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PubMed2004

Evidence that RNA editing modulates splice site selection in the 5-HT2C receptor gene.

Adenosine to inosine editing of mRNA from the human 5-HT2C receptor gene (HTR2C) occurs at five exonic positions (A-E) in a stable stem-loop that includes the normal 5' splice site of intron 5 and is flanked by two alternative splice sites. Using in vitro editing, we identified a novel editing site (F) located in the intronic part of the stem-loop and demonstrated editing at this site in human brain. We have shown that in cell culture, base substitutions to mimic editing at different combinations of the six sites profoundly affect relative splicing at the normal and the upstream alternative splice site, but splicing at the downstream alternative splice site was consistently rare. Editing combinations in different splice variants from human brain were determined and are consistent with the effects of editing on splicing observed in cell culture. As RNA editing usually occurs close to exon/intron boundaries, this is likely to be a general phenomenon and suggests an important novel role for RNA editing.

Aged↗

PubMed1983

LAMP. A data management and analysis system for patient registries and clinical studies.

A computer system for the management and analysis of clinical data is described. The system is implemented in the ANSI standard MUMPS language and runs on popular minicomputers. The system is designed to allow clinical investigators or research assistants to define a data base, enter and edit data, produce patient-specific reports, and perform a variety of analyses on user-specified groups of subjects. Programmer intervention is not required at any stage of the management or analysis process, and on-line documentation provides a friendly environment for inexperienced users.

Computers↗

PubMed2026

Genome-wide identification, structural characterization, and evolutionary analysis of growth-related gene families in African catfish (Clarias gariepinus).

The somatotropic axis encompassing growth hormone (GH), insulin-like growth factor (IGF), myostatin (MSTN), and prolactin (PRL) signalling cascades is the master regulator of somatic growth, metabolism, and development in vertebrates. African catfish (Clarias gariepinus), a commercially pivotal aquaculture species, now possesses a chromosome-level reference genome (CGAR_prim_01v2); however, a systematic, genome-wide characterization spanning all five interconnected growth-related gene families has not previously been undertaken in this species. Here, we identified and characterized 15 growth-related genes spanning gh1, ghra, ghrb, Igf1, Igf2a, Igf2b, igf1ra, Igf1rb, Igf2r, Mstna, Mstnb, prl, prlra, prlrb, and smtlb distributed across 13 chromosomes. Complete one-to-one orthology with zebrafish confirmed strong dosage-balance conservation across >120 million years of teleost divergence. Physicochemical analysis resolved a clear biochemical dichotomy between compact, basic secreted ligands (19.88-45.81 kDa; pI up to 10.02) and large, acidic, heavily glycosylated membrane receptors (56.82-270.80 kDa; pI 4.85-5.97). Phylogenetic analysis confirmed 3R whole-genome duplication origins for all paralog pairs, while synteny analysis revealed a disruption of the ancestral gh1-prl chromosomal block in C. gariepinus, a finding that warrants further comparative and functional investigation. This genomic atlas provides the sequence and structural information including exon-intron boundaries, domain architecture, and chromosomal coordinates needed as a prerequisite for future marker-assisted selection and CRISPR-based myostatin-editing efforts in African catfish aquaculture, though translation into applied breeding outcomes will require subsequent functional and expression studies.

Animals↗

PubMed2001

Personality disorders.

