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PubMed1993

Editing of transfer RNAs in Acanthamoeba castellanii mitochondria.

With the discovery of RNA editing, a process whereby the primary sequence of RNA is altered after transcription, traditional concepts of genetic information transfer had to be revised. The known RNA editing systems act mainly on messenger RNAs, introducing sequence changes that alter their coding properties. An editing system that acts on transfer RNAs is described here. In the mitochondria of Acanthamoeba castellanii, an amoeboid protozoan, certain transfer RNAs differ in sequence from the genes that encode them. The changes consist of single-nucleotide conversions (U to A, U to G, and A to G) that appear to arise posttranscriptionally, are localized in the acceptor stem, and have the effect of correcting mismatched base pairs. Editing thus restores the base pairing expected of a normal transfer RNA in this region.

Acanthamoeba↗
PubMed2002

A putative RNA editing from U to C in a mouse mitochondrial transcript.

Recently, we isolated and characterized a new mouse mitochondrial RNA molecule containing the mitochondrial 16S RNA plus 121 nt joined to the 5' end of the RNA. This fragment arises from the L strand of the same gene and we have named this transcript chimeric RNA. At position 121 of the RNA there is a C, which, according to the sequence of the mitochondrial 16S RNA gene, should be a U. We hypothesized that this RNA is synthesized having a U at position 121, which is later substituted to a C by a putative editing reaction. Based on the presence of sites for the restriction endonucleases RsaI and Fnu4HI around position 121, both forms of the RNA were detected in mouse tissues. To confirm the presence of the non-edited and putative edited RNA, a fragment containing the first 154 nt of the RNA was amplified by RT-PCR and cloned. The substitution of U for C was demonstrated by sequencing these clones. In vitro transcription experiments demonstrated that the substitution of U for C is not due to artifact of amplification or cloning. Moreover, in mitochondria from testis only the non-edited form was found. This, together with other experimental evidence, demonstrated that the base substitution was not due to polymorphism of the mitochondrial 16S RNA gene. This is the first demonstration of a substitution reaction from U to C in a mammalian mitochondrial transcript.

Animals↗
PubMed1990

Differences in editing at homologous sites in messenger RNAs from angiosperm mitochondria.

Recent work has shown that amino acid sequence comparisons can be used to infer sites of C-to-U RNA editing in plant mitochondrial mRNAs (1). In order to test such predictions further and to search for conserved mRNA structural motifs that might provide insight into the mechanism of recognition of editing sites, the complete sequences of the cytochrome c oxidase subunit II (COXII) mRNAs of wheat, maize and pea were determined by reverse transcriptase sequencing. The results affirm the high reliability of editing predictions based on amino acid sequence alignments, and prompt us to make the further inference that COXI (cytochrome oxidase subunit I) mRNA is extensively edited in dicotyledonous plants but not in monocotyledons. In plant COXII mRNAs, additional non-predicted editing occurs such that the resulting derived amino acid sequences are more similar to those of non-plants than is indicated by the respective plant COXII DNA sequences. A number of homologous sites show differences in editing among species, and certain positions show partial editing within a species. Despite some deviation from expected nucleotide frequencies in the vicinity of editing sites, no extensive conserved primary or secondary structural motifs are apparent. The relevance of these data to the mechanism of RNA editing in plant mitochondria is discussed.

Amino Acid Sequence↗
PubMed1994

RNA editing in trypanosomes.

The nucleotide sequence of mitochondrial pre-mRNAs in trypanosomes is posttranscriptionally edited by the insertion and deletion of uridylate (U) residues. In some RNAs editing is limited to small sections but in African trypanosomes, such as Trypanosoma brucei, 9 of the 18 known mitochondrial mRNAs are created by massive editing which can produce more than 50% of the coding sequence. In all cases, however, RNA editing is a key event in gene expression during which translatable RNAs are generated. The information for the editing process and possibly also the inserted Us are provided by small guide RNAs, which are encoded in both the maxicircle and minicircle components of the trypanosome mitochondrial DNA. Current models of editing are largely based on the characteristics of partially edited RNAs and on the occurrence in vivo and the possibility of synthesis in vitro of chimeric molecules in which a guide RNA is covalently linked through its 3' oligo(U) tail to an editing site in pre-mRNA. In this paper, I will review the research in this rapidly growing field and illustrate how different interpretations of the available data can lead to different views of the mechanism and the biochemistry of the editing process.

