全文获取类型
收费全文 | 614篇 |
免费 | 35篇 |
出版年
2023年 | 2篇 |
2022年 | 6篇 |
2021年 | 7篇 |
2020年 | 6篇 |
2019年 | 4篇 |
2018年 | 10篇 |
2017年 | 4篇 |
2016年 | 11篇 |
2015年 | 23篇 |
2014年 | 46篇 |
2013年 | 38篇 |
2012年 | 49篇 |
2011年 | 49篇 |
2010年 | 43篇 |
2009年 | 31篇 |
2008年 | 37篇 |
2007年 | 36篇 |
2006年 | 38篇 |
2005年 | 33篇 |
2004年 | 24篇 |
2003年 | 34篇 |
2002年 | 36篇 |
2001年 | 3篇 |
2000年 | 2篇 |
1999年 | 2篇 |
1998年 | 6篇 |
1997年 | 3篇 |
1996年 | 7篇 |
1995年 | 6篇 |
1994年 | 3篇 |
1993年 | 2篇 |
1992年 | 4篇 |
1991年 | 3篇 |
1989年 | 1篇 |
1988年 | 2篇 |
1987年 | 2篇 |
1986年 | 3篇 |
1985年 | 2篇 |
1984年 | 5篇 |
1983年 | 2篇 |
1982年 | 6篇 |
1981年 | 5篇 |
1980年 | 1篇 |
1979年 | 3篇 |
1978年 | 3篇 |
1977年 | 1篇 |
1975年 | 1篇 |
1974年 | 1篇 |
1972年 | 1篇 |
1969年 | 1篇 |
排序方式: 共有649条查询结果,搜索用时 31 毫秒
121.
Godet J Ramalanjaona N Sharma KK Richert L de Rocquigny H Darlix JL Duportail G Mély Y 《Nucleic acids research》2011,39(15):6633-6645
122.
Mathurin K Gallant MA Germain P Allard-Chamard H Brisson J Iorio-Morin C de Brum Fernandes A Caron MG Laporte SA Parent JL 《The Journal of biological chemistry》2011,286(4):2696-2706
L-type prostaglandin synthase (L-PGDS) produces PGD(2), a lipid mediator involved in neuromodulation and inflammation. Here, we show that L-PGDS and arrestin-3 (Arr3) interact directly and can be co-immunoprecipitated endogenously from MG-63 osteoblasts. Perinuclear L-PGDS/Arr3 co-localization is observed in PGD(2)-producing MG-63 cells and is induced by the addition of the L-PGDS substrate or co-expression of COX-2 in HEK293 cells. Inhibition of L-PGDS activity in MG-63 cells triggers redistribution of Arr3 and L-PGDS to the cytoplasm. Perinuclear localization of L-PGDS is detected in wild-type mouse embryonic fibroblasts (MEFs) but is more diffused in MEFs-arr-2(-/-)-arr-3(-/-). Arrestin-3 promotes PGD(2) production by L-PGDS in vitro. IL-1β-induced PGD(2) production is significantly lower in MEFs-arr-2(-/-)-arr-3(-/-) than in wild-type MEFs but can be rescued by expressing Arr2 or Arr3. A peptide corresponding to amino acids 86-100 of arrestin-3 derived from its L-PGDS binding domain stimulates L-PGDS-mediated PGD(2) production in vitro and in MG-63 cells. We report the first characterization of an interactor/modulator of a PGD(2) synthase and the identification of a new function for arrestin, which may open new opportunities for improving therapies for the treatment of inflammatory diseases. 相似文献
123.