Some general recommendations can be made, collected from these subjective descriptions of personality types. Because determining an accurate psychiatric diagnosis is not the internist's aim, it is better for him or her to have a stance that generalizes to all patients, which can be refined as personality characteristics emerge. Tolerate the patient's affect (such as anger or anxiety), being firm and kind, rather than punitive or overinvested. Accept dependency and vulnerability. Accept and respect the underlying coping style. Understand that the patient's personality style is the best (and usually only) way he or she knows to have a relationship, including a relationship with the physician. Understand that personality traits additionally may have a function (e.g., to guard against anxiety or depression). Recognize that personality traits do not come in pure form. One personality trait is likely to blend into or overlap with other traits. Identify and treat any underlying symptom disorder, such as anxiety, depression, irritability, or thought disorder. Educate the patient clearly (and without patronizing) about medical illness. Document what was explained to the patient and how the patient responded, including dispassionate observations about behavior and emotional expression. Appreciate the patient's possible attachment to medical symptoms. Avoid arguments with patients who make unreasonable demands. Make timely judgments about whether or not to accede to a demand. When in doubt about a patient's honesty, give the patient the benefit of the doubt. Do not worry about being used because all patients use their physicians to some extent. Go to the limits of your tolerance for a patient's personality, but know your limits and refer to a colleague when you cannot work with the patient. Terminate an interaction and get help if there is a risk (or fear) of violence. Given the time it takes to manage the relationship and the psychiatric elements of treatment, a referral to a psychiatrist or other mental health professional often is wise if the patient will accept it. Include the mental health professional as part of the medical team. Although these various recommendations have been emphasized in connection with certain personality types, one can be flexible about their application in a variety of patients. It is important also to reiterate the limits of subjective descriptions. It is rare to find any of the aforementioned subjective descriptions in unmodified form; characteristics of more than one personality type usually appear in the same person. The descriptions are composites that provide a starting point for the physician. The physician should edit the composites based on experience with real patients. This article has described human characteristics and rough guidelines for helpful human responses and possible pharmacologic interventions. So equipped, the primary care physician may find it less troubling and more interesting to face the wide variation in human character.

Adaptation, Psychological↗

PubMed1997

QC Validator 2.0: a computer program for automatic selection of statistical QC procedures for applications in healthcare laboratories.

A computer program has been developed to help healthcare laboratories select statistical control rules and numbers of control measurements that will assure the quality required by clinical decision interval criteria or analytical total error criteria. The program (QC Validator 2.0 (QC Validator and OPSpecs are registered trademarks of Westgard Quality Corporation, which has applied for a patent for this automatic QC selection process. Windows is a registered trademark of Microsoft Corporation)) runs on IBM compatible personal computers operating under Windows. The user enters information about the method imprecision, inaccuracy, and expected frequency of errors, defines the quality required in terms of a medically important change (clinical decision interval) or an analytical allowable total error, then initiates automatic selection by indicating the number of control materials that are to be analyzed (1, 2, or 3). The program returns with a chart of operating specifications (OPSpecs chart) that displays the selected control rules and numbers of control measurements. The automatic QC selection process is based on user editable criteria for the types of control rules that can be implemented by the laboratory, total numbers of control measurements that are practical, maximum levels of false rejections that can be tolerated and minimum levels of error detection that are acceptable for detection of medically important systematic or random errors.

Biometry↗

PubMed2005

A quantitative reconstruction of the amide I contour in the IR spectra of globular proteins: from structure to spectrum.

The Amide I contours of six globular proteins of varied secondary structure content along with a peptide model for collagen and pulmonary surfactant protein C have been simulated very closely by using a modified GF matrix method. The starting point for the method uses the three-dimensional structure as obtained from the Protein Data Bank. Elements of the interactions between peptide groups (e.g., transition dipole coupling) are very sensitive to tertiary structure, thus the current formalism demonstrates that the Amide I contour may be useful for a more detailed probe of 3-D conformation that goes beyond the traditional use of this band to probe the percentages of particular elements of secondary structure. For example, postulated changes to a known structure can be tested by comparing the new simulated band to the experimental band. A number of refinements to the transition dipole interaction calculation have been made. Most of the important interactions between the C=O oscillators that define the Amide I mode appear to have been identified, including through space transition dipole coupling, through valence bond and through hydrogen bond coupling. The eigenvector matrix produced by the method permits the contribution of each peptide group to the spectrum to be precisely determined. Analysis of the results shows that the often-used structure-frequency correlations are at best approximate and at worst misleading. The subbands from helices, sheets, turns, and loops are much broader and more overlapped than has been commonly assumed. Furthermore, the traditional alpha-helical marker band may be substantially distorted in short segments. Difference spectra based on isotope editing, a technique thought capable of revealing the spectral contributions of individual peptide groups, are shown to be prone to misinterpretation.

