全文获取类型
收费全文 | 343篇 |
免费 | 41篇 |
专业分类
384篇 |
出版年
2022年 | 4篇 |
2019年 | 4篇 |
2017年 | 5篇 |
2016年 | 7篇 |
2015年 | 17篇 |
2014年 | 12篇 |
2013年 | 12篇 |
2012年 | 14篇 |
2011年 | 14篇 |
2010年 | 14篇 |
2009年 | 10篇 |
2008年 | 11篇 |
2007年 | 14篇 |
2006年 | 21篇 |
2005年 | 10篇 |
2004年 | 8篇 |
2003年 | 13篇 |
2002年 | 5篇 |
2001年 | 14篇 |
2000年 | 6篇 |
1999年 | 9篇 |
1998年 | 9篇 |
1996年 | 6篇 |
1995年 | 8篇 |
1994年 | 3篇 |
1992年 | 10篇 |
1991年 | 15篇 |
1990年 | 18篇 |
1989年 | 8篇 |
1988年 | 4篇 |
1987年 | 4篇 |
1986年 | 3篇 |
1985年 | 4篇 |
1984年 | 4篇 |
1983年 | 3篇 |
1982年 | 2篇 |
1981年 | 5篇 |
1980年 | 3篇 |
1979年 | 5篇 |
1978年 | 4篇 |
1977年 | 3篇 |
1976年 | 2篇 |
1975年 | 3篇 |
1973年 | 5篇 |
1972年 | 3篇 |
1971年 | 2篇 |
1970年 | 2篇 |
1968年 | 3篇 |
1967年 | 2篇 |
1966年 | 2篇 |
排序方式: 共有384条查询结果,搜索用时 0 毫秒
81.
82.
Cornu JN Drouin S Cancel-Tassin G Bigot P Azzouzi AR Koutlidis N Cormier L Gaffory C Rouprêt M Sèbe P Bitker MO Haab F Cussenot O 《Molecular medicine (Cambridge, Mass.)》2011,17(5-6):473-477
Single nucleotide polymorphisms (SNPs) have been associated with prostate cancer (PCa) risk and tumor aggressiveness in retrospective studies. To assess the value of genotyping in a clinical setting, we evaluated the correlation between three genotypes (rs1447295 and rs6983267[8q24] and rs4054823[17p12]) and prostatic biopsy outcome prospectively in a French population of Caucasian men. Five hundred ninety-eight patients with prostatic-specific antigen (PSA) >4 ng/mL or abnormal digital rectal examination (DRE) participated in this prospective, multicenter study. Age, familial history of PCa, body mass index (BMI), data of DRE, International Prostate Symptom Score (I-PSS) score, PSA value and prostatic volume were collected prospectively before prostatic biopsy. Correlation between genotypes and biopsy outcome (positive or negative) and Gleason score (≤6 or >6) were studied by univariate and multivariable analysis. rs1447295 and rs6983267 risk variants were found to be associated with the presence of PCa in univariate analysis. rs6983267 genotype remained significantly linked to a positive biopsy (odds ratio [OR] = 1.66, 95% confidence interval [CI]: 1.06-2.59, P = 0.026) in multivariable analysis, but rs1447295 genotype did not (OR = 1.47, 95% CI: 0.89-2.43, P = 0.13).When biopsy outcome was stratified according to Gleason score, risk variants of rs1447295 were associated with aggressive disease (Gleason score ≥7) in univariate and multivariable analysis (OR = 2.05 95% CI: 1.10-3.79, P = 0.023). rs6983267 GG genotype was not related to aggressiveness. The results did not reach significance concerning rs4054823 for any analysis. This inaugural prospective evaluation thus confirmed potential usefulness of genotyping PCa assessment. Ongoing clinical evaluation of larger panels of SNPs will detail the actual impact of genetic markers on clinical practice. 相似文献
83.
