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PubMed2001

Looking back or looking all around: comparing two spell checking strategies for documents edition in an electronic patient record.

We report on the comparison of two systems for correcting spelling errors resulting in non-existent words (i.e. not listed in any lexicon). Both systems aim at improving edition of medical reports. Unlike traditional systems, based on word language models, both semantic and syntactic contexts are considered here. Both systems share the same string-to-string edit distance module, and the same contextual disambiguation principles. The differences between the two systems are located at the user interaction level: while the first system is using exclusively the left context, simulating the underlining of every mis-spelling at the end of every word typing, the second system uses the left as well as the right context and simulate a post-edition correction, when asked by the author. Our conclusion shows the improvements brought by the second approach.

Medical Records Systems, Computerized↗
PubMed2006

Dry period length to maximize production across adjacent lactations and lifetime production.

The primary objectives of this research were to determine the dry period lengths that maximize production across adjacent lactations and also dry period length that maximizes lifetime yield. Effect of days dry (DD) after lactations 1 through 3 were determined separately for both adjacent lactation sums and lifetime yield. Field data, collected through the Dairy Herd Improvement Association, on US Holstein cows first calving between January 1997 and January 2004 were utilized. Lifetime records were restricted to cows first calving no later than December 1999. Actual lactation yields, in contrast to standardized records, were used to calculate lactation sums and lifetime records. Herds were required to be on test for the entire period to avoid partial records. Another important edit was that actual calving dates had to agree with expected calving dates, based on reported days open, within 10 d. This edit ensured that the producer knew, at least at one point in time, when the cow was going to calve. Cow effects were corrected for in both the adjacent lactation and lifetime analyses. The minimum DD to maximize production across adjacent lactations depended on parity. For yield across first and second lactations, there was little loss in production with a minimum of 40 to 45 DD. Longer dry periods (55 to 65 DD) were required after second and third lactations however, presumably due to the lower persistency of second and later lactation cows. Lifetime production was maximized by 40 to 50 DD after first lactation and 30 to 40 DD after second and later lactations. Fewer DD were required to maximize lifetime yield than adjacent lactation yield because cows with fewer DD also had more lifetime days in milk. Although dry periods of 30 to 40 d can be used after second and later lactations without cost in lifetime yield, their benefit to lifetime production is minimal. Dry periods shorter than 30 d or longer than 70 d are costly to lifetime yield and should be avoided. Dry periods longer than 80 d are even more costly than dry periods less than 30 d.

Animals↗
PubMed2026

A-to-I RNA editing remodels 5'-UTR initiation codons to tune translational output.

A-to-I RNA editing is a prevalent post-transcriptional modification in higher eukaryotes that converts adenosine to inosine within RNA molecules. Because inosine is interpreted as guanosine during translation, editing can alter codon identity and potentially influence translation initiation signals. Here, we examined whether A-to-I editing within the 5' untranslated region (5'-UTR) can remodel upstream initiation codons and thereby tune downstream translation. Using luciferase-based reporter systems, we show that AUA-to-AUI editing generates an initiation-competent inosine-containing codon, whereas AUG-to-IUG editing markedly attenuates initiation and can relieve uORF-mediated repression. Quantitative in vitro and cellular assays establish the initiation hierarchy AUA&#x2009;<&#x2009;AUI&#x2009;<&#x2009;AUG, with IUG exhibiting strongly reduced initiation efficiency. Importantly, AUI-mediated upstream initiation did not behave like a canonical AUG-initiated uORF in the tested contexts; its effect on downstream ORF translation was modest and context-dependent. Transcriptome-wide bioinformatic analysis identified endogenous human transcripts whose 5'-UTRs harbor editing sites compatible with initiation-codon gain or attenuation. Reporter validation using native 5'-UTR sequences supports the possibility that editing-dependent initiation-codon remodeling can tune translational output in living cells, particularly through AUG-to-IUG-mediated derepression. Together, these findings establish a reporter-based framework in which A-to-I editing can remodel 5'-UTR initiation codons, while highlighting the need for endogenous protein-level and native-locus validation to determine physiological relevance.