Amides↗

PubMed1990

Development of a stable Leishmania expression vector and application to the study of parasite surface antigen genes.

Trypanosomatid protozoan parasites cause several important tropical diseases and have been a fertile ground for the discovery of molecular paradigms such as trans-splicing and RNA editing. Transfection-based methods for the study of these organisms have recently been developed, and we have now designed an expression vector, pX, which contains only 2.3 kilobases of Leishmania DNA and can be stably transfected with high efficiency. Genes encoding Escherichia coli beta-galactosidase or a Leishmania amazonensis protective membrane glycoprotein (GP46A/M-2) were inserted into the pX expression site and transfected into Leishmania major, where they directed the synthesis of high levels of mRNAs formed by 5' and 3' processing events occurring predominantly at the sites used by the normal transcripts. Colony assays and immunoblot analysis showed that both proteins were produced; enzymatically active beta-galactosidase comprised approximately 1% of total protein. Sizes of the GP46A protein synthesized in transfected L. major or L. amazonensis were similar and differed from the predominant L. amazonensis GP46, suggesting that the GP46A gene may encode a variant GP46 family member. Because these vectors function efficiently in pathogenic species of Leishmania, pX will facilitate the genetic analyses of parasite proteins crucial for infectivity as well as the identification of cis-acting elements mediating transcription and replication.

Animals↗

PubMed1986

A general DNA analysis program for the Hewlett-Packard Model 86/87 microcomputer.

A program is described to perform general DNA sequence analysis on the Hewlett-Packard Model 86/87 microcomputer operating on 128 K of RAM. The following analytical procedures can be performed: 1. display of the sequence, in whole or part, or its complement; 2. search for specified sequences e.g. restriction sites, and in the case of the latter give fragment sizes; 3. perform a comprehensive search for all known restriction enzyme sites; 4. map sites graphically; 5. perform editing functions; 6. base frequency analysis; 7. search for repeated sequences; 8. search for open reading frames or translate into the amino acid sequence and analyse for basic and acidic amino acids, hydrophobicity, and codon usage. Two sequences, or parts thereof, can be merged in various orientations to mimic recombination strategies, or can be compared for homologies. The program is written in HP BASIC and is designed principally as a tool for the laboratory investigator manipulating a defined set of vectors and recombinant DNA constructs.

Amino Acid Sequence↗

PubMed2005

Superimposition of 3D cone-beam CT models of orthognathic surgery patients.

OBJECTIVES: To evaluate the registration of 3D models from cone-beam CT (CBCT) images taken before and after orthognathic surgery for the assessment of mandibular anatomy and position. METHODS: CBCT scans were taken before and after orthognathic surgery for ten patients with various malocclusions undergoing maxillary surgery only. 3D models were constructed from the CBCT images utilizing semi-automatic segmentation and manual editing. The cranial base was used to register 3D models of pre- and post-surgery scans (1 week). After registration, a novel tool allowed the visual and quantitative assessment of post-operative changes via 2D overlays of superimposed models and 3D coloured displacement maps. RESULTS: 3D changes in mandibular rami position after surgical procedures were clearly illustrated by the 3D colour-coded maps. The average displacement of all surfaces was 0.77 mm (SD=0.17 mm), at the posterior border 0.78 mm (SD=0.25 mm), and at the condyle 0.70 mm (SD=0.07 mm). These displacements were close to the image spatial resolution of 0.60 mm. The average interobserver differences were negligible. The range of the interobserver errors for the average of all mandibular rami surface distances was 0.02 mm (SD=0.01 mm). CONCLUSION: Our results suggest this method provides a valid and reproducible assessment of craniofacial structures for patients undergoing orthognathic surgery. This technique may be used to identify different patterns of ramus and condylar remodelling following orthognathic surgery.

Adult↗

PubMed2006

Borderline personality symptomatology and employment disability: a survey among outpatients in an internal medicine clinic.