Dahui You David T. Siefker Bishwas Shrestha Jordy Saravia Stephania A. Cormier 《Respiratory research》2015,16(1)
Background
Respiratory syncytial virus (RSV) is the number one cause of lower respiratory tract infection in infants; and severe RSV infection in infants is associated with asthma development. Today, there are still no vaccines or specific antiviral therapies against RSV. The mechanisms of RSV pathogenesis in infants remain elusive. This is partly due to the fact that the largely-used mouse model is semi-permissive for RSV. The present study sought to determine if a better neonatal mouse model of RSV infection could be obtained using a chimeric virus in which the F protein of A2 strain was replaced with the F protein from the line 19 clinical isolate (rA2-19F).Methods
Five-day-old pups were infected with the standard laboratory strain A2 or rA2-19F and various immunological and pathophysiological parameters were measured at different time points post infection, including lung histology, bronchoalveolar lavage fluid (BALF) cellularity and cytokines, pulmonary T cell profile, and lung viral load. A cohort of infected neonates were allowed to mature to adulthood and reinfected. Pulmonary function, BALF cellularity and cytokines, and T cell profiles were measured at 6 days post reinfection.Results
The rA2-19F strain in neonatal mice caused substantial lung pathology including interstitial inflammation and airway mucus production, while A2 caused minimal inflammation and mucus production. Pulmonary inflammation was characterized by enhanced Th2 and reduced Th1 and effector CD8+ T cells compared to A2. As with primary infection, reinfection with rA2-19F induced similar but exaggerated Th2 and reduced Th1 and effector CD8+ T cell responses. These immune responses were associated with increased airway hyperreactivity, mucus hyperproduction and eosinophilia that was greater than that observed with A2 reinfection. Pulmonary viral load during primary infection was higher with rA2-19F than A2.Conclusions
Therefore, rA2-19F caused enhanced lung pathology and Th2 and reduced effector CD8+ T cell responses compared to A2 during initial infection in neonatal mice and these responses were exacerbated upon reinfection. The exact mechanism is unknown but appears to be associated with increased pulmonary viral load in rA2-19F vs. A2 infected neonatal lungs. The rA2-19F strain represents a better neonatal mouse model of RSV infection.Electronic supplementary material
The online version of this article (doi:10.1186/s12931-015-0244-0) contains supplementary material, which is available to authorized users. 相似文献84.
Lapasset L Pradet-Balade B Vergé V Lozano JC Oulhen N Cormier P Peaucellier G 《Molecular reproduction and development》2008,75(11):1617-1626
Translation of cyclin mRNAs represents an important event for proper meiotic maturation and post-fertilization mitoses in many species. Translational control of cyclin B mRNA has been described to be achieved through two separate but related mechanisms: translational repression and polyadenylation. In this paper, we evaluated the contribution of global translational regulation by the cap-dependent translation repressor 4E-BP (eukaryotic initiation factor 4E-binding protein) on the cyclin B protein synthesis during meiotic maturation of the starfish oocytes. We used the immunosupressant drug rapamycin, a strong inhibitor of cap-dependent translation, to check for the involvement of this protein synthesis during this physiological process. Rapamycin was found to prevent dissociation of 4E-BP from the initiation factor eIF4E and to suppress correlatively a burst of global protein synthesis occurring at the G2/M transition. The drug had no effect on first meiotic division but defects in meiotic spindle formation prevented second polar body emission, demonstrating that a rapamycin-sensitive pathway is involved in this mechanism. While rapamycin affected the global protein synthesis, the drug altered neither the specific translation of cyclin B mRNA nor the expression of the Mos protein. The expression of these two proteins was correlated with the phosphorylation and the dissociation of the cytoplasmic polyadenylation element-binding protein from eIF4E. 相似文献
85.
Purification of a p47 phosphoprotein from Xenopus laevis oocytes and identification as an in vivo and in vitro p34cdc2 substrate 总被引:1,自引:0,他引:1
This paper describes the purification of a 47 kDa protein from Xenopus laevis oocytes that becomes phosphorylated when the oocytes undergo meiotic maturation. This protein (p47) is part of a high molecular mass complex containing at least two other proteins of molecular mass 30 and 36 kDa. This complex can be isolated from stage VI oocytes before maturation. We obtained a pattern for phosphopeptides in p47 phosphorylated in vivo very similar to that of the purified protein phosphorylated in vitro by p34cdc2 (a H1 kinase which is a component of the M-phase promoting factor) and [gamma-32P]ATP. Therefore, the purified p47, already described as a marker of MPF activity, is the first reported in vivo substrate for the cell division control kinase. 相似文献
86.
