全文获取类型
收费全文 | 794篇 |
免费 | 80篇 |
国内免费 | 1篇 |
出版年
2023年 | 5篇 |
2022年 | 14篇 |
2021年 | 23篇 |
2020年 | 15篇 |
2019年 | 20篇 |
2018年 | 18篇 |
2017年 | 18篇 |
2016年 | 27篇 |
2015年 | 41篇 |
2014年 | 46篇 |
2013年 | 52篇 |
2012年 | 66篇 |
2011年 | 53篇 |
2010年 | 36篇 |
2009年 | 31篇 |
2008年 | 42篇 |
2007年 | 45篇 |
2006年 | 38篇 |
2005年 | 36篇 |
2004年 | 30篇 |
2003年 | 35篇 |
2002年 | 24篇 |
2001年 | 13篇 |
2000年 | 12篇 |
1999年 | 12篇 |
1998年 | 18篇 |
1997年 | 3篇 |
1996年 | 5篇 |
1995年 | 5篇 |
1994年 | 5篇 |
1993年 | 10篇 |
1992年 | 11篇 |
1991年 | 8篇 |
1990年 | 8篇 |
1989年 | 4篇 |
1988年 | 2篇 |
1987年 | 2篇 |
1986年 | 4篇 |
1985年 | 6篇 |
1984年 | 2篇 |
1983年 | 2篇 |
1982年 | 4篇 |
1974年 | 1篇 |
1973年 | 5篇 |
1972年 | 2篇 |
1971年 | 1篇 |
1970年 | 3篇 |
1968年 | 1篇 |
1965年 | 5篇 |
1963年 | 1篇 |
排序方式: 共有875条查询结果,搜索用时 62 毫秒
61.
Pehuén Pereyra Gerber Mercedes Cabrini Carolina Jancic Luciana Paoletti Claudia Banchio Catalina von Bilderling Lorena Sigaut Lía I. Pietrasanta Gabriel Duette Eric O. Freed Genevieve de Saint Basile Catarina Ferreira Moita Luis Ferreira Moita Sebastian Amigorena Philippe Benaroch Jorge Geffner Matías Ostrowski 《The Journal of cell biology》2015,209(3):435-452
During the late stages of the HIV-1 replication cycle, the viral polyprotein Pr55Gag is recruited to the plasma membrane (PM), where it binds phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and directs HIV-1 assembly. We show that Rab27a controls the trafficking of late endosomes carrying phosphatidylinositol 4-kinase type 2 α (PI4KIIα) toward the PM of CD4+ T cells. Hence, Rab27a promotes high levels of PM phosphatidylinositol 4-phosphate and the localized production of PI(4,5)P2, therefore controlling Pr55Gag membrane association. Rab27a also controls PI(4,5)P2 levels at the virus-containing compartments of macrophages. By screening Rab27a effectors, we identified that Slp2a, Slp3, and Slac2b are required for the association of Pr55Gag with the PM and that Slp2a cooperates with Rab27a in the recruitment of PI4KIIα to the PM. We conclude that by directing the trafficking of PI4KIIα-positive endosomes toward the PM, Rab27a controls PI(4,5)P2 production and, consequently, HIV-1 replication. 相似文献
62.
Victoria Cano Catalina March Jose Luis Insua Nacho Aguiló Enrique Llobet David Moranta Verónica Regueiro Gerard P. Brennan Maria Isabel Millán‐Lou Carlos Martín Junkal Garmendia José A. Bengoechea 《Cellular microbiology》2015,17(11):1537-1560
Klebsiella pneumoniae is an important cause of community‐acquired and nosocomial pneumonia. Evidence indicates that Klebsiella might be able to persist intracellularly within a vacuolar compartment. This study was designed to investigate the interaction between Klebsiella and macrophages. Engulfment of K. pneumoniae was dependent on host cytoskeleton, cell plasma membrane lipid rafts and the activation of phosphoinositide 3‐kinase (PI3K). Microscopy studies revealed that K. pneumoniae resides within a vacuolar compartment, the Klebsiella‐containing vacuole (KCV), which traffics within vacuoles associated with the endocytic pathway. In contrast to UV‐killed bacteria, the majority of live bacteria did not co‐localize with markers of the lysosomal compartment. Our data suggest that K. pneumoniae triggers a programmed cell death in macrophages displaying features of apoptosis. Our efforts to identify the mechanism(s) whereby K. pneumoniae prevents the fusion of the lysosomes to the KCV uncovered the central role of the PI3K–Akt–Rab14 axis to control the phagosome maturation. Our data revealed that the capsule is dispensable for Klebsiella intracellular survival if bacteria were not opsonized. Furthermore, the environment found by Klebsiella within the KCV triggered the down‐regulation of the expression of cps. Altogether, this study proves evidence that K. pneumoniae survives killing by macrophages by manipulating phagosome maturation that may contribute to Klebsiella pathogenesis. 相似文献
63.