OBJECTIVE: The relationship between borderline personality symptomatology and employment disability has undergone limited study. Four previous studies indicate a possible relationship, but each has its own inherent limitations. In the present study, we examined this relationship among 94 internal medicine outpatients. METHOD: Using a sample of convenience, we administered 2 self-report measures for borderline personality (the Personality Diagnostic Questionnaire-4th Edition, which is based on DSM criteria, and the Self-Harm Inventory, which correlates with scores on the Diagnostic Interview for Borderlines) and inquired about the lifetime presence and length of either psychiatric or medical disability. The study was active from February 2003 through January 2005. RESULTS: There was a significant and positive correlation between scores on both borderline personality measures and the length of psychiatric disability for women (r = .33, r = .36, p = .05); however, no significant relationship was found between scores on either measure for borderline personality and the length of either psychiatric or medical disability for men. CONCLUSIONS: These findings suggest that, in contrast to men, there may be a relationship between borderline personality symptomatology and psychiatric disability only among women (i.e., there may be a gender difference). We discuss the possible implications of these results.

Journal Article↗

PubMed2001

[Development and applications of a computer aided complete denture design system].

OBJECTIVE: The purpose of this study was to develop a practical CAD/CAM system with knowledge databases for complete denture. METHODS: A three-dimensional coordinate measuring machine (3DCMM) was used to collect three-dimensional information of edentulous models and bite plates and the mathematics model of complete denture was established using B-Spline method. This system was established by seting eight functional models: the measuring model, the converting data model, the constructing curve-surface model, the producing base and the editing model, the arranging artificial and the editing model, the outputting income model, the imitating dynamic model and the managing model. RESULTS: (1) The soft and hard system of a computer aided complete denture design (CACDD) was established, including 3DCMM, 8 functional models and databases. (2) A CACDD system and the three-dimensional demonstration were completed. CONCLUSION: This system lay down the foundation for setting up the computer aided complete denture design/manufacturing system.

Computer-Aided Design↗

PubMedDate not supplied

[Social inequities of health in Spain. Report of the Scientific Commission for the Study of Social Inequities in Health in Spain].

In 1993 the Ministry of Health of the Spanish Government appointed a Scientific Commission to analyze social inequalities in health in Spain, as well as to make recommendations for improving Spanish health, through the practical implementation of public policies to reduce existing inequalities. The present report is the result of the work carried out by the said Commission. It has the following aims: first, to present a general introduction to the topic of social inequalities in health; second, to offer a global vision of the topic in Spain based upon the editing of available information: finally, to encourage the need for an in-depth analysis of the study and the reduction in social inequalities in health in the scientific and social fields, offering illustrative examples. The first chapter points out the importance of the topic, and Spain is located in the international historical and geographical context. The second chapter presents the most important concepts regarding the definition and measurement of health and inequality. The third and fourth chapters review various international and national studies of particular importance, and the Spanish case includes the current limitations to research. The fifth chapter presents two original investigations on the four perspectives of social inequalities in health in Spain: death rate, noticeable health, conducts related to health and the use and access to health services. Chapter six comments on some examples of policies aimed at reducing inequalities in health. Finally, the seventh chapter summarises the main conclusions of the report and makes some recommendations both for the improvement of current information systems as well as for obtaining the main conclusions for the health policies. Amongst the report's main conclusions the following may be pointed out: 1) an ecological study on the social inequalities in the death rate of small areas between 1990-1992 has revealed the existence of inequalities at a small area level. Autonomous Communities and regions. Inequality is confirmed between North-Northwestern Spain (with a high level) and South-Southwestern Spain (with a low level). Likewise, a positive relationship may be observed between various social indicators and the death rate; 2) the analysis of health surveys for 1987 and 1993 according to social class has revealed the existence of inequalities in health. Thus, in most of the health variables studied regarding the state of health-the conducts related to health or health services-the most disadvantaged social classes present greater health problems; 3) the political social and health experiences carried out in the Basque Country and Barcelona respectively, aimed at improving living standards, social welfare and the health of the most vulnerable sectors of the population have been positive and should be expanded and studied in depth; 4) the study and decrease of social inequalities in health by putting into practice social and health public policies should be a main objective of all political and social forces.

