全文获取类型
收费全文 | 211篇 |
免费 | 26篇 |
出版年
2022年 | 4篇 |
2021年 | 7篇 |
2020年 | 6篇 |
2019年 | 10篇 |
2018年 | 5篇 |
2017年 | 4篇 |
2016年 | 13篇 |
2015年 | 11篇 |
2014年 | 11篇 |
2013年 | 5篇 |
2012年 | 11篇 |
2011年 | 5篇 |
2010年 | 5篇 |
2009年 | 4篇 |
2008年 | 3篇 |
2007年 | 5篇 |
2006年 | 9篇 |
2005年 | 7篇 |
2004年 | 5篇 |
2003年 | 2篇 |
2002年 | 7篇 |
2001年 | 2篇 |
2000年 | 6篇 |
1999年 | 2篇 |
1998年 | 7篇 |
1997年 | 2篇 |
1995年 | 5篇 |
1994年 | 2篇 |
1993年 | 2篇 |
1992年 | 6篇 |
1991年 | 3篇 |
1989年 | 4篇 |
1988年 | 3篇 |
1987年 | 6篇 |
1986年 | 10篇 |
1985年 | 2篇 |
1984年 | 3篇 |
1983年 | 2篇 |
1981年 | 4篇 |
1980年 | 4篇 |
1979年 | 3篇 |
1978年 | 2篇 |
1975年 | 2篇 |
1974年 | 2篇 |
1972年 | 4篇 |
1968年 | 1篇 |
1966年 | 1篇 |
1965年 | 1篇 |
1964年 | 1篇 |
1963年 | 1篇 |
排序方式: 共有237条查询结果,搜索用时 78 毫秒
71.
Lucotte GL;French MS Consortium 《Genetic counseling (Geneva, Switzerland)》2002,13(2):133-138
To identify the chromosomal localizations of the multiple sclerosis (MS) genes, we conducted a genomewide linkage analysis using eighteen affected families. A MS gene is linked to markers located in the 19q13.3 region (multipoint lod-score = 2.1). Apolipoprotein E (ApoE) gene, located in this region, is an excellent candidate gene for MS because the ApoEe4 allele is acting as a severity allele in the disease. 相似文献
72.
73.
Substitution bias, rapid saturation, and the use of mtDNA for nematode systematics 总被引:13,自引:0,他引:13
Only relatively recently have researchers turned to molecular methods for
nematode phylogeny reconstruction. Thus, we lack the extensive literature
on evolutionary patterns and phylogenetic usefulness of different DNA
regions for nematodes that exists for other taxa. Here, we examine the
usefulness of mtDNA for nematode phylogeny reconstruction and provide data
that can be used for a priori character weighting or for parameter
specification in models of sequence evolution. We estimated the
substitution pattern for the mitochondrial ND4 gene from intraspecific
comparisons in four species of parasitic nematodes from the family
Trichostrongylidae (38-50 sequences per species). The resulting pattern
suggests a strong mutational bias toward A and T, and a lower
transition/transversion ratio than is typically observed in other taxa. We
also present information on the relative rates of substitution at first,
second, and third codon positions and on relative rates of saturation of
different types of substitutions in comparisons ranging from intraspecific
to interordinal. Silent sites saturate extremely quickly, presumably owing
to the substitution bias and, perhaps, to an accelerated mutation rate.
Results emphasize the importance of using only the most closely related
sequences in order to infer patterns of substitution accurately for
nematodes or for other taxa having strongly composition-biased DNA. ND4
also shows high amino acid polymorphism at both the intra- and
interspecific levels, and in higher level comparisons, there is evidence of
saturation at variable amino acid sites. In general, we recommend using
mtDNA coding genes only for phylogenetics of relatively closely related
nematode species and, even then, using only nonsynonymous substitutions and
the more conserved mitochondrial genes (e.g., cytochrome oxidases). On the
other hand, the high substitution rate in genes such as ND4 should make
them excellent for population genetics studies, identifying cryptic
species, and resolving relationships among closely related congeners when
other markers show insufficient variation.
相似文献
74.
