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61.
Ras mediates the cAMP-dependent activation of extracellular signal-regulated kinases (ERKs) in melanocytes 下载免费PDF全文
Buscà R Abbe P Mantoux F Aberdam E Peyssonnaux C Eychène A Ortonne JP Ballotti R 《The EMBO journal》2000,19(12):2900-2910
In melanocytes and melanoma cells, cAMP activates extracellular signal-regulated kinases (ERKs) and MEK-1 by an unknown mechanism. We demonstrate that B-Raf is activated by cAMP in melanocytes. A dominant-negative mutant of B-Raf, but not of Raf-1, blocked the cAMP-induced activation of ERK, indicating that B-Raf is the MEK-1 upstream regulator mediating this cAMP effect. Studies using Clostridium sordelii lethal toxin and Clostridium difficile toxin B have suggested that Rap-1 or Ras might transduce cAMP action. We show that Ras, but not Rap-1, is activated cell-specifically and mediates the cAMP-dependent activation of ERKs, while Rap-1 is not involved in this process in melanocytes. Our results suggest a novel, cell-specific mechanism involving Ras small GTPase and B-Raf kinase as mediators of ERK activation by cAMP. Also, in melanocytes, Ras or ERK activation by cAMP is not mediated through protein kinase A activation. Neither the Ras exchange factor, Son of sevenless (SOS), nor the cAMP-responsive Rap-1 exchange factor, Epac, participate in the cAMP-dependent activation of Ras. These findings suggest the existence of a melanocyte-specific Ras exchange factor directly regulated by cAMP. 相似文献
62.
Castagnone-Sereno P; Semblat JP; Leroy F; Abad P 《Molecular biology and evolution》1998,15(9):1115-1122
A highly abundant satellite DNA comprising 20% of the Meloidogyne fallax
(Nematoda, Tylenchida) genome was cloned and sequenced. The satellite
monomer is 173 bp long and has a high A + T content of 72.3%, with frequent
runs of A's and T's. The sequence variability of the monomers is 2.7%,
mainly due to random distribution of single-point mutations. A search for
evidence of internal repeated subunits in the monomer sequence revealed a
6-bp motif (AAATTT) for which five degenerated repeats, differing by just a
single base pair, could be identified. Pairwise comparison of the M. fallax
satellite with those from the sympatric species Meloidogyne chitwoodi and
Meloidogyne hapla revealed a high sequence similarity (68.39%) with one
satellite DNA subfamily in M. chitwoodi, which indicated an unexpected
close relationship between them. Given the high copy number and the extreme
sequence homogeneity among monomeric units, it may be assumed that the
satellite DNA of M. fallax could have evolved through some recent and
extensive amplification burst in the nematode genome. In this case, its
relatively short life would not yet have allowed the accumulation of random
mutations in independent amplified repeats. Considering the morphological
resemblance between the two species and their ability to produce
interspecific fertile hybrids under controlled conditions, these results
indicate that M. fallax may share a common ancestor with M. chitwoodi, from
which it could have diverged recently. All these data suggest that M.
fallax could be the result of a recent speciation process and show that
Meloidogyne satellite DNAs may be of interest to resolve phylogenetic
relationships among closely related species from this genus.
相似文献
63.
Corinne Miquel Laurent Gagnoux-Palacios Monique Durand-Clement Peter Marinkovich Jean Paul Ortonne Guerrino Meneguzzi 《Experimental cell research》1996,224(2):279
Herlitz junctional epidermolysis bullosa (H-JEB) is characterized by hampered expression of the adhesion ligand laminin-5. Thus far, analysis of the processes underlying the epithelial–mesenchymal dysadhesion marking this disease has been limited by the reduced growth and adhesive capabilities of the epithelial cells derived from H-JEB patients. To overcome these difficulties, we used SV40 virus to immortalize H-JEB keratinocytes with a homozygous nonsense mutation in the gene that encodes the γ2 chain of laminin-5. Cell lines (LSV) derived from infected keratinocytes maintain a stable karyotype, grow independent of 3T3 feeder layers and are not tumorigenic. Further analysis of clone LSV5 showed an increased secretion of laminin-6 and fibronectin compared to normal keratinocytes. Similar to parental H-JEB keratinocytes, these cells regenerate stratified epidermisin vitroand, inin vivomodels, they synthesize a basement membrane lacking laminin-5. LSV cells show hypermotility and reduced adhesive properties resulting from an incomplete association with the underlying culture substrate. These results demonstrate that LSV5 cells retain the pathologic phenotype of H-JEB keratinocytes and can serve as a model system to study the adhesion processes mediated by laminin-5. 相似文献
64.