Animals↗
PubMed1992

RNA editing in trans-splicing intron sequences of nad2 mRNAs in Oenothera mitochondria.

The complete open reading frame of subunit 2 of the NADH dehydrogenase in Oenothera mitochondria is split into five exons. The first two and the last three exons are encoded in distant genomic locations and are transcribed separately. Three tRNA genes coding for tRNA(Cys), tRNA(Asn), and tRNA(Tyr) are located upstream of the terminal three exons c, d, and e. The genomic distance, the interspersed tRNA genes, and the group II intron sequences flanking the two separated exons suggest trans-splicing to be required to connect exons b and c. Maturation of the mRNA includes RNA editing at 36 sites in the open reading frame. Three RNA editing events are observed in the split group II intron sequences. Two of these events allow after editing additional base pairings in the secondary structure, one in the stem of domain I, the other in the putative trans-pairing region of domain IV. These RNA editings may thus be involved in the trans-splicing reaction.

Amino Acid Sequence↗
PubMed1995

Transfer RNA editing in land snail mitochondria.

Some mitochondrial tRNA genes of land snails show mismatches in the acceptor stems predicted from their gene sequences. The majority of these mismatches fall in regions where the tRNA genes overlap with adjacent downstream genes. We have synthesized cDNA from four circularized tRNAs and determined the sequences of the 5' and 3' parts of their acceptor stems. Three of the four tRNAs differ from their corresponding genes at a total of 13 positions, which all fall in the 3' part of the acceptor stems as well as the discriminator bases. The editing events detected involve changes from cytidine, thymidine, and guanosine to adenosine residues, which generally restore base-pairing in the stems. However, in one case an A-A mismatch is created from an A-C mismatch. It is suggested that this form of RNA editing may involve polyadenylylation of the maturing tRNAs as an intermediate.

Animals↗
PubMed1995

Organization and complexity of minicircle-encoded guide RNAs in Trypanosoma cruzi.

The previously observed extensive sequence heterogeneity of the kinetoplast minicircle DNA in Trypanosoma cruzi, both intra- and interstrain, has raised the question as to how the minicircle DNA in this species can have any guide RNA (gRNA)-coding capacity at all, because there do not appear to be any variable-region sequences conserved between different strains. To address this question, we obtained the complete edited sequence of maxicircle unidentified reading frame 4 mRNA and identified 25 cognate gRNAs from gRNA libraries constructed from two clonal strains of T. cruzi--Sylvio X10/CL1 and CAN III/CL1. Libraries of PCR-amplified minicircle-variable regions were also constructed for both strains. A single gene for each gRNA was identified in the same polarity within specific minicircle-variable regions from both strains, 60-100 nt downstream from the conserved 12mer sequence. GTP-capped total gRNA from one strain failed to cross-hybridize with minicircle DNA from the other strain. The explanation for this proved to be the number of polymorphisms, mainly transitions, within the homologous gRNAs in the two strains. In most cases, these transitions did not destroy the edited mRNA/gRNA base pairing, as a result of the allowed G-U wobble base pairing. The sequences of the variable regions containing homologous gRNAs in the two strains probably derived from an ancestral sequence, and each has accumulated sufficient polymorphisms so as not to allow hybridization. Within a strain, multiple redundant gRNAs were identified that encode identical editing information but have different sequences.

Amino Acid Sequence↗
PubMed2003

Messenger RNA editing in mammals: new members of the APOBEC family seeking roles in the family business.

Alteration of mRNA sequence through base modification mRNA editing frequently generates protein diversity. Several proteins have been identified as being similar to C-to-U mRNA editing enzymes based on their structural domains and the occurrence of a catalytic domain characteristic of cytidine deaminases. In light of the hypothesis that these proteins might represent novel mRNA editing systems that could affect proteome diversity, we consider their structure, expression and relevance to biomedically significant processes or pathologies.

APOBEC-1 Deaminase↗
PubMed1982

[Analytical expression of acid-base equilibrium in human blood. I. Editing of a subroutine program].

A subroutine for evaluating the acid-base status in human blood is described. It employs as inputs seven parameters: pH-pO2-pCO2-Hb-Ht-the subject's temperature T and the plasmaprotein content PP and is based on a series of mathematical interrelationships existing between these various blood constituents. As output it returns the base excess (BE) of the whole blood and a number of pertinent data relating to the acid-base status and to the gas transport mechanisms in erythrocytes and plasma. An important advantage of this subroutine on other major procedures is that it can be accommodated into the memory space of a medium seized electronic calculator.

