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Functional human CFTR produced by a stable minichromosome.

ABSTRACT: Artificial chromosomes have been claimed to be the ideal vector for gene therapy, but their use has been hampered by an inability to produce stable and well designed molecules. We have used a structurally defined minichromosome to clone the human cystic fybrosis transmembrane conductance regulator (CFTR) locus. To guarantee the presence of the proper regulatory elements, we used the 320 kb yeast artificial chromosome (YAC) 37AB12 with the intact CFTR gene and upstream sequences. The resulting minichromosome was analyzed for the presence of the entire CFTR gene and for its functional activity by molecular and functional methods. We have identified clones showing the presence of both the transcript and the CFTR protein. Moreover, in the same clones, a chloride secretory response to cAMP was detected. Mitotic and molecular stability after prolonged growth without selection demonstrated that the constructs were stable. This is the first example of a structurally known minichromosome made to contain an active therapeutic gene.

SUBMITTER: Auriche C

PROVIDER: S-EPMC1084227 | biostudies-literature | 2002 Sep

REPOSITORIES: biostudies-literature

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Functional human CFTR produced by a stable minichromosome.

Auriche Cristina C Carpani Daniela D Conese Massimo M Caci Emanuela E Zegarra-Moran Olga O Donini Pierluigi P Ascenzioni Fiorentina F

EMBO reports 20020816 9

Artificial chromosomes have been claimed to be the ideal vector for gene therapy, but their use has been hampered by an inability to produce stable and well designed molecules. We have used a structurally defined minichromosome to clone the human cystic fybrosis transmembrane conductance regulator (CFTR) locus. To guarantee the presence of the proper regulatory elements, we used the 320 kb yeast artificial chromosome (YAC) 37AB12 with the intact CFTR gene and upstream sequences. The resulting mi ...[more]

PMID: 12189175

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Project description:Despite many advances in the study of large-scale human functional networks, the question of timing, stability, and direction of communication between cortical regions has not been fully addressed. At the cellular level, neuronal communication occurs through axons and dendrites, and the time required for such communication is well defined and preserved. At larger spatial scales, however, the relationship between timing, direction, and communication between brain regions is less clear. Here, we use a measure of effective connectivity to identify connections between brain regions that exhibit communication with consistent timing. We hypothesized that if two brain regions are communicating, then knowledge of the activity in one region should allow an external observer to better predict activity in the other region, and that such communication involves a consistent time delay. We examine this question using intracranial electroencephalography captured from nine human participants with medically refractory epilepsy. We use a coupling measure based on time-lagged mutual information to identify effective connections between brain regions that exhibit a statistically significant increase in average mutual information at a consistent time delay. These identified connections result in sparse, directed functional networks that are stable over minutes, hours, and days. Notably, the time delays associated with these connections are also highly preserved over multiple time scales. We characterize the anatomic locations of these connections, and find that the propagation of activity exhibits a preferred posterior to anterior temporal lobe direction, consistent across participants. Moreover, networks constructed from connections that reliably exhibit consistent timing between anatomic regions demonstrate features of a small-world architecture, with many reliable connections between anatomically neighbouring regions and few long range connections. Together, our results demonstrate that cortical regions exhibit functional relationships with well-defined and consistent timing, and the stability of these relationships over multiple time scales suggests that these stable pathways may be reliably and repeatedly used for large-scale cortical communication.

Dataset Information

Functional human CFTR produced by a stable minichromosome.

Publications

Functional human CFTR produced by a stable minichromosome.

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