The murid rodent subfamily Sigmodontinae contains 79 genera which are
distributed throughout the New World. The time of arrival of the first
sigmodontines in South America and the estimated divergence time(s) of the
different lineages of South American sigmodontines have been controversial
due to the lack of a good fossil record and the immense number of extant
species. The "early-arrival hypothesis" states that the sigmodontines must
have arrived in South America no later than the early Miocene, at least 20
MYA, in order to account for their vast present-day diversity, whereas the
"late-arrival hypothesis" includes the sigmodontines as part of the
Plio-Pleistocene Great American Interchange, which occurred approximately
3.5 MYA. The phylogenetic relationships among 33 of these genera were
reconstructed using mitochondrial DNA (mtDNA) sequence data from the ND3,
ND4L, arginine tRNA, and ND4 genes, which we show to be evolving at the
same rate. A molecular clock was calibrated for these genes using published
fossil dates, and the genetic distances were estimated from the DNA
sequences in this study. The molecular clock was used to estimate the dates
of the South American sigmodontine origin and the main sigmodontine
radiation in order to evaluate the "early-" and "late-arrival" scenarios.
We estimate the time of the sigmodontine invasion of South America as
between approximately 5 and 9 MYA, supporting neither of the scenarios but
suggesting two possible models in which the invading lineage was either (1)
ancestral to the oryzomyines, akodonts, and phyllotines or (2) ancestral to
the akodonts and phyllotines and accompanied by the oryzomyines. The
sigmodontine invasion of South America provides an example of the advantage
afforded to a lineage by the fortuitous invasion of a previously
unexploited habitat, in this case an entire continent.
相似文献
87.
Joseph W Cormier Ilaria Rivolta Michihiro Tateyama An-Suei Yang Robert S Kass 《The Journal of biological chemistry》2002,277(11):9233-9241
Little is known about the structure of the C terminus of the human cardiac voltage-gated sodium channel alpha subunit (SCN5A), but disease-linked mutations within this 244-amino acid intracellular region of the channel have marked effects on channel inactivation. Here we report a structural analysis of the C-terminal tail of the cardiac Na(+) channel that sheds new light on mechanisms that control its inactivation gating. Homology modeling of the SCN5A C terminus predicts predominant alpha-helical structure (six helices) in the proximal half of this intracellular tail but little structure in the distal half. Circular dichroism of isolated and purified C terminus supports this prediction. Whole cell and single channel patch clamp recordings of wild type and mutant alpha subunits co-expressed with the hbeta(1) subunit in HEK 293 cells indicate that truncation of the distal, nonstructured, C terminus (L1921stop mutant) reduces current density but does not affect channel gating (n = 6). In contrast, truncation of the sixth helix containing a concentration of positively charged residues along with the distal C terminus (S1885stop mutant) also reduces current density but, in addition, has profound and selective effects on inactivation (no effect on activation). Channel availability is shifted (-11 +/- 0.6 mV), and there is a 10-fold increase in the percentage of channels that burst (fail to inactivate) during prolonged depolarization (0.025% S1885stop (n = 7) versus 0.0028% wild type (n = 9), p < 0.005). These results suggest that the charged structured region of the SCN5A C terminus plays a major role in channel inactivation, stabilizing the inactivated state. 相似文献
88.
We suggest that there are six fundamental characteristics of causation: time order, co-occurrence, preceding causation, sufficiency, interaction, and alteration. The cause precedes the effect (time order). The cause co-occurs with the unaffected entity in space and time (co-occurrence). Causes and their effects are the result of a web of causation (preceding causation). The intensity, frequency, and duration of the cause are adequate and the susceptible entity can exhibit the type and magnitude of the effect (sufficiency). The cause effectively interacts with the entity in a way that induces the effect (interaction). And, the entity is changed by the interactions with the cause (alteration). In contrast to Hill's criteria, the causal characteristics are distinct from the: (1) evidence that is used to document causal characteristics, (2) sources of information used to develop the evidence, and (3) qualities used to evaluate evidence of causal characteristics and body of evidence for the causal relationship. Evidence of causal characteristics can form the basis for assessments of epidemiological studies and can structure an explanatory narrative that is causally relevant and substantive. Six core characteristics may be easier to organize, evaluate, communicate, and for decision-makers to assimilate, remember, and inspire action. 相似文献
89.
90.