Differentiation-associated modulation of heparan sulfate structure and function in CaCo-2 colon carcinoma cells 总被引:3,自引:2,他引:1
Salmivirta M; Safaiyan F; Prydz K; Andresen MS; Aryan M; Kolset SO 《Glycobiology》1998,8(10):1029-1036
Heparan sulfate species expressed by different cell and tissue types differ
in their structural and functional properties. Limited information is
available on differences in regulation of heparan sulfate biosynthesis
within a single tissue or cell population under different conditions. We
have approached this question by studying the effect of cell
differentiation on the biosynthesis and function of heparan sulfate in
human colon carcinoma cells (CaCo-2). These cells undergo spontaneous
differentiation in culture when grown on semipermeable supports; the
differentiated cells show phenotypic similarity to small intestine
enterocytes. Metabolically labeled heparan sulfate was isolated from the
apical and basolateral media from cultures of differentiated and
undifferentiated cells. Compositional analysis of disaccharides, derived
from the contiguous N-sulfated regions of heparan sulfate, indicated a
greater proportion of 2-O- sulfated iduronic acid units and a smaller
amount of 6-O-sulfated glucosamine units in differentiated than in
undifferentiated cells. By contrast, the overall degree of sulfation, the
chain length and the size distribution of the N-acetylated regions were
similar regardless the differentiation status of the cells. The structural
changes were found to affect the binding of heparan sulfate to the long
isoform of platelet-derived growth factor A chain but not to fibroblast
growth factor 2. These findings show that heparan sulfate structures change
during cell differentiation and that heparan sulfate-growth factor
interactions may be affected by such changes.
相似文献
75.
Gopinathan K. Menon Peter M. Elias Seung Hun Lee Kenneth R. Feingold 《Cell and tissue research》1992,270(3):503-512
Summary Perturbation of the cutaneous permeability barrier results in rapid secretion of epidermal lamellar bodies, and synthesis and secretion of new lamellar bodies leading to barrier repair. Since external Ca2+ significantly impedes the repair response, we applied ion capture cytochemistry to localize Ca2+ in murine epidermis following barrier disruption. In controls, the numbers of Ca2+ precipitates in the basal layer were small, increasing suprabasally and reaching the highest density in the stratum granulosum. Barrier disruption with acetone produced an immediate, marked decrease in Ca2+ in the stratum granulosum, accompanied by secretion of lamellar bodies. Loss of this pattern of Ca2+ distribution was associated with the appearance of large Ca2+ aggregates within the intercellular spaces of the stratum corneum. The Ca2+-containing precipitates progressively reappeared in parallel with barrier recovery over 24 h. Disruption of the barrier with tape stripping also resulted in loss of Ca2+ from the nucleated layers of the epidermis, but small foci persisted where the stratum corneum was not removed; in these sites the Ca2+ distribution did not change and accelerated secretion of lamellar bodies was not observed. Following acetone-induced barrier disruption and immersion in isoosmolar sucrose, the epidermal Ca2+ gradient did not return, and both lamellar body secretion and barrier recovery occurred. However, with immersion in isoosmolar sucrose plus Ca2+, the epidermal Ca2+ reservoir was replenished, and both secretion of lamellar bodies and barrier recovery were impeded. These results demonstrate that barrier disruption results in loss of the epidermal Ca2+ reservoir, which may be the signal that initiates lamellar body secretion leading to barrier repair. 相似文献
76.
Kemmer D Huang Y Shah SP Lim J Brumm J Yuen MM Ling J Xu T Wasserman WW Ouellette BF 《Genome biology》2005,6(12):R106
We developed Ulysses as a user-oriented system that uses a process called Interolog Analysis for the parallel analysis and
display of protein interactions detected in various species. Ulysses was designed to perform such Interolog Analysis by the
projection of model organism interaction data onto homologous human proteins, and thus serves as an accelerator for the analysis
of uncharacterized human proteins. The relevance of projections was assessed and validated against published reference collections.
All source code is freely available, and the Ulysses system can be accessed via a web interface . 相似文献
77.
Meiotic studies of the F1 hybrid between rice bean (Vigna umbellata) and its wild relative V. minima
The interspecific F1 hybrid V. umbellata x V. minima, together with the parental species was investigated cytogenetically. Both parents showed normal meiosis, with 11 bivalents at diakinesis. The hybrid was completely pollen sterile. The cytological causes underlying sterility in the hybrid include an array of meiotic abnormalities ranging from non-pairing of chromosomes through the presence of univalents, chain and ring multivalents and anaphase bridges to the formation of micronuclei, during microsporogenesis. The presence of chain and ring multivalents at diakinesis not only demonstrates the structural hybridity of the F1 hybrid, but also suggests that small interchanges and inversions played a significant role in the speciation within the genus Vigna. 相似文献
78.