C. AbrusciJ.L. Pablos T. CorralesJ. López-Marín I. MarínF. Catalina 《International biodeterioration & biodegradation》2011,65(3):451-459
Polyethylene film materials persist in the environment for a long time. Several bacterial species have been isolated from films buried in soil located in Murcia, Spain. Bacterial strains were characterized with a combination of culture-dependent methods and sequencing of part of the 16S ribosomal RNA gene (rDNA) after amplification by polymerase chain reaction (PCR). Three bacterial species common in soil were found attached to the polymer and identified as Bacillus. cereus, B. megaterium, and B. subtilis. These microorganisms, as well as Brevibacillus borstelensis, were tested for biodegradation susceptibility at 30 and 45 °C on highly photo-degraded polyethylene films (500 h under irradiation of Xe-Lamp-solar filter) that contained calcium and iron stearates as pro-oxidant additives. Biofilm formation developed on the photo-degraded materials after one week of bacterial treatment. Biodegradation of the polyethylene films was studied by chemiluminescence, ATR-FTIR, and GC-product analysis and the data confirm a more efficient biodegradation on the bioassays carried out at higher temperature. The CL emissions due to decomposition of oxidation species take place at lower temperatures; the decrease of carbonyl index and the disappearance of photogenerated low-molecular products with biodegradation were more efficient on the biodegraded films at 45 °C. Also, mineralization was evaluated by carbon dioxide measurements using an indirect impedance technique. Biodegradation by B. borstelensis and MIX at 30 °C was slow and in the range of 0.7-1.2% of mineralization after 90 days of bacterial bioassay. At 45 °C biodegradation was more efficient and in particular in the more photo-degraded films containing Ca and Fe stearates where mineralization extents reached values of 11.5% with B. borstelensis and 7-10% with the mixture of Bacillus (MIX). 相似文献
64.
65.
Caldés C Vilanova B Adrover M Muñoz F Donoso J 《Bioorganic & medicinal chemistry》2011,19(15):4536-4543
Non-enzymatic aminophospholipid glycation is an especially important process because it alters the stability of lipid bilayers and interferes with cell function and integrity as a result. However, the kinetic mechanism behind this process has scarcely been studied. As in protein glycation, the process has been suggested to involve the formation of a Schiff base as the initial, rate-determining step. In this work, we conducted a comparative kinetic study of Schiff base formation under physiological conditions in three low-molecular weight analogues of polar heads in the naturally occurring aminophospholipids O-phosphorylethanolamine (PEA), O-phospho-DL-serine (PSer) and 2-aminoethylphenethylphosphate (APP) with various glycating carbonyl compounds (glucose, arabinose and acetol) and the lipid glycation inhibitor pyridoxal 5'-phosphate (PLP). Based on the results, the presence of a phosphate group and a carboxyl group in α position respect to the amino group decrease the formation constant for the Schiff base relative to amino acids. On the other hand, esterifying the phosphate group with a non-polar substituent in APP increases the stability of its Schiff base. The observed kinetic formation constants of aminophosphates with carbonyl groups were smaller than those for PLP. Our results constitute an important contribution to understanding the competitive inhibition effect of PLP on aminophospholipid glycation. 相似文献
66.
