4篇 |
1982年 | 5篇 |
1980年 | 2篇 |
1979年 | 2篇 |
1978年 | 5篇 |
1976年 | 2篇 |
1975年 | 4篇 |
1974年 | 6篇 |
1973年 | 2篇 |
1971年 | 4篇 |
1969年 | 2篇 |
1957年 | 2篇 |
排序方式: 共有598条查询结果,搜索用时 15 毫秒
121.
Landry F Chan CC Huang Z Leclair G Li CS Oballa R Zhang L Bateman K 《Journal of lipid research》2011,52(8):1494-1499
A positive correlation between stearoyl-CoA desaturase (SCD)1 expression and metabolic diseases has been reported in rodents and humans. These findings indicate that SCD1 is a promising therapeutic target for the chronic treatment of diabetes and dyslipidemia. The SCD1 enzyme is expressed at high levels in several human tissues and is required for the biosynthesis of monounsaturated fatty acids, which are involved in many biological processes. Liver-targeted SCD inhibitors were designed to pharmacologically manipulate SCD1 activity in the liver to avoid adverse events due to systemic inhibition. This article describes the development of a plasma-based SCD assay to assess the level of SCD inhibition, which is defined in this article as target engagement. Essentially, animals are dosed with an exogenous deuterated tracer (d7-stearic acid) as substrate, and the converted d7-oleic acid product is measured to monitor SCD1 inhibition. This study reveals that this plasma-based assay correlates with liver SCD1 inhibition and can thus have clinical utility. 相似文献
122.
de Buron I France SG Connors VA Roumillat WA Tsoi LC 《The Journal of parasitology》2011,97(3):466-475
Two species of philometrid nematode, Philometra overstreeti and Philometroides paralichthydis, infect the southern flounder, Paralichthys lethostigma. Individuals of P. overstreeti are located between the teeth and inside the bony part of the branchial arches of the fish. Individuals of P. paralichthydis are associated with the bones of the buccal cavity and among muscles that control the dorsal and anal fins. Sequencing of part of the cytochrome oxidase I gene revealed 4 distinct genetic clades, each corresponding exactly to the 4 respective locations of the parasites in the host, suggesting the need for taxonomic revision. We hypothesized that each clade represented a separate species and, because the worms are morphologically indistinguishable, compared population level parameters of the clades comprising each currently recognized species. For each currently recognized species, the presence of worms from 1 clade was negatively correlated with the presence of worms from the other. Results also indicated significant differences between the clades in prevalences relative to both biotic and abiotic factors. Results clearly indicated major differences in the ecology of the philometrids constituting each clade. Taken as a whole, molecular and ecological data support the contention that the 4 genetic clades are likely 4 distinct species. 相似文献
123.
He K Chan CB Liu X Jia Y Luo HR France SA Liu Y Wilson WD Ye K 《The Journal of biological chemistry》2011,286(43):37379-37388
Insulin exerts its actions through the insulin receptor (IR) and plays an essential role in diabetes. The inconvenient daily injection and undesirable side-effects associated with insulin injection demand novel drugs for the diseases. To search for bioactive insulin mimetics, we developed an in vitro screening assay using phospho-IR ELISA. After screening the small molecule chemical libraries, we have obtained a compound (5,8-diacetyloxy-2,3-dichloro-1,4-naphthoquinone) that provokes IR activation by directly binding to the receptor kinase domain to trigger its kinase activity at micromolar concentrations. This compound selectively activates IR but not other receptors and sensitizes insulin's action. Moreover, it elevates glucose uptake in adipocytes and has oral hypoglycemic effect in wild-type C57BL/6J mice and db/db and ob/ob mice without demonstrable toxicity. Hence, this promising compound mimics the biological functions of insulin and is useful for further drug development for diabetes treatment. 相似文献
124.
