Dataset Information

A/T mutagenesis in hypermutated immunoglobulin genes strongly depends on PCNAK164 modification.

ABSTRACT: B cells use translesion DNA synthesis (TLS) to introduce somatic mutations around genetic lesions caused by activation-induced cytidine deaminase. Monoubiquitination at lysine(164) of proliferating cell nuclear antigen (PCNA(K164)) stimulates TLS. To determine the role of PCNA(K164) modifications in somatic hypermutation, PCNA(K164R) knock-in mice were generated. PCNA(K164R/K164R) mutants are born at a sub-Mendelian frequency. Although PCNA(K164R/K164R) B cells proliferate and class switch normally, the mutation spectrum of hypermutated immunoglobulin (Ig) genes alters dramatically. A strong reduction of mutations at template A/T is associated with a compensatory increase at G/C, which is a phenotype similar to polymerase eta (Poleta) and mismatch repair-deficient B cells. Mismatch recognition, monoubiquitinated PCNA, and Poleta likely cooperate in establishing mutations at template A/T during replication of Ig genes.

SUBMITTER: Langerak P

PROVIDER: S-EPMC2118671 | biostudies-other | 2007 Aug

REPOSITORIES: biostudies-other

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A/T mutagenesis in hypermutated immunoglobulin genes strongly depends on PCNAK164 modification.

Langerak Petra P Nygren Anders O H AO Krijger Peter H L PH van den Berk Paul C M PC Jacobs Heinz H

The Journal of experimental medicine 20070730 8

B cells use translesion DNA synthesis (TLS) to introduce somatic mutations around genetic lesions caused by activation-induced cytidine deaminase. Monoubiquitination at lysine(164) of proliferating cell nuclear antigen (PCNA(K164)) stimulates TLS. To determine the role of PCNA(K164) modifications in somatic hypermutation, PCNA(K164R) knock-in mice were generated. PCNA(K164R/K164R) mutants are born at a sub-Mendelian frequency. Although PCNA(K164R/K164R) B cells proliferate and class switch norma ...[more]

PMID: 17664295

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Project description:ObjectiveTo identify non-EEG-based signals and algorithms for detection of motor and non-motor seizures in people lying in bed during video-EEG (VEEG) monitoring and to test whether these algorithms work in freely moving people during mobile EEG recordings.MethodsData of three groups of adult people with epilepsy (PwE) were analyzed. Group 1 underwent VEEG with additional devices (accelerometry, ECG, electrodermal activity); group 2 underwent VEEG; and group 3 underwent mobile EEG recordings both including one-lead ECG. All seizure types were analyzed. Feature extraction and machine-learning techniques were applied to develop seizure detection algorithms. Performance was expressed as sensitivity, precision, F1 score, and false positives per 24 hours.ResultsThe algorithms were developed in group 1 (35 PwE, 33 seizures) and achieved best results (F1 score 56%, sensitivity 67%, precision 45%, false positives 0.7/24 hours) when ECG features alone were used, with no improvement by including accelerometry and electrodermal activity. In group 2 (97 PwE, 255 seizures), this ECG-based algorithm largely achieved the same performance (F1 score 51%, sensitivity 39%, precision 73%, false positives 0.4/24 hours). In group 3 (30 PwE, 51 seizures), the same ECG-based algorithm failed to meet up with the performance in groups 1 and 2 (F1 score 27%, sensitivity 31%, precision 23%, false positives 1.2/24 hours). ECG-based algorithms were also separately trained on data of groups 2 and 3 and tested on the data of the other groups, yielding maximal F1 scores between 8% and 26%.SignificanceOur results suggest that algorithms based on ECG features alone can provide clinically meaningful performance for automatic detection of all seizure types. Our study also underscores that the circumstances under which such algorithms were developed, and the selection of the training and test data sets need to be considered and limit the application of such systems to unseen patient groups behaving in different conditions.

Dataset Information

A/T mutagenesis in hypermutated immunoglobulin genes strongly depends on PCNAK164 modification.

Publications

A/T mutagenesis in hypermutated immunoglobulin genes strongly depends on PCNAK164 modification.

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