Krig SR Frietze S Simion C Miller JK Fry WH Rafidi H Kotelawala L Qi L Griffith OL Gray JW Carraway KL Sweeney C 《Molecular cancer research : MCR》2011,9(10):1406-1417
Lrig1 is the founding member of the Lrig family and has been implicated in the negative regulation of several oncogenic receptor tyrosine kinases including ErbB2. Lrig1 is expressed at low levels in several cancer types but is overexpressed in some prostate and colorectal tumors. Given this heterogeneity, whether Lrig1 functions to suppress or promote tumor growth remains a critical question. Previously, we found that Lrig1 was poorly expressed in ErbB2-positive breast cancer, suggesting that Lrig1 has a growth-inhibitory role in this tumor type. However, breast cancer is a complex disease, with ErbB2-positive tumors accounting for just 25% of all breast cancers. To gain a better understanding of the role of Lrig1 in breast cancer, we examined its expression in estrogen receptor α (ERα)-positive disease which accounts for the majority of breast cancers. We find that Lrig1 is expressed at significantly higher levels in ERα-positive disease than in ERα-negative disease. Our study provides a molecular rationale for Lrig1 enrichment in ERα-positive disease by showing that Lrig1 is a target of ERα. Estrogen stimulates Lrig1 accumulation and disruption of this induction enhances estrogen-dependent tumor cell growth, suggesting that Lrig1 functions as an estrogen-regulated growth suppressor. In addition, we find that Lrig1 expression correlates with prolonged relapse-free survival in ERα-positive breast cancer, identifying Lrig1 as a new prognostic marker in this setting. Finally, we show that ErbB2 activation antagonizes ERα-driven Lrig1 expression, providing a mechanistic explanation for Lrig1 loss in ErbB2-positive breast cancer. This work provides strong evidence for a growth-inhibitory role for Lrig1 in breast cancer. 相似文献
67.
Ricardo A. Scrosati Amanda S. Knox Nelson Valdivia Markus Molis 《Helgoland Marine Research》2011,65(2):91-102
Environmental stress affects species richness and diversity in communities, but the precise form of the relationship is unclear.
We tested an environmental stress model (ESM) that predicts a unimodal pattern for total richness and diversity in local communities
across the full stress gradient where a regional biota can occur. In 2008, we measured richness and diversity (considering
all macrobenthic species) across the entire intertidal range on three rocky shores on Helgoland Island, Germany. Intertidal
elevation is known to be positively related to abiotic stress. Since Helgoland is between the northern and southern biogeographic
boundaries for the cold-temperate NE Atlantic intertidal biota, it exhibits low stress levels for this biota at low elevations
and high stress at high elevations because of long (>6 h) emersion times. Thus, we predicted a unimodal trend for richness
and diversity across elevation. On all three shores, richness increased from high to middle elevations, but remained similar
between middle and low elevations. Diversity followed the same trend on one shore and different trends (although also non-unimodal)
on the other two. Evenness explained the trend differences between richness and diversity. Overall, our study yielded little
support for the ESM. Reasons for richness and diversity not decreasing at low elevations may be related to influences of mostly
subtidal species, Helgoland’s intertidal range, or sampling resolution. Our study also suggests that the ESM must be developed
further to differentiate between richness and diversity. We offer recommendations to improve future ESM research using intertidal
systems. 相似文献
68.
Identification of F1 hybrids of artichoke by ISSR markers and morphological analysis 总被引:1,自引:0,他引:1
Chiara Lo Bianco Juan A. Fernández Daniele Migliaro Paola Crinò Catalina Egea-Gilabert 《Molecular breeding : new strategies in plant improvement》2011,27(2):157-170
Five different artichoke hybrid populations (crosses between a male sterile artichoke (MS6) and three American accessions
(AMA3, AMA7, AMB1) and two Spanish accessions (SP2, SPA2)) plus a commercial hybrid population (Opal F1, Nunhems, Netherlands)
were used for molecular and morphological characterisation in order to identify the purity of the F1 populations. Molecular
analysis was carried out using the inter-simple sequence repeat (ISSR) technique with twenty primers. Out of these, nine were
polymorphic, producing 82 DNA bands per primer on average, 56 of which were polymorphic among the populations. A dendrogram,
drawn on the basis of a similarity matrix using the UPGMA algorithm, revealed that the 66 samples (10 plants per F1 populations
and their respective progenitors) could be classified into two major clusters at a Nei’s genetic distance of 0.13. The male
parents were genetically quite similar to all their respective progenies. In order to confirm hybrid purity, only the primers
which amplified bands specific to the male parent of each hybrid were considered and the inheritance of the single locus for
each cross-combination was analysed. Three ISSR markers (857c, 857g and 878) were able to confirm the hybrid purity. The morphological
trait analysis showed that eight of the 17 morphological characters were significantly different among the six F1 populations.