Hugues Jaccard Pascal Miéville Caroline Cannizzo Cédric R. Mayer Lothar Helm 《Journal of biological inorganic chemistry》2014,19(2):145-159
A compound binding three Gd3+ ions, {Ph4[Gd(DTTA)(H2O)2]? 3} (where H5DTTA is diethylenetriaminetetraacetic acid), has been synthesized around a hydrophobic center made up of four phenyl rings. In aqueous solution the molecules start to self-aggregate at concentrations well below 1 mM as shown by the increase of rotational correlation times and by the decrease of the translational self-diffusion constant. NMR spectra recorded in aqueous solution of the diamagnetic analogue {Ph4[Y(DTTA)(H2O)2]? 3} show that the aggregation is dynamic and due to intermolecular π-stacking interactions between the hydrophobic aromatic centers. From estimations of effective radii, it can be concluded that the aggregates are composed of two to three monomers. The paramagnetic {Ph4[Gd(DTTA)(H2O)2]? 3} exhibits concentration-dependent 1H NMR relaxivities with high values of approximately 50 mM?1 s?1 (30 MHz, 25 °C) at gadolinium concentrations above 20 mM. A combined analysis of 1H NMR dispersion profiles measured at different concentrations of the compound and 17O NMR data measured at various temperatures was performed using different theoretical approaches. The fitted parameters showed that the increase in relaxivity with increasing concentration of the compound is due to slower global rotational motion and an increase of the Lipari–Szabo order parameter S 2. 相似文献
124.
Alessandra Rogato Hugues Richard Alexis Sarazin Bj?rn Voss Soizic Cheminant Navarro Rapha?l Champeimont Lionel Navarro Alessandra Carbone Wolfgang R Hess Angela Falciatore 《BMC genomics》2014,15(1)
Background
Marine diatoms constitute a major component of eukaryotic phytoplankton and stand at the crossroads of several evolutionary lineages. These microalgae possess peculiar genomic features and novel combinations of genes acquired from bacterial, animal and plant ancestors. Furthermore, they display both DNA methylation and gene silencing activities. Yet, the biogenesis and regulatory function of small RNAs (sRNAs) remain ill defined in diatoms.Results
Here we report the first comprehensive characterization of the sRNA landscape and its correlation with genomic and epigenomic information in Phaeodactylum tricornutum. The majority of sRNAs is 25 to 30 nt-long and maps to repetitive and silenced Transposable Elements marked by DNA methylation. A subset of this population also targets DNA methylated protein-coding genes, suggesting that gene body methylation might be sRNA-driven in diatoms. Remarkably, 25-30 nt sRNAs display a well-defined and unprecedented 180 nt-long periodic distribution at several highly methylated regions that awaits characterization. While canonical miRNAs are not detectable, other 21-25 nt sRNAs of unknown origin are highly expressed. Besides, non-coding RNAs with well-described function, namely tRNAs and U2 snRNA, constitute a major source of 21-25 nt sRNAs and likely play important roles under stressful environmental conditions.Conclusions
P. tricornutum has evolved diversified sRNA pathways, likely implicated in the regulation of largely still uncharacterized genetic and epigenetic processes. These results uncover an unexpected complexity of diatom sRNA population and previously unappreciated features, providing new insights into the diversification of sRNA-based processes in eukaryotes.Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-698) contains supplementary material, which is available to authorized users. 相似文献125.