Acid-Base Equilibrium↗
PubMed2005

Polynomial-time metrics for attributed trees.

We address the problem of comparing attributed trees and propose four novel distance measures centered around the notion of a maximal similarity common subtree. The proposed measures are general and defined on trees endowed with either symbolic or continuous-valued attributes and can be applied to rooted as well as unrooted trees. We prove that our measures satisfy the metric constraints and provide a polynomial-time algorithm to compute them. This is a remarkable and attractive property, since the computation of traditional edit-distance-based metrics is, in general, NP-complete, at least in the unordered case. We experimentally validate the usefulness of our metrics on shape matching tasks and compare them with (an approximation of) edit-distance.

Algorithms↗
PubMedDate not supplied

Medicare cost controls and program compliance: the rationale of physician claims edits.

This article attempts to demystify and create a context for the enactment of several Medicare cost control and compliance systems for physician reimbursement. The focus is on claims "edits" and Medicare compliance. Portions of Medicare, including health care provider reimbursement, remain fee-for-service programs that can be easily defrauded. To protect the Trust, the Centers for Medicare and Medicaid Services (CMS) has taken a multi-pronged approach, using program administration, enforcement, and rules-based claims editing systems. The Evaluation and Management codes, the Correct Coding Initiative (CCI), and medical necessity rules are claims edits that affect procedure codes. The Medicare program has a complicated system of billing procedures and an apparatus to enforce them. A solid compliance plan must incorporate proper claims editing, because consistent incorrect Medicare billing can be considered abuse. Many resources are available to aid physicians, including computerized tools, new CMS initiatives, and Internet materials.

Aged↗
PubMedDate not supplied

Designing self-report instruments for family assessment.

As family medicine research expands, more and better self-report measures for quantifying family systems variables will be required. These measures should be developed from an accepted paradigm for instrument design that includes the following. They should be: 1) grounded in a contemporary conceptual framework; 2) constructed following a rational theoretical design that includes the sequential stages of construct identification, construct definition, item generation, item editing, item formatting, and item scoring; 3) analyzed empirically at the item level for item distribution characteristics, item-scale correlation, and item-response style correlations; 4) analyzed at the scale level for scale distribution characteristics, scale-scale correlations, and scale-response style correlation; 5) revised based on editing and empirical analysis; and 6) psychometrically evaluated for reliability (eg, internal consistency, test-retest) and validity (construct related, criterion related, and content related). Normative data from various reference populations must also be obtained to provide a basis for interpreting scores. Finally, test manuals must be written to summarize test development data and provide information on administration procedures, scoring, and interpretation.

Behavior↗
PubMed1997

A potential role for NF1 mRNA editing in the pathogenesis of NF1 tumors.

Neurofibromatosis type I (NF1) is a common disorder that predisposes to neoplasia in tissues derived from the embryonic neural crest. The NF1 gene encodes a tumor suppressor that most likely acts through the interaction of its GTPase-activating protein (GAP)-related domain (GRD) with the product of the ras protooncogene. We have previously identified a site in the NF1 mRNA, within the first half of the NF1 GRD, which undergoes base-modification editing. Editing at that site changes a C to a U, thereby introducing an in-frame stop codon. NF1 RNA editing has been detected in all cell types studied, to date. In order to investigate the role played by editing in NF1 tumorigenesis, we analyzed RNA from 19 NF1 and 4 non-NF1 tumors. We observed varying levels of NF1 mRNA editing in different tumors, with a higher range of editing levels in more malignant tumors (e.g., neurofibrosarcomas) compared to benign tumors (cutaneous neurofibromas). Plexiform neurofibromas have an intermediate range of levels of NF1 mRNA editing. We also compared tumor and nontumor tissues from several NF1 individuals, to determine the extent of variability present in the constitutional levels of NF1 mRNA editing and to determine whether higher levels are present in tumors. The constitutional levels of NF1 mRNA editing varied slightly but were consistent with the levels observed in non-NF1 individuals. In every case, there was a greater level of NF1 mRNA editing in the tumor than in the nontumor tissue from the same patient. These results suggest that inappropriately high levels of NF1 mRNA editing does play a role in NF1 tumorigenesis and that editing may result in the functional equivalent of biallelic inactivation of the NF1 tumor suppressor.