Côté B Frenette R Prescott S Blouin M Brideau C Ducharme Y Friesen RW Laliberté F Masson P Styhler A Girard Y 《Bioorganic & medicinal chemistry letters》2003,13(4):741-744
The synthesis and the biological evaluation of new potent phosphodiesterase type 4 (PDE4) inhibitors are presented. This new series was elaborated by replacement of the metabolically resistant phenyl hexafluorocarbinol of L-791,943 (1) by a substituted aminopyridine residue. The structure-activity relationship of N-substitution on 3 led to the identification of (-)-3n which exhibited a good PDE4 inhibitor activity (HWB-TNFalpha=0.12 microM) and an improved pharmacokinetic profile over L-791,943 (rat t(1/2)=2 h). (-)-3n was well tolerated in ferret with an emetic threshold of 30 mg/kg (po) and was found to be active in the ovalbumin-induced bronchoconstriction model in guinea pig (54%, 0.1 mg/kg, ip) as well as the ascaris-induced bronchoconstriction model in sheep (64%/97%, early/late, 0.5 mg/kg, iv). 相似文献
125.
Betina M. Porcel France Denoeud Fred Opperdoes Benjamin Noel Mohammed-Amine Madoui Tansy C. Hammarton Mark C. Field Corinne Da Silva Arnaud Couloux Julie Poulain Michael Katinka Kamel Jabbari Jean-Marc Aury David A. Campbell Roxana Cintron Nicholas J. Dickens Roberto Docampo Nancy R. Sturm V. Lila Koumandou Sandrine Fabre Pavel Flegontov Julius Luke? Shulamit Michaeli Jeremy C. Mottram Balázs Sz??r Dan Zilberstein Frédéric Bringaud Patrick Wincker Michel Dollet 《PLoS genetics》2014,10(2)
Members of the family Trypanosomatidae infect many organisms, including animals, plants and humans. Plant-infecting trypanosomes are grouped under the single genus Phytomonas, failing to reflect the wide biological and pathological diversity of these protists. While some Phytomonas spp. multiply in the latex of plants, or in fruit or seeds without apparent pathogenicity, others colonize the phloem sap and afflict plants of substantial economic value, including the coffee tree, coconut and oil palms. Plant trypanosomes have not been studied extensively at the genome level, a major gap in understanding and controlling pathogenesis. We describe the genome sequences of two plant trypanosomatids, one pathogenic isolate from a Guianan coconut and one non-symptomatic isolate from Euphorbia collected in France. Although these parasites have extremely distinct pathogenic impacts, very few genes are unique to either, with the vast majority of genes shared by both isolates. Significantly, both Phytomonas spp. genomes consist essentially of single copy genes for the bulk of their metabolic enzymes, whereas other trypanosomatids e.g. Leishmania and Trypanosoma possess multiple paralogous genes or families. Indeed, comparison with other trypanosomatid genomes revealed a highly streamlined genome, encoding for a minimized metabolic system while conserving the major pathways, and with retention of a full complement of endomembrane organelles, but with no evidence for functional complexity. Identification of the metabolic genes of Phytomonas provides opportunities for establishing in vitro culturing of these fastidious parasites and new tools for the control of agricultural plant disease. 相似文献
126.