Stéphanie Cornen Arnaud Guille José Adéla?de Lynda Addou-Klouche Pascal Finetti Marie-Rose Saade Marwa Manai Nadine Carbuccia Ismahane Bekhouche Anne Letessier Stéphane Raynaud Emmanuelle Charafe-Jauffret Jocelyne Jacquemier Salvatore Spicuglia Hugues de The Patrice Viens Fran?ois Bertucci Daniel Birnbaum Max Chaffanet 《PloS one》2014,9(1)
Breast cancers (BCs) of the luminal B subtype are estrogen receptor-positive (ER+), highly proliferative, resistant to standard therapies and have a poor prognosis. To better understand this subtype we compared DNA copy number aberrations (CNAs), DNA promoter methylation, gene expression profiles, and somatic mutations in nine selected genes, in 32 luminal B tumors with those observed in 156 BCs of the other molecular subtypes. Frequent CNAs included 8p11-p12 and 11q13.1-q13.2 amplifications, 7q11.22-q34, 8q21.12-q24.23, 12p12.3-p13.1, 12q13.11-q24.11, 14q21.1-q23.1, 17q11.1-q25.1, 20q11.23-q13.33 gains and 6q14.1-q24.2, 9p21.3-p24,3, 9q21.2, 18p11.31-p11.32 losses. A total of 237 and 101 luminal B-specific candidate oncogenes and tumor suppressor genes (TSGs) presented a deregulated expression in relation with their CNAs, including 11 genes previously reported associated with endocrine resistance. Interestingly, 88% of the potential TSGs are located within chromosome arm 6q, and seven candidate oncogenes are potential therapeutic targets. A total of 100 candidate oncogenes were validated in a public series of 5,765 BCs and the overexpression of 67 of these was associated with poor survival in luminal tumors. Twenty-four genes presented a deregulated expression in relation with a high DNA methylation level. FOXO3, PIK3CA and TP53 were the most frequent mutated genes among the nine tested. In a meta-analysis of next-generation sequencing data in 875 BCs, KCNB2 mutations were associated with luminal B cases while candidate TSGs MDN1 (6q15) and UTRN (6q24), were mutated in this subtype. In conclusion, we have reported luminal B candidate genes that may play a role in the development and/or hormone resistance of this aggressive subtype. 相似文献
126.
Louise Balfour Johanna N. Spaans Dean Fergusson Harold Huff Edward J. Mills Charles J. la Porte Sharon Walmsley Neera Singhal Ron Rosenes Nancy Tremblay M. John Gill Hugues Loemba Brian Conway Anita Rachlis Edward Ralph Mona Loutfy Ranjeeta Mallick Rika Moorhouse D. William Cameron 《PloS one》2014,9(1)
Introduction
The MAINTAIN study is an on-going RCT comparing high-dose micronutrient and anti-oxidant supplementation versus recommended daily allowance (RDA) vitamins in slowing HIV immune deficiency progression in ART-naïve people with HIV infection.Objective
We planned analysis of the first 127 participants to determine the baseline prevalence of serum micronutrient deficiencies and correlates, as well as tolerance and adherence to study interventions.Methods
Participants receive eight capsules twice daily of 1) high-dose or 2) RDA supplements for two years and are followed-up quarterly for measures of immune deficiency progression, safety and tolerability. Regression analysis was used to identify correlates of micronutrient levels at baseline. Adherence was measured by residual pill count, self-report using the General Treatment Scale (GTS) and short-term recall HIV Adherence Treatment Scale (HATS).Results
Prior micronutrient supplementation (within 30 days) was 27% at screening and 10% of study population, and was not correlated with baseline micronutrient levels. Low levels were frequent for carotene (24%<1 nmol/L), vitamin D (24%<40 nmol/L) and serum folate (20%<15 nmol/L). The proportion with B12 deficiency (<133 pmol/L) was 2.4%. Lower baseline levels of B12 correlated lower baseline CD4 count (r = 0.21, p = 0.02) with a 21 pmol/L reduction in B12 per 100 cells/µL CD4. Vitamin D levels were higher in men (p<0.001). After a median follow-up of 1.63 years, there were 19 (15%) early withdrawals from the study treatment. Mean treatment adherence using pill count was 88%. Subjective adherence by the GTS was 81% and was moderately but significantly correlated with pill count (r = 0.29, p<0.001). Adherence based on short-term recall (HATS) was >80% in 75% of participants.Conclusion
Micronutrient levels in asymptomatic HIV+ persons are in keeping with population norms, but micronutrient deficiencies are frequent. Adherence levels are high, and will permit a valid evaluation of treatment effects.Trial Registration
ClinicalTrials.gov NCT00798772相似文献127.