Astrocytoma↗
PubMed2025

Rescue of imprinted genes by epigenome editing in human cellular models of Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a genomic imprinting disorder caused by the loss of function of the paternal chromosome 15q11-13, resulting in a spectrum of symptoms associated with hypothalamic dysfunction. PWS patients lack the expression of paternally expressed genes (PEGs) in the 15q11-13 locus but possess an epigenetically silenced set of these genes in the maternal allele. Thus, activation of these silenced genes can serve as a therapeutic target for PWS. Here, we leverage CRISPR-based epigenome editing system to modulate the DNA methylation status of the PWS imprinting control region (PWS-ICR) in induced pluripotent stem cells (iPSCs) derived from PWS patients. Successful demethylation in the PWS-ICR restores the PEG expression from the maternal allele and reorganizes the methylation patterns in other PWS-associated imprinted regions beyond the PWS-ICR. Remarkably, these corrected epigenomic patterns and PEG expression are maintained following the differentiation of these cells into hypothalamic organoids. Finally, the single-cell transcriptomic analysis of epigenome-edited organoids demonstrates a partial restoration of the transcriptomic dysregulation observed in PWS. This study highlights the utility of epigenome editing technology as a therapeutic approach in addressing PWS and potentially other imprinting disorders.

Prader-Willi Syndrome↗
PubMed2026

Establishment of Stable Immortalized Human Choroidal Melanocytes for Ocular Research.

PURPOSE: The short lifespan of primary normal choroidal melanocytes (NCMs) in vitro represents a major barrier to mechanistic, functional, and translational studies of choroid biology and uveal melanoma (UM). This study aimed to establish and characterize immortalized human NCM lines that retain melanocytic function, maintain a non-cancerous profile, and are amenable to gene editing. METHODS: NCMs from four donors were immortalized by lentiviral transduction of cyclin-dependent kinase 4 (CDK4R24C), cyclin D1, and human telomerase reverse transcriptase (hTERT), establishing NCM-K4DT lines. Their morphology, melanocytic marker expression, proliferation, and functional properties (melanin synthesis and tyrosinase activity) were evaluated. Genomic stability was assessed by targeted mutation profiling, karyotyping, and copy number variation (CNV) analysis. The tumorigenicity was tested in immunodeficient mice. Plasmid-based CRISPR/Cas9 editing was performed to determine their suitability for gene editing. RESULTS: NCM-K4DT lines retained dendritic-shaped morphology, pigmentation, and expression of PMEL, TYRP1, Melan-A, and SOX10. Cells exhibited enhanced proliferative capacity with preserved cell cycle regulation. Melanin production and tyrosinase activity were comparable to primary NCMs. Genomic profiling confirmed the absence of UM-associated driver mutations and chromosomal abnormalities. In vivo growth assays demonstrated that NCM-K4DT lines did not form tumors within the 3-month observation period. Notably, NCM-K4DT cells were efficiently edited by CRISPR/Cas9. CONCLUSIONS: NCM-K4DT lines represent stable, non-cancerous, and genetically tractable models for studying choroidal melanocyte biology, modeling UM-associated mechanisms, and advancing therapeutic development in ocular research.

Humans↗
PubMed1997

Computer-based desktop system for surgical videotape editing.

BACKGROUND: The educational role of surgical video presentations should be optimized by linking surgical images to graphic evaluation of indications, techniques, and results. We describe a PC-based video production system for personal editing of surgical tapes, according to the objectives of each presentation. METHODS: The hardware requirement is a personal computer (100 MHz processor, 1-Gb hard disk, 16 Mb RAM) with a PC-to-TV/video transfer card plugged into a slot. Computer-generated numerical data, texts, and graphics are transformed into analog signals displayed on TV/video. A Genlock interface (a special interface card) synchronizes digital and analog signals, to overlay surgical images to electronic illustrations. The presentation is stored as digital information or recorded on a tape. RESULTS: The proliferation of multimedia tools is leading us to adapt presentations to the objectives of lectures and to integrate conceptual analyses with dynamic image-based information. We describe a system that handles both digital and analog signals, production being recorded on a tape. Movies may be managed in a digital environment, with either an "on-line" or "off-line" approach. System requirements are high, but handling a single device optimizes editing without incurring such complexity that management becomes impractical to surgeons. CONCLUSIONS: Our experience suggests that computerized editing allows linking surgical scientific and didactic messages on a single communication medium, either a videotape or a CD-ROM.

Analog-Digital Conversion↗