RNA Editing↗
PubMed2006

T. brucei RNA editing: action of the U-insertional TUTase within a U-deletion cycle.

Trypanosome RNA editing is massive post-transcriptional U-insertion and U-deletion, which generates mature mRNA coding regions through cycles of endonuclease, terminal U transferase (TUTase) or 3'-U-exo, and ligase action. Both types of editing are thought to be catalyzed by distinct sets of proteins of a multiprotein complex, and no enzymatic activity of wild-type editing complex had been shown to function in both forms of editing. By examining the individual steps of the U-deletion cycle using purified editing complex, traditional mitochondrial extract, and rapidly prepared cell lysate, we here demonstrate that TbMP57 TUTase of U-insertion can act efficiently within a U-deletion cycle. When physiological UTP levels are provided, it adds U's to the upstream cleavage fragment after U-deletional endonuclease and 3'-U-exo action, but before rejoining by the U-deletional ligase, generating partial U-deletion products. TUTase activity in U-deletion was not previously appreciated since its detection requires UTP, which is not normally added to in vitro U-deletion reactions. Fractionation and RNAi analyses show this U-addition in U-deletion requires TbMP57 TUTase be present and competent for U-insertion; such U-addition does not occur with another mitochondrial TUTase that is separate from the basic editing complex. Efficient TbMP57 action in both U-insertion and U-deletion suggests these two editing forms may be less separate than generally envisioned. Should such promiscuous TUTase action also occur in vivo, it could explain why editing utilizes substantially fewer U-deletional than U-insertional events and why partial editing appears preferential in U-deletion.

Animals↗
PubMed2026

Zinc-dependent turnover of ZIP3 transporter mRNA by trypanosome ZNK1.

Like other cells, parasitic and other trypanosomatids sense Zn2+ and regulate Zn2+ transport, but the mechanisms involved remained unknown. Here, we identify a trypanosome RNA-binding protein that specifically eliminates ZIP3 transporter mRNA in Zn2+-replete conditions. We first demonstrate that Trypanosoma brucei ZIP3 mRNA abundance is subject to 3'-untranslated region (3'-UTR) and Zn2+-dependent negative control. A genome-wide RNA interference library screen, using a reporter associated with the ZIP3 3'-UTR, identifies Tb927.11.9510 as a candidate Zn2+-sensor, and we name this protein Zinc Nuclear Knuckles 1 (ZNK1) since it localizes to the nucleus and contains several Zn2+-knuckle motifs. ZNK1 is conserved among trypanosomatids, and a PIN domain suggests a ribonuclease-based mechanism. We use Cas9-editing to knockout ZNK1 and observe specific accumulation of&#xa0;ZIP3 transcripts, and increased intracellular Zn2+, in znk1 null cells. We validate ZNK1 as a ZIP3 3'-UTR-dependent negative regulator and identify a GU-repeat motif in the ZIP3 3'-UTR that is predictive of ZNK1-based negative control. In conclusion, ZNK1 eliminates ZIP3 transporter mRNA in a Zn2+-dependent manner. We suggest that trypanosomatid ZNK1 is a highly selective zinc finger nuclease that binds GU-repeat motifs within ZIP3 3'-UTRs and degrades Zn2+ transporter mRNA only when the tandem sensor knuckle modules are coordinated with Zn2+.

Trypanosoma brucei brucei↗
PubMed1996

A graph theoretic approach to the analysis of DNA sequencing data.

The analysis of data from automated DNA sequencing instruments has been a limiting factor in the development of new sequencing technology. A new base-calling algorithm that is intended to be independent of any particular sequencing technology has been developed and shown to be effective with data from the Applied Biosystems 373 sequencing system. This algorithm makes use of a nonlinear deconvolution filter to detect likely oligomer events and a graph theoretic editing strategy to find the subset of those events that is most likely to correspond to the correct sequence. Metrics evaluating the quality and accuracy of the resulting sequence are also generated and have been shown to be predictive of measured error rates. Compared to the Applied Biosystems Analysis software, this algorithm generates 18% fewer insertion errors, 80% more deletion errors, and 4% fewer mismatches. The tradeoff between different types of errors can be controlled through a secondary editing step that inserts or deletes base calls depending on their associated confidence values.