Microphthalmia Gene Product as a Signal Transducer in cAMP-Induced Differentiation of Melanocytes 总被引:11,自引:0,他引:11
Corine Bertolotto Patricia Abbe Timothy J. Hemesath Karine Bille David E. Fisher Jean-Paul Ortonne Robert Ballotti 《The Journal of cell biology》1998,142(3):827-835
Islets of Langerhans are microorgans scattered throughout the pancreas, and are responsible for synthesizing and secreting pancreatic hormones. While progress has recently been made concerning cell differentiation of the islets of Langerhans, the mechanism controlling islet morphogenesis is not known. It is thought that these islets are formed by mature cell association, first differentiating in the primitive pancreatic epithelium, then migrating in the extracellular matrix, and finally associating into islets of Langerhans. This mechanism suggests that the extracellular matrix has to be degraded for proper islet morphogenesis. We demonstrated in the present study that during rat pancreatic development, matrix metalloproteinase 2 (MMP-2) is activated in vivo between E17 and E19 when islet morphogenesis occurs. We next demonstrated that when E12.5 pancreatic epithelia develop in vitro, MMP-2 is activated in an in vitro model that recapitulates endocrine pancreas development (Miralles, F., P. Czernichow, and R. Scharfmann. 1998. Development. 125: 1017–1024). On the other hand, islet morphogenesis was impaired when MMP-2 activity was inhibited. We next demonstrated that exogenous TGF-β1 positively controls both islet morphogenesis and MMP-2 activity. Finally, we demonstrated that both islet morphogenesis and MMP-2 activation were abolished in the presence of a pan-specific TGF-β neutralizing antibody. Taken together, these observations demonstrate that in vitro, TGF-β is a key activator of pancreatic MMP-2, and that MMP-2 activity is necessary for islet morphogenesis. 相似文献
65.
66.
Tim?Lu Christine?M?Costello Peter?JP?Croucher Robert?H?sler Günther?Deuschl Stefan?SchreiberEmail author 《BMC bioinformatics》2005,6(1):37
Background
Normalization is the process of removing non-biological sources of variation between array experiments. Recent investigations of data in gene expression databases for varying organisms and tissues have shown that the majority of expressed genes exhibit a power-law distribution with an exponent close to -1 (i.e. obey Zipf's law). Based on the observation that our single channel and two channel microarray data sets also followed a power-law distribution, we were motivated to develop a normalization method based on this law, and examine how it compares with existing published techniques. A computationally simple and intuitively appealing technique based on this observation is presented. 相似文献67.
Detection of novel LAMC2 mutations in Herlitz junctional epidermolysis Bullosa. 总被引:3,自引:0,他引:3 下载免费PDF全文
L. Pulkkinen J. McGrath T. Airenne H. Haakana K. Tryggvason S. Kivirikko G. Meneguzzi J. P. Ortonne A. M. Christiano J. Uitto 《Molecular medicine (Cambridge, Mass.)》1997,3(2):124-135
BACKGROUND: Laminin 5, an anchoring filament attachment protein within the lamina lucida of the basement membrane zone involved in the pathogenesis of junctional epidermolysis bullosa (JEB), consists of three polypeptide subunits, the alpha 3, beta 3, and gamma 2 chains which are encoded by the LAMA3, LAMB3, and LAMC2 genes, respectively. To facilitate identification of pathogenetic mutations in LAMC2, a strategy based on direct amplification of genomic DNA by PCR or mRNA by RT-PCR, followed by heteroduplex analysis of the PCR products, was developed. MATERIALS AND METHODS: Primer pairs for amplification of the complete cDNA as well as the 23 individual exons in the genomic DNA, which encode the entire gamma 2 chain of laminin 5, were established. The primers for amplification of exons from genomic DNA were positioned at least 24 bp away from the intron-exon borders in the flanking intronic sequences. For amplification of cDNA generated by RT-PCR, eight primer pairs covering overlapping segments of the entire coding sequence of LAMC2 mRNA were used. The amplified sequences were scanned for pathogenetic mutations and sequence variations in JEB patients and unrelated control individuals by heteroduplex analysis by means of conformation sensitive gel electrophoresis (CSGE). RESULTS: Utilizing the strategy developed in this study, we identified pathogenetic mutations in three patients with the Herlitz (lethal) variant of JEB, and eight intragenic normal polymorphisms, which are useful for linkage analysis, in the LAMC2 gene. CONCLUSIONS: The methodology described in this study is capable of detecting single-base substitutions or small insertions and deletions in the LAMC2 gene. Demonstration of mutations in this gene in JEB patients further emphasizes the role of laminin 5 in providing integrity to the cutaneous basement membrane zone. 相似文献
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