Greiciane MS Florim Heloisa C Caldas Julio CR de Melo Maria Alice SF Baptista Ida MM Fernandes Marcela Savoldi-Barbosa Gustavo H Goldman Mario Abbud-Filho 《Arthritis research & therapy》2015,17(1)
IntroductionMicrochimeric male fetal cells (MFCs) have been associated with systemic lupus erythematosus, and published studies have further correlated MFC with lupus nephritis (LN). In the present study, we evaluated the frequency of MFC in the renal tissue of patients with LN.MethodsTwenty-seven renal biopsies were evaluated: Fourteen were from women with clinical and laboratory findings of LN, and thirteen were from controls. Genomic DNA was extracted from kidney biopsies, and the male fetal DNA was quantified using real-time quantitative polymerase chain reactions for the detection of specific Y chromosome sequences.ResultsMFCs were detected in 9 (64%) of 14 of patients with LN, whereas no MFCs were found in the control group (P = 0.0006). No differences in pregnancy history were found between patients with LN and the control group. Significantly higher amounts of MFCs were found in patients with LN with serum creatinine ≤1.5 mg/dl. Furthermore, women with MFCs had significantly better renal function at the time of biopsy (P = 0.03). In contrast, patients with LN without MFCs presented with more severe forms of glomerulonephritis (World Health Organization class IV = 60% and class V = 40%).ConclusionsOur data indicate a high prevalence of MFCs in renal biopsy specimens from women with LN, suggesting a role for MFCs in the etiology of LN. The present report also provides some evidence that MFCs could have a beneficial effect in this disease.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-015-0615-4) contains supplementary material, which is available to authorized users. 相似文献79.
Tobias Goldmann Nicolas Zeller Jenni Raasch Katrin Kierdorf Kathrin Frenzel Lars Ketscher Anja Basters Ori Staszewski Stefanie M Brendecke Alena Spiess Tuan Leng Tay Clemens Kreutz Jens Timmer Grazia MS Mancini Thomas Blank Günter Fritz Knut Biber Roland Lang Danielle Malo Doron Merkler Mathias Heikenwälder Marco Prinz 《The EMBO journal》2015,34(12):1612-1629
Microglia are tissue macrophages of the central nervous system (CNS) that control tissue homeostasis. Microglia dysregulation is thought to be causal for a group of neuropsychiatric, neurodegenerative and neuroinflammatory diseases, called “microgliopathies”. However, how the intracellular stimulation machinery in microglia is controlled is poorly understood. Here, we identified the ubiquitin‐specific protease (Usp) 18 in white matter microglia that essentially contributes to microglial quiescence. We further found that microglial Usp18 negatively regulates the activation of Stat1 and concomitant induction of interferon‐induced genes, thereby terminating IFN signaling. The Usp18‐mediated control was independent from its catalytic activity but instead required the interaction with Ifnar2. Additionally, the absence of Ifnar1 restored microglial activation, indicating a tonic IFN signal which needs to be negatively controlled by Usp18 under non‐diseased conditions. These results identify Usp18 as a critical negative regulator of microglia activation and demonstrate a protective role of Usp18 for microglia function by regulating the Ifnar pathway. The findings establish Usp18 as a new molecule preventing destructive microgliopathy. 相似文献
80.
Rini Chaturvedi Jyoti Chhibber-Goel Ishika Verma Sreehari Gopinathan Suhel Parvez Amit Sharma 《International journal for parasitology》2021,51(7):505-525
The global spread of sulfadoxine (Sdx, S) and pyrimethamine (Pyr, P) resistance is attributed to increasing number of mutations in DHPS and DHFR enzymes encoded by malaria parasites. The association between drug resistance mutations and SP efficacy is complex. Here we provide an overview of the geographical spread of SP resistance mutations in Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) encoded dhps and dhfr genes. In addition, we have collated the mutation data and mapped it on to the three-dimensional structures of DHPS and DHFR which have become available. Data from genomic databases and 286 studies were collated to provide a comprehensive landscape of mutational data from 2005 to 2019. Our analyses show that the Pyr-resistant double mutations are widespread in Pf/PvDHFR (P. falciparum ~61% in Asia and the Middle East, and in the Indian sub-continent; in P. vivax ~33% globally) with triple mutations prevailing in Africa (~66%) and South America (~33%). For PfDHPS, triple mutations dominate South America (~44%), Asia and the Middle East (~34%) and the Indian sub-continent (~27%), while single mutations are widespread in Africa (~45%). Contrary to the status for P. falciparum, Sdx-resistant single point mutations in PvDHPS dominate globally. Alarmingly, highly resistant quintuple and sextuple mutations are rising in Africa (PfDHFR-DHPS) and Asia (Pf/PvDHFR-DHPS). Structural analyses of DHFR and DHPS proteins in complexes with substrates/drugs have revealed that resistance mutations map proximal to Sdx and Pyr binding sites. Thus new studies can focus on discovery of novel inhibitors that target the non-substrate binding grooves in these two validated malaria parasite drug targets. 相似文献