Health Status↗

PubMed2002

A hammerhead ribozyme substrate and reporter for in vitro kinetoplastid RNA editing.

Current in vitro assays for RNA editing in kinetoplastids directly examine the products generated by incubation of pre-mRNA substrate with guide RNA (gRNA) and mitochondrial (mt) extract. RNA editing substrates that are modeled on hammerhead ribozymes were designed with catalytic cores that contained or lacked additional uridylates (Us). They proved to be sensitive reporters of editing activity when used for in vitro assays. A deletion editing substrate that is based on A6 pre-mRNA had no ribozyme activity, but its incubation with gRNA and mt extract resulted in its deletion editing and production of a catalytically active ribozyme. Hammerhead ribozymes are thus sensitive tools to assay in vitro RNA editing.

Animals↗

PubMed2001

The role of binding domains for dsRNA and Z-DNA in the in vivo editing of minimal substrates by ADAR1.

RNA editing changes the read-out of genetic information, increasing the number of different protein products that can be made from a single gene. One form involves the deamination of adenosine to form inosine, which is subsequently translated as guanosine. The reaction requires a double-stranded RNA (dsRNA) substrate and is catalyzed by the adenosine deaminase that act on dsRNA (ADAR) family of enzymes. These enzymes possess dsRNA-binding domains (DRBM) and a catalytic domain. ADAR1 so far has been found only in vertebrates and is characterized by two Z-DNA-binding motifs, the biological function of which remains unknown. Here the role of the various functional domains of ADAR1 in determining the editing efficiency and specificity of ADAR1 is examined in cell-based assays. A variety of dsRNA substrates was tested. It was found that a 15-bp dsRNA stem with a single base mismatch was sufficient for editing. The particular adenosine modified could be varied by changing the position of the mismatch. Editing efficiency could be increased by placing multiple pyrimidines 5' to the edited adenosine. With longer substrates, editing efficiency also increased and was partly due to the use of DRBMs. Additional editing sites were also observed that clustered on the complementary strand 11-15 bp from the first. An unexpected finding was that the DRBMs are not necessary for the editing of the shorter 15-bp substrates. However, mutation of the Z-DNA-binding domains of ADAR1 decreased the efficiency with which such a substrate was edited.

Adenosine Deaminase↗

PubMed2025

CRISPR RNP-Mediated Transgene-Free Genome Editing in Plants: Advances, Challenges and Future Directions for Tree Species.

CRISPR ribonucleoprotein (RNP)-mediated genome editing offers a transgene-free platform for precise genetic modification in diverse herbaceous and tree species, including rice, wheat, apple, poplar, oil palm, rubber tree and grapevine. However, its application in woody plants faces distinct challenges, notably inefficient delivery and regeneration difficulties, particularly in species such as bamboo. While some of these issues also occur in herbaceous plants, they are often significantly more complex in woody species due to factors such as intricate cell wall architecture, widespread recalcitrant genotypes and inherent limitations of current delivery platforms. This review presents the first in-depth, critical re-evaluation of recent advancements in RNP-mediated editing in woody plants, highlighting these obstacles that warrant focused attention. Unlike plasmid-based CRISPR systems, RNP editing utilises Cas9/Cas12a protein-guide RNA complexes without integrating foreign DNA. This enables a DNA-free editing strategy that simplifies regulatory approval and minimises off-target effects due to the transient presence and rapid degradation of RNPs within plant cells. While PEG-mediated protoplast transfection and particle bombardment remain the primary reported methods for RNP delivery in trees, we evaluate promising alternative strategies such as lipofection, electroporation, cell-penetrating peptides and nanoparticle-based systems for targeted RNP delivery. Despite their promise, these advanced methods remain largely untested in woody species. Finally, we outline future research directions, including the development of tree-specific RNP delivery systems and regeneration protocols to enhance efficiency and minimise cytotoxicity. These innovations are essential for unlocking the full potential of RNP-mediated genome editing in long-lived tree species. This review provides a focused and timely roadmap for expanding the application of RNP technology across diverse woody plants.