When the Mantel test was applied to the matrix of the Nei’s genetic distances and the matrix of morphological traits, a significant
degree of correlation was observed between them. A selection method using ISSR markers based on cluster analysis is suggested
to confirm the purity of artichoke hybrids and to predict the characters expected by any F1 hybrid offspring. 相似文献
69.
Santiago C Ruiz JR Rodríguez-Romo G Fiuza-Luces C Yvert T Gonzalez-Freire M Gómez-Gallego F Morán M Lucia A 《PloS one》2011,6(1):e16323
The Lys(K)153Arg(R) polymorphism in exon 2 (rs1805086, 2379 A>G replacement) of the myostatin (MSTN) gene is a candidate to influence skeletal muscle phenotypes. We examined the association between the MSTN K153R polymorphism and 'explosive' leg power, assessed during sprint (30 m) and stationary jumping tests [squat (SJ) and counter-movement jumps (CMJ)] in non-athletic young adults (University students) [n = 281 (214 men); age: 21-32 years]. We also genotyped the MSTN exonic variants E164K (rs35781413), I225T, and P198A, yet no subject carried any of these variant MSTN alleles. As for the K153R polymorphism, we found only one woman with the KR genotype; thus, we presented the results only for men. The results of a one-way ANCOVA (with age, weight and height entered as covariates) showed that men with the KR genotype (n = 15) had a worse performance in vertical jumps compared with those with the KK genotype [SJ: vertical displacement of center of gravity (CG) of 35.17 ± 1.42 vs. 39.06 ± 0.39 cm, respectively, P = 0.009; CMJ: vertical displacement of CG of 36.44 ± 1.50 vs. 40.63 ± 0.41 cm, respectively, P = 0.008]. The results persisted after adjusting for multiple comparisons according to Bonferroni. Performance in 30 m sprint tests did however not differ by K153R genotypes. In summary, the MSTN K153R polymorphism is associated with the ability to produce 'peak' power during muscle contractions, as assessed with vertical jump tests, in young non-athletic men. Although more research is still needed, this genetic variation is among the numerous candidates to explain, alone or in combination with other polymorphisms, individual variations in muscle phenotypes. 相似文献
70.
Maternal prenatal undernutrition predisposes offspring to higher adiposity in adulthood. Mechanisms involved in these programming effects, apart from those described in central nervous system development, have not been established. Here we aimed to evaluate whether moderate caloric restriction during early pregnancy in rats affects white adipose tissue (WAT) sympathetic innervation in the offspring, and its relationship with adiposity development. For this purpose, inguinal and retroperitoneal WAT (iWAT and rpWAT, respectively) were analyzed in male and female offspring of control and 20% caloric-restricted (from 1-12 d of pregnancy) (CR) dams. Body weight (BW), the weight, DNA-content, morphological features and the immunoreactive tyrosine hydroxylase and Neuropeptide Y area (TH+ and NPY+ respectively, performed by immunohistochemistry) of both fat depots, were studied at 25 d and 6 m of age, the latter after 2 m exposure to high fat diet. At 6 m of life, CR males but not females, exhibited greater BW, and greater weight and total DNA-content in iWAT, without changes in adipocytes size, suggesting the development of hyperplasia in this depot. However, in rpWAT, CR males but not females, showed larger adipocyte diameter, with no changes in DNA-content, suggesting the development of hypertrophy. These parameters were not different between control and CR animals at the age of 25 d. In iWAT, both at 25 d and 6 m, CR males but not females, showed lower TH(+) and NPY(+), suggesting lower sympathetic innervation in CR males compared to control males. In rpWAT, at 6 m but not at 25 d, CR males but not females, showed lower TH(+) and NPY(+). Thus, the effects of caloric restriction during gestation on later adiposity and on the differences in the adult phenotype between internal and subcutaneous fat depots in the male offspring may be associated in part with specific alterations in sympathetic innervation, which may impact on WAT architecture. 相似文献