Algorithms↗
PubMed2004

A historical perspective on RNA editing: how the peculiar and bizarre became mainstream.

The known examples of RNA editing now encompass a variety of alterations of RNA primary sequence that arise from base modifications, nucleotide insertions or deletions, and nucleotide replacements. Hence, the definition of RNA editing has evolved as new systems have been described. This chapter presents a historical perspective on some of the pivotal discoveries that helped direct the current avenues of research in the field of RNA editing.

Animals↗
PubMed1994

Measurement of lactate in acutely ischemic rat kidneys using magnetic resonance spectroscopy.

RATIONALE AND OBJECTIVES: Quantification of lactate in the kidney by 1H magnetic resonance spectroscopy (MRS) is a difficult task because of the presence of large amounts of peri-renal fat. When an editing scheme is used to detect lactate that filters out all resonances except lactate, there is no suitable metabolite to serve as an internal standard. In this study, the authors evaluate the potential of MRS to measure the absolute lactate concentration in rat kidneys during acute ischemia using MRS. MATERIALS AND METHODS: The authors propose a method based on a double resonance lactate editing scheme used in combination with the fully relaxed water peak as an internal standard. Experiments were performed on the left kidney rendered ischemic in eight rats. RESULTS: Renal lactate concentrations measured by MRS were compared with values derived from chemical analysis. The mean (+/- standard deviation) renal lactate concentrations measured by MRS and determined chemically were 12 +/- 1.2 umol/g, and 12.94 +/- 1.07 umol/g wet weight, respectively. The coefficient of variation for paired observations was 2.96%, indicating excellent agreement between the two methods used for measuring lactate. DISCUSSION: The study results demonstrate that it is possible to assess the lactate concentration in a rat model of ischemic kidney with MRS and suggest that the total lactate pool is detectable by this method under these experimental conditions.

Animals↗
PubMed2003

WASP--a generic web-based, interactive, patient simulation system.

Computer based patient case simulation systems have during the recent years been introduced in medical education to allow students to "meet" more cases that are educationally optimized and adapted to the actual learning situation. However, three major problems exist with most computer based case simulation systems today: They are expensive to develop, experienced multimedia developers are needed for the development and teachers/clinicians can not develop and adjust cases to fit their own specific educational needs. The WASP project (Web-Activated Simulation of Patients) tries to solve these three problems, and still allow very realistic and highly-interactive simulations of clinical cases, delivered and edited via the Web. WASP is based on experience from a number of national and international visualization and simulation projects. Most important case simulation features are available, including: interactive history taking, complete physical examination (inspection, auscultation, palpation, percussion, vitals, neurological exams etc.), complete lab section including chemical labs, X-ray, MRI, ultrasound, CT, phys lab, pharmacology lab, pathology lab etc.), diagnosis and differentials, therapy, interactive session feedback and integrated references and online database sources.

Education, Medical, Undergraduate↗
PubMed1992

Structural requirements for RNA editing in hepatitis delta virus: evidence for a uridine-to-cytidine editing mechanism.

Hepatitis delta virus (HDV) nucleotide 1012 is edited from uridine to cytidine in 10-40% of the RNA genomes during replication. This editing event is an important control point in the HDV life cycle because it results in both the packaging of viral RNA and the inhibition of HDV replication. We find that the editing event is highly specific for both the sequences neighboring nucleotide 1012 and the base-paired context of position 1012 within the unbranched rod structure of HDV RNA. Prior studies identified the base transition at nucleotide 1012 but were unable to distinguish between editing of the genomic versus the antigenomic strands [Luo, G. X., Chao, M., Hsieh, S. Y., Sureau, C., Nishikura, K. & Taylor, J. (1990) J. Virol. 64, 1021-1027]. In this study, comparisons of mutations that differentiate between base pairing in genomic and antigenomic RNAs indicate that the genomic strand of HDV is the actual editing substrate. We conclude that the virus uses a uridine to cytidine editing mechanism, which is provided by the host cell.