Stephanie Etienne Martin Guthrie Michel Goillandeau Tho Hai Nguyen Hugues Orignac Christian Gross Thomas Boraud 《PloS one》2014,9(5)
The neurological bases of spatial navigation are mainly investigated in rodents and seldom in primates. The few studies led on spatial navigation in both human and non-human primates are performed in virtual, not in real environments. This is mostly because of methodological difficulties inherent in conducting research on freely-moving monkeys in real world environments. There is some incertitude, however, regarding the extrapolation of rodent spatial navigation strategies to primates. Here we present an entirely new platform for investigating real spatial navigation in rhesus monkeys. We showed that monkeys can learn a pathway by using different strategies. In these experiments three monkeys learned to drive the wheelchair and to follow a specified route through a real maze. After learning the route, probe tests revealed that animals successively use three distinct navigation strategies based on i) the place of the reward, ii) the direction taken to obtain reward or iii) a cue indicating reward location. The strategy used depended of the options proposed and the duration of learning. This study reveals that monkeys, like rodents and humans, switch between different spatial navigation strategies with extended practice, implying well-conserved brain learning systems across different species. This new task with freely driving monkeys provides a good support for the electrophysiological and pharmacological investigation of spatial navigation in the real world by making possible electrophysiological and pharmacological investigations. 相似文献
128.
Yiu-Wing Kam Wendy W. L. Lee Diane Simarmata Roger Le Grand Hugues Tolou Andres Merits Pierre Roques Lisa F. P. Ng 《PloS one》2014,9(4)
Chikungunya virus (CHIKV) is an Alphavirus that causes chronic and incapacitating arthralgia in humans. Although patient cohort studies have shown the production of CHIKV specific antibodies, the fine specificity of the antibody response against CHIKV is not completely defined. The macaque model of CHIKV infection was established due to limitations of clinical specimens. More importantly, its close relation to humans will allow the study of chronic infection and further identify important CHIKV targets. In this study, serum samples from CHIKV-infected macaques collected at different time-points post infection were used to characterize the antibody production pattern and kinetics. Results revealed that anti-CHIKV antibodies were neutralizing and the E2 glycoprotein, Capsid, nsP1, nsP3 and nsP4 proteins were targets of the anti-CHIKV antibody response in macaques. Furthermore, linear B-cell epitopes recognized by these anti-CHIKV antibodies were identified, and mapped to their structural localization. This characterizes the specificity of anti-CHIKV antibody response in macaques and further demonstrates the importance of the different regions in CHIKV-encoded proteins in the adaptive immune response. Information from this study provides critical knowledge that will aid in the understanding of CHIKV infection and immunity, vaccine design, and pre-clinical efficacy studies. 相似文献
129.
130.
Umut Sahin Omar Ferhi Marion Jeanne Shirine Benhenda Caroline Berthier Florence Jollivet Michiko Niwa-Kawakita Orestis Faklaris Niclas Setterblad Hugues de Thé Valérie Lallemand-Breitenbach 《The Journal of cell biology》2014,204(6):931-945
The promyelocytic leukemia (PML) protein organizes PML nuclear bodies (NBs), which are stress-responsive domains where many partner proteins accumulate. Here, we clarify the basis for NB formation and identify stress-induced partner sumoylation as the primary NB function. NB nucleation does not rely primarily on intermolecular interactions between the PML SUMO-interacting motif (SIM) and SUMO, but instead results from oxidation-mediated PML multimerization. Oxidized PML spherical meshes recruit UBC9, which enhances PML sumoylation, allow partner recruitment through SIM interactions, and ultimately enhance partner sumoylation. Intermolecular SUMO–SIM interactions then enforce partner sequestration within the NB inner core. Accordingly, oxidative stress enhances NB formation and global sumoylation in vivo. Some NB-associated sumoylated partners also become polyubiquitinated by RNF4, precipitating their proteasomal degradation. As several partners are protein-modifying enzymes, NBs could act as sensors that facilitate and confer oxidative stress sensitivity not only to sumoylation but also to other post-translational modifications, thereby explaining alterations of stress response upon PML or NB loss. 相似文献