Dylan A?ssi Jessica Dennis Martin Ladouceur Vinh Truong Nora Zwingerman Ares Rocanin-Arjo Marine Germain Tara A. Paton Pierre-Emmanuel Morange France Gagnon David-Alexandre Trégou?t 《PloS one》2014,9(9)
In order to investigate whether DNA methylation marks could contribute to the incomplete penetrance of the FV Leiden mutation, a major genetic risk factor for venous thrombosis (VT), we measured genome-wide DNA methylation levels in peripheral blood samples of 98 VT patients carrying the mutation and 251 VT patients without the mutation using the dedicated Illumina HumanMethylation450 array. The genome-wide analysis of 388,120 CpG probes identified three sites mapping to the SLC19A2 locus whose DNA methylation levels differed significantly (p<3 10−8) between carriers and non-carriers. The three sites replicated (p<2 10−7) in an independent sample of 214 individuals from five large families ascertained on VT and FV Leiden mutation among which 53 were carriers and 161 were non-carriers of the mutation. In both studies, these three CpG sites were also associated (2.33 10−11<p<3.02 10−4) with biomarkers of the Protein C pathway known to be influenced by the FV Leiden mutation. A comprehensive linkage disequilibrium (LD) analysis of the whole locus revealed that the original associations were due to LD between the FV Leiden mutation and a block of single nucleotide polymorphisms (SNP) located in SLC19A2. After adjusting for this block of SNPs, the FV Leiden mutation was no longer associated with any CpG site (p>0.05). In conclusion, our work clearly illustrates some promises and pitfalls of DNA methylation investigations on peripheral blood DNA in large epidemiological cohorts. DNA methylation levels at SLC19A2 are influenced by SNPs in LD with FV Leiden, but these DNA methylation marks do not explain the incomplete penetrance of the FV Leiden mutation. 相似文献
127.
Stéphane Vassilopoulos Christel Gentil Jeanne Lainé Pierre-Olivier Buclez Agathe Franck Arnaud Ferry Guillaume Précigout Robyn Roth John E. Heuser Frances M. Brodsky Luis Garcia Gisèle Bonne Thomas Voit France Piétri-Rouxel Marc Bitoun 《The Journal of cell biology》2014,204(3):377-393
Export of newly synthesized G protein–coupled receptors (GPCRs) remains poorly characterized. We show in this paper that lipocalin-type prostaglandin D2 (PGD2) synthase (L-PGDS) interacts intracellularly with the GPCR DP1 in an agonist-independent manner. L-PGDS promotes cell surface expression of DP1, but not of other GPCRs, in HEK293 and HeLa cells, independent of L-PGDS enzyme activity. In addition, formation of a DP1–Hsp90 complex necessary for DP1 export to the cell surface is dependent on the interaction between L-PGDS and the C-terminal MEEVD residues of Hsp90. Surprisingly, PGD2 synthesis by L-PGDS is promoted by coexpression of DP1, suggesting a possible intracrine/autocrine signaling mechanism. In this regard, L-PGDS increases the formation of a DP1–ERK1/2 complex and increases DP1-mediated ERK1/2 signaling. Our findings define a novel cooperative mechanism in which a GPCR (DP1) promotes the activity of the enzyme (L-PGDS) that produces its agonist (PGD2) and in which this enzyme in turn acts as a cofactor (of Hsp90) to promote export and agonist-dependent activity of the receptor. 相似文献
128.
While Entamoeba histolytica (Eh)-induced pro-inflammatory responses are critical in disease pathogenesis, the downstream signaling pathways that subsequently dampens inflammation and the immune response remains unclear. Eh in contact with macrophages suppresses NF-κB signaling while favoring NLRP3-dependent pro-inflammatory cytokine production by an unknown mechanism. Cullin-1 and cullin-5 (cullin-1/5) assembled into a multi-subunit RING E3 ubiquitin ligase complex are substrates for neddylation that regulates the ubiquitination pathway important in NF-κB activity and pro-inflammatory cytokine production. In this study, we showed that upon live Eh contact with human macrophages, cullin-1/4A/4B/5 but not cullin-2/3, were degraded within 10 minutes. Similar degradation of cullin-1/5 were observed from colonic epithelial cells and proximal colonic loops tissues of mice inoculated with live Eh. Degradation of cullin-1/5 was dependent on Eh-induced activation of caspase-1 via the NLRP3 inflammasome. Unlike cullin-4B, the degradation of cullin-4A was partially dependent on caspase-1 and was inhibited with a pan caspase inhibitor. Cullin-1/5 degradation was dependent on Eh cysteine proteinases EhCP-A1 and EhCP-A4, but not EhCP-A5, based on pharmacological inhibition of the cysteine proteinases and EhCP-A5 deficient parasites. siRNA silencing of cullin-1/5 decreased the phosphorylation of pIκ-Bα in response to Eh and LPS stimulation and downregulated NF-κB-dependent TNF-α mRNA expression and TNF-α and MCP-1 pro-inflammatory cytokine production. These results unravel a unique outside-in strategy employed by Eh to attenuate NF-κB-dependent pro-inflammatory responses via NLRP3 activation of caspase-1 that degraded cullin-1/5 from macrophages. 相似文献
129.