Gene Editing↗

PubMed2003

Scrutinizing ACGIH risk assessments: the trichloroethylene case.

BACKGROUND: The American Conference of Governmental Industrial Hygienists (ACGIH) threshold limit values (TLVs) for occupational exposure to chemicals and physical agents have been very influential in the setting of occupational exposure limits in many countries. METHODS: Three ACGIH risk assessments of the chlorinated solvent trichloroethylene (TCE) [ACGIH (1989): 5th edition; ACGIH (1992): 5th edition. Revised Vol II; ACGIH (1996): Suppl. 6th edition] are compared to 26 other risk assessments made of the same chemical substance. The documents are compared in terms of their overall conclusions and the data selected for assessment. RESULTS: It is shown that these ACGIH risk assessment documents were based on incomplete and biased data sets. CONCLUSIONS: The data on which the ACGIH [ACGIH (1996): Suppl. 6th edition] base their TCE risk assessment do not adequately reflect the available scientific knowledge about TCE toxicity and carcinogenicity. This may have influenced their conclusion that TCE is not carcinogenic in either animals or humans which stand out compared to contemporary risk assessments.

Animals↗

PubMed2001

Substrate recognition by ADAR1 and ADAR2.

RNA editing catalyzed by ADAR1 and ADAR2 involves the site-specific conversion of adenosine to inosine within imperfectly duplexed RNA. ADAR1- and ADAR2-mediated editing occurs within transcripts of glutamate receptors (GluR) in the brain and in hepatitis delta virus (HDV) RNA in the liver. Although the Q/R site within the GluR-B premessage is edited more efficiently by ADAR2 than it is by ADAR1, the converse is true for the +60 site within this same transcript. ADAR1 and ADAR2 are homologs having two common functional regions, an N-terminal double-stranded RNA-binding domain and a C-terminal deaminase domain. It is neither understood why only certain adenosines within a substrate molecule serve as targets for ADARs, nor is it known which domain of an ADAR confers its specificity for particular editing sites. To assess the importance of several aspects of RNA sequence and structure on editing, we evaluated 20 different mutated substrates, derived from four editing sites, for their ability to be edited by either ADAR1 or ADAR2. We found that when these derivatives contained an A:C mismatch at the editing site, editing by both ADARs was enhanced compared to when A:A or A:G mismatches or A:U base pairs occurred at the same site. Hence substrate recognition and/or catalysis by ADARs could involve the base that opposes the edited adenosine. In addition, by using protein chimeras in which the deaminase domains were exchanged between ADAR1 and ADAR2, we found that this domain played a dominant role in defining the substrate specificity of the resulting enzyme.

Adenosine Deaminase↗

PubMed1993

RNA editing of AMPA receptor subunit GluR-B: a base-paired intron-exon structure determines position and efficiency.

A functionally critical position (Q/R site) of the AMPA receptor subunit GluR-B is controlled by RNA editing that operates in the nucleus, since in brain and clonal cell lines of neural origin, unspliced GluR-B transcripts occur edited in the Q/R site CAG codon and, additionally, in intronic adenosines. Transfection of GluR-B gene constructs into PC12 cells revealed that the proximal part of the intron downstream of the unedited exonic site is required for Q/R site editing. This intron portion contains an imperfect inverted repeat preceding a 10 nt sequence with exact complementarity to the exon centered on the unedited codon. Single nucleotide substitutions in this short intronic sequence or its exonic complement curtailed Q/R site editing, which was recovered by restoring complementarity in the respective partner strand. Base conversion in the channel-coding region of GluR-B directed by base paired sequences may be executed by a ubiquitous nuclear adenosine deaminase specific for double-stranded RNA.

Adenosine Deaminase↗