Animals↗
PubMed1998

Neurofibromatosis type 1 (NF1): a protein truncation assay yielding identification of mutations in 73% of patients.

Neurofibromatosis type 1 (NF1) is caused by mutations in a tumour suppressor gene located on chromosome 17 (17q11.2). Disease causing mutations are dispersed throughout the gene, which spans 350 kilobases and includes 59 exons. A common consequence of NF1 mutations is introduction of a premature stop codon, and the majority of mutant genes encode truncated forms of neurofibromin. We used a protein truncation assay to screen for mutations in 15 NF1 patients and obtained positive results in 11 of them (73%). Sequencing of cDNA and genomic DNA yielded identification of 10 different mutations, including four splicing errors, three small deletions, two nonsense mutations, and one small insertion. Nine mutations were predicted to cause premature termination of translation, while one mutation caused in frame deletion as a result ofexon skipping. In one other case involving abnormal splicing, five different aberrantly spliced transcripts were detected. One germline nonsense mutation (R1306X, 3916C>T) corresponded to the same base change that occurs by mRNA editing in normal subjects. The second nonsense mutation (R2496X) was the sole germline mutation that has been previously described. The subjects studied represented typically affected NF1 patients and no correlations between genotype and phenotype were apparent. A high incidence of ocular hypertelorism was observed.

Adult↗
PubMed2003

The complete nucleotide sequence of the hornwort (Anthoceros formosae) chloroplast genome: insight into the earliest land plants.

It is generally believed that bryophytes are the earliest land plants. However, the phylogenetic relationships among bryophytes, including mosses, liverworts and hornworts, are not clearly resolved. To obtain more information on the earliest land plants, we determined the complete nucleotide sequence of the chloroplast genome from the hornwort Anthoceros formosae. The circular double-stranded DNA of 161 162 bp is the largest genome ever reported among land plant chloroplasts. It contains 76 protein, 32 tRNA and 4 rRNA genes and 10 open reading frames (ORFs), which are identical with the chloroplast genome of the other green plants analyzed. The major difference is a larger inverted repeat than that of the liverwort Marchantia, Anthoceros contains an excess of ndhB and rps7 genes and the 3' exon of rps12. The genes matK and rps15, commonly found in the chloroplast genomes of land plants, are pseudogenes. The intron of rrn23 is the first finding in the known chloroplast genomes of land plants. A striking feature of the hornwort chloroplast is that more than half of the protein-coding genes have nonsense codons, which are converted into sense codons by RNA editing. Maximum-likelihood (ML) analysis, based on 11 518 amino acid sites of 52 proteins encoded in the chloroplast genomes of the green plants, placed liverworts as the sister to all other land plants.

DNA, Chloroplast↗
PubMed1998

Fragile X DNA triplet repeats, (GCC)n, form hairpins with single hydrogen-bonded cytosine.cytosine mispairs at the CpG sites: isotope-edited nuclear magnetic resonance spectroscopy on (GCC)n with selective 15N4-labeled cytosine bases.

Here, we provide a direct proof that the formation of hairpins by (GCC)n at the 5'-UTR of the FMR-1 gene offers a mechanism for CpG hypermethylation associated with the fragile X syndrome. For this, we have performed hetero-nuclear (15N-1H) magnetic resonance spectroscopy to probe the structure of the CpG sites in the (GCC)n hairpins that are 15N-labeled at the amino (N4) groups of specific cytosine bases. Analyses of chemical shift, pH-induced chemical exchange, and NOE pattern of the (15N-labeled) amino protons of cytosine bases reveal that the cytosine bases at the CpG sites are intrahelical and well-stacked with the neighboring G.C base-pairs in the stem of these hairpins and probably form single hydrogen-bonded C.C mispairs. Measurements of pH-dependent 1H line-width also demonstrate that the C.C mispairs are more susceptible to open-closure than the G.C base-pairs. Thus, the Cs at the CpG sites of the (GCC)n hairpin are "flipped out" more easily to the activated state than those in the corresponding Watson-Crick duplex, (GCC)n. (GGC)n and this makes the hairpin a better target for methylation by the human methyltransferase, the enzyme that methylates the Cs at the CpG sites.