The opossum, Monodelphis domestica, is born very immature but crawls, unaided, with its forelimbs (FL) from the mother''s birth canal to a nipple where it attaches to pursue its development. What sensory cues guide the newborn to the nipple and trigger its attachment to it? Previous experiments showed that low intensity electrical stimulation of the trigeminal ganglion induces FL movement in in vitro preparations and that trigeminal innervation of the facial skin is well developed in the newborn. The skin does not contain Vater-Pacini or Meissner touch corpuscles at this age, but it contains cells which appear to be Merkel cells (MC). We sought to determine if touch perceived by MC could exert an influence on FL movements. Application of the fluorescent dye AM1-43, which labels sensory cells such as MC, revealed the presence of a large number of labeled cells in the facial epidermis, especially in the snout skin, in newborn opossums. Moreover, calibrated pressure applied to the snout induced bilateral and simultaneous electromyographic responses of the triceps muscle in in vitro preparations of the neuraxis and FL from newborn. These responses increase with stimulation intensity and tend to decrease over time. Removing the facial skin nearly abolished these responses. Metabotropic glutamate 1 receptors being involved in MC neurotransmission, an antagonist of these receptors was applied to the bath, which decreased the EMG responses in a reversible manner. Likewise, bath application of the purinergic type 2 receptors, used by AM1-43 to penetrate sensory cells, also decreased the triceps EMG responses. The combined results support a strong influence of facial mechanosensation on FL movement in newborn opossums, and suggest that this influence could be exerted via MC. 相似文献
130.
France Massicot Guillaume Hache Ludivine David Dominique Chen Charlotte Leuxe Laure Garnier-Legrand Patrice Rat Olivier Laprévote Fran?ois Coudoré 《PloS one》2013,8(6)
Limited information is available regarding the cellular mechanisms of oxaliplatin-induced painful neuropathy during exposure of patients to this drug. We therefore determined oxidative stress in cultured cells and evaluated its occurrence in C57BL/6 mice. Using both cultured neuroblastoma (SH-SY5Y) and macrophage (RAW 264.7) cell lines and also brain tissues of oxaliplatin-treated mice, we investigated whether oxaliplatin (OXA) induces oxidative stress and apoptosis. Cultured cells were treated with 2–200 µM OXA for 24 h. The effects of pharmacological inhibitors of oxidative stress or inflammation (N-acetyl cysteine, ibuprofen, acetaminophen) were also tested. Inhibitors were added 30 min before OXA treatment and then in combination with OXA for 24 h. In SH-SY5Y cells, OXA caused a significant dose-dependent decrease in viability, a large increase in ROS and NO production, lipid peroxidation and mitochondrial impairment as assessed by a drop in mitochondrial membrane potential, which are deleterious for the cell. An increase in levels of negatively charged phospholipids such as cardiolipin but also phosphatidylserine and phosphatidylinositol, was also observed. Additionally, OXA caused concentration-dependent P2X7 receptor activation, increased chromatin condensation and caspase-3 activation associated with TNF-α and IL-6 release. The majority of these toxic effects were equally observed in Raw 264.7 which also presented high levels of PGE2. Pretreatment of SH-SY5Y cells with pharmacological inhibitors significantly reduced or blocked all the neurotoxic OXA effects. In OXA-treated mice (28 mg/kg cumulated dose) significant cold hyperalgesia and oxidative stress in the tested brain areas were shown. Our study suggests that targeting P2X7 receptor activation and mitochondrial impairment might be a potential therapeutic strategy against OXA-induced neuropathic pain. 相似文献