1,720,981 research outputs found
Mutations in the extracellular domain cause RET loss of function by a dominant negative mechanism
No full textThe RET proto-oncogene encodes a tyrosine kinase receptor expressed in neuroectoderm-derived cells. Mutations in specific regions of the gene are responsible for the tumor syndromes multiple endocrine neoplasia types 2A and 2B (MEN 2A and 2B), while mutations along the entire gene are involved in a developmental disorder of the gastrointestinal tract, Hirschsprung's disease (HSCR disease). Two mutants in the extracellular domain of RET, one associated with HSCR disease and one carrying a flag epitope, were analyzed to investigate the impact of the mutations on RET function. Both mutants were impeded in their maturation, resulting in the lack of the 170-kDa mature form and the accumulation of the 150-kDa immature form in the endoplasmic reticulum. Although not exposed on the cell surface, the 150-kDa species formed dimers and aggregates; this was more pronounced in a double mutant bearing a MEN 2A mutation. Tyrosine phosphorylation and the transactivation potential were drastically reduced in single and double mutants. Finally, in cotransfection experiments both mutants exerted a dominant negative effect over protoRET and RET2A through the formation of a heteromeric complex that prevents their maturation and function. These results suggest that HSCR mutations in the extracellular region cause RET loss of function through a dominant negative mechanism
The multiple sulfatase deficiency gene encodes an essential and limiting factor for the activity of sulfatases
No full textIn multiple sulfatase deficiency (MSD), a human inherited disorder, the activities of all sulfatases are impaired due to a defect in posttranslational modification. Here we report the identification, by functional complementation using microcell-mediated chromosome transfer, of a gene that is mutated in MSD and is able to rescue the enzymatic deficiency in patients' cell lines. Functional conservation of this gene was observed among distantly related species, suggesting a critical biological role. Coexpression of SUMF1 with sulfatases results in a strikingly synergistic increase of enzymatic activity, indicating that SUMF1 is both an essential and a limiting factor for sulfatases. These data have profound implications on the feasibility of enzyme replacement therapy for eight distinct inborn errors of metabolism
Loss of heterozygosity at the RET protooncogene locus in a case of multiple endocrine neoplasia type 2A.
No full textPARENTAL IMPRINTING OF RAT INSULIN-LIKE GROWTH-FACTOR-II GENE PROMOTERS IS COORDINATELY REGULATED
No full textThe insulin-like growth factor II (IGF-II) gene is parentally imprinted in the mouse and human species. By following the inheritance of natural polymorphisms of IGF-II mRNA, we demonstrated that the tissue-specific parental imprinting of the IGF-II gene is conserved in the rat. The expression of the paternal IGF-II allele exceeded by more than 3 orders of magnitude that of the maternal allele in livers of 3-day-old Wistar x Fisher interstrain rat crosses. In contrast, the two alleles were both expressed in the rat central nervous system, which is also the only district of the organism where this gene is active in adult rodents. We also analyzed the allelic usage of the three IGF-II promoters, which generate alternatively spliced transcripts, and showed that parental imprinting of all transcription starts sites is coordinately regulated since P1, P2, and P3 are all repressed on the maternal allele in neonatal rat liver, and all of them are activated on both alleles in the choroid plexus of the central nervous system. RNase protection assays demonstrated that the activity ratio of the three IGF-II promoters can be different in tissues that show the same imprinting mode
Parental imprinting of rat insulin-like growth factor II gene promoters is coordinately regulated.
No full textThe insulin-like growth factor II (IGF-II) gene is parentally imprinted in the mouse and human species. By following the inheritance of natural polymorphisms of IGF-II mRNA, we demonstrated that the tissue-specific parental imprinting of the IGF-II gene is conserved in the rat. The expression of the paternal IGF-II allele exceeded by more than 3 orders of magnitude that of the maternal allele in livers of 3-day-old Wistar x Fisher interstrain rat crosses. In contrast, the two alleles were both expressed in the rat central nervous system, which is also the only district of the organism where this gene is active in adult rodents. We also analyzed the allelic usage of the three IGF-II promoters, which generate alternatively spliced transcripts, and showed that parental imprinting of all transcription starts sites is coordinately regulated since P1, P2, and P3 are all repressed on the maternal allele in neonatal rat liver, and all of them are activated on both alleles in the choroid plexus of the central nervous system. RNase protection assays demonstrated that the activity ratio of the three IGF-II promoters can be different in tissues that show the same imprinting mode
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Diagnosis and treatment of multiple sulfatase deficiency and other sulfatase deficiencies
No full textvon Figura K, Schmidt B, Dierks T, Heartlein M, Ballabio A, Cosma MP. Diagnosis and treatment of multiple sulfatase deficiency and other sulfatase deficiencies. 2004
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
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