5' Untranslated Regions↗
PubMed1993

The RNA editing process in Trypanosoma brucei.

Twelve mitochondrial mRNAs are edited in Trypanosoma brucei, nine extensively, by addition and removal of uridines. The accumulation of the edited RNAs is regulated during the life cycle. Hundreds of different gRNAs, encoded three or four per minicircle, specify the editing and minicircle content accounts for variation in editing among species and in mutants. The current understanding of the process of gRNA utilization, the editing mechanism and the editing machinery is discussed.

Animals↗
PubMed1994

Model-based compartmental analyses in nutrition research.

Kinetic tracer studies have been used extensively in understanding digestion, absorption, and whole-body metabolism of nutrients. Optimal interpretation of changes in tracer levels over time and movement across body pools often requires sophisticated data analysis. The use of model-based compartmental analysis (MCA) can yield more detailed quantitative and predictive information concerning system dynamics, compared with direct stochastic approaches. With MCA, tracer and tracee data from both experimental and literature values are fit to a model that best approximates the system on the basis of experimental data at hand. The number of compartments of the model is determined by the shape of the curve fit to the tracee and tracer data and by literature information. On this basis, MCA can yield information about compartment numbers and sizes, fractional and net turnover, as well as catabolic and synthetic rates. PC-based MCA programs are now available. Whereas earlier editions required use of a programming language, the most recent versions being developed are completely menu driven. Model-based compartmental analyses thus represent important biotechnological advances permitting maximal interpretation of kinetic data in nutrition research.

Animal Nutritional Physiological Phenomena↗
PubMed1997

Family characteristics of subjects with panic attacks.

BACKGROUND AND OBJECTIVES: This study identified associations between panic states and family 1) structure, 2) functioning, and 3) stress/support. METHODS: Ninety-seven adults with panic disorder or infrequent panic attacks, based on the structured Clinical Interview of the Diagnostic and Statistical Manual, Third Edition, Revised, were matched to 97 subjects without panic symptoms based on age, gender, and race/ethnicity. All subjects completed a structured interview concerning health care use by family members and family characteristics. Family functioning was assessed using the Family Adaptability and Cohesion Evaluation Scales, and family stress/support were assessed using the Duke Social Support and Stress Scales. RESULTS: Although groups did not differ in either perceived or ideal family cohesion or adaptability, the panic group perceived their families as more dysfunctional and reported higher levels of family stress and total stress but lower levels of support, including family support, nonfamily support, and total support. CONCLUSIONS: Subjects with panic symptoms have families with high levels of dysfunction and stress but low levels of support. Increased family dysfunction may be due to comorbid substance abuse.

Adult↗
PubMed1984

Immunology and embryogenesis: the chromosomal editing hypothesis.

We have elaborated the chromosomal editing hypothesis of development. This hypothesis, based on evolutionary arguments, states that the immune system must have evolved from pre-existent cell receptor systems on other tissues. Therefore we feel that what we know about development in the immune system can serve as a provisional model for studying development in other organ systems. The model predicts that specifically programmed somatic-genetic events occur as lineages develop. These DNA cutting and splicing events, similar to those which generate antibody molecules, generate a wide diversity of specific cell receptors which allow the cell to properly orient itself in the developing organism. In addition, the chromosomal editing events occur sequentially and generate a temporal organization so that developmental events occur in an orderly fashion as lineages develop. At any point in development, epigenetic factors play a crucial role in triggering cells to undergo specific differentiative events. We believe that this hypothesis explains the apparent contradiction between rigid mosaic development and regulative development by proposing that the same general types of somatic-genetic and epigenetic events occur in both. In mosaic development, however, the organism does not have the residual and redundant stem cells which allow for the cell replacement, repair and regeneration seen in regulative development. We feel that by drawing analogies as we have from the development of the immune system one may gain insights into the genetic and epigenetic factors which govern the development of other tissues and formulate specific experiments to test the resulting hypothesis.

Biological Evolution↗