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PubMed1994

Human gastric adenocarcinoma cathepsin B: isolation and sequencing of full-length cDNAs and polymorphisms of the gene.

Four full-length cDNA clones coding for preprocathepsin B were isolated from a human gastric adenocarcinoma cDNA library (AGS 1-6-30-1) and analyzed for possible sequence modifications that might be linked to altered intracellular trafficking and secretion of cathepsin B (CTSB) in malignant tumors. Comparison of AGS 1-6-30-1 cDNAs with human kidney/hepatoma cDNAs revealed: (1) three potential N-glycosylation sites instead of two, (2) a nucleotide (nt) substitution in the coding region for the propeptide from GTG to CTG which would result in a Val26-->Leu change, (3) three silent nt replacements in the coding region for the mature protein, (4) five single-nt differences in the 5'- and 3'-UTR (untranslated regions), (5) heterogeneity in the 5'-UTR, and (6) a 10-bp insertion in the 3'-UTR. The 10-bp insertion in the 3'-UTR may alter the stability of CTSB mRNA transcripts and thereby the expression of CTSB. These clones should be useful for expressing human tumor CTSB and analyzing the function of this enzyme in malignant progression. Two restriction-fragment length polymorphisms (RFLPs), EcoRI and TaqI, were detected by Southern blot analysis of genomic DNA from 36 unrelated Caucasians. Inheritance and distribution of the EcoRI alleles (13.0 and 11.0 kb) and the TaqI alleles (5.7 and 4.6 kb) indicated they were independent polymorphisms. In contrast to the EcoRI alleles of 13.0 and 11.0 kb observed in the population survey, genomic DNA from two AGS gastric adenocarcinoma subclones revealed two EcoRI alleles of 13.0 and 7.8 kb.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenocarcinoma↗
PubMed2005

Reduction of Gstm1 expression in the stroke-prone spontaneously hypertension rat contributes to increased oxidative stress.

Human essential hypertension is a classic example of a complex, multifactorial, polygenic disease with a substantial genetic influence in which the underlying genetic components remain unknown. The stroke-prone spontaneously hypertension rat (SHRSP) is a well-characterized experimental model for essential hypertension and endothelial dysfunction. Previous work, identified glutathione S-transferase mu type 1, a protein involved in detoxification of reactive oxygen species, as a positional and functional candidate gene. Quantitative real-time polymerase chain reaction showed a highly significant, 4-fold reduction of glutathione S-transferase mu type 1 mRNA expression in 5- and 16-week-old SHRSP compared with the congenic and normotensive Wistar Kyoto rats. This suggests that differential expression is not attributable to long-term changes in blood pressure. DNA sequencing identified one coding single nucleotide polymorphism (R202H) and multiple single nucleotide polymorphisms in the promoter region. mRNA expression changes were reflected at the protein level, with significant reductions in the SHRSP glutathione S-transferase mu type 1. Protein was colocalized with aquaporin 2 to the principle cells of the renal collecting ducts. Coupled to significant increases in nitrotyrosine levels in the kidney, this suggests a pathophysiological role of this protein in hypertension and oxidative stress. Similar processes may underlie oxidative stress in the vasculature.

Amino Acid Sequence↗
PubMed1985

Isolation and characterization of mutants of the RP4 plasmid coding for increased resistance to ampicillin.

E. coli strain J53(RP4) was mutagenized with ethyl methanesulfonate and N-methyl-N'-nitro-N-nitrosoguanidine. Clones showing a two-to threefold increase in resistance to ampicillin were produced. This increase was not due to an increased number of RP4 copies per chromosome. The level of penicillinase activity was twice higher in comparison with the parental strain. No detectable changes were found in the region coding for the resistance to ampicillin on the plasmid by restriction analysis.

Ampicillin↗
PubMed1996

Analysis of phosducin as a candidate gene for retinopathies.

Phosducin, a retina-expressed gene mapped to chromosome 1q25-32.1, was analyzed as a candidate gene for retinopathies. The phosducin gene was cloned and characterized, and PCR primers were designed. Eighty-three patients with various retinopathies and 45 control subjects (24 American, 21 Japanese) were analyzed for mutations in the phosducin gene by PCR, denaturing gradient gel electrophoresis (DGGE), and sequencing. A heterozygous sequence variant changing a glycine to arginine at codon 178 was found in one Usher syndrome type II (USH2) patient, while the other USH2 patients did not show any coding sequence variant. A heterozygous sequence variant changing an asparagine to lysine at codon 174 was found in a patient with a severe retinal degeneration in the category of diseases known as acute zonal occult outer retinopathy (AZOOR). Three non-coding sequence variants were found. Two of these were always present together and found in 20.8% of American and 2.4% of Japanese control subjects, reflecting a difference in population pools. In conclusion, the phosducin gene did not show mutations consistent with it being the causative gene for USH2, but its possible pathogenicity in AZOOR or other retinopathies remains an open question which may be answered by further analysis.

Base Sequence↗
PubMed1990

The cDNA and protein sequences of mouse lactate dehydrogenase B. Molecular evolution of vertebrate lactate dehydrogenase genes A (muscle), B (heart) and C (testis).

Mouse lactate dehydrogenase-B cDNAs were isolated from cDNA libraries of macrophage (ICR strain) and thymus (F1 hybrid of C57BL/6 and CBA strains), and their nucleotide sequences determined. The lactate dehydrogenase-B cDNA insert of thymus clone mB188 consists of the protein-coding sequence (1002 nucleotides), the 5' (46 nucleotides) and 3' (190 nucleotides) non-coding regions, and poly(A) tail (19 nucleotides), while macrophage clone mB168 contains a partial lactate dehydrogenase cDNA insert from codon no. 55 to the poly(A) tail. Seven silent nucleotide substitutions at codon no. 142, 143, 186, 187, 241, 285 and 292, as well as a single nucleotide change in the 3' non-coding region, were found between these different strains of mice. The predicted sequence of 333 amino acids, excluding initiation methionine, was confirmed by sequencing and/or compositional analyses of a total of 103 (31%) amino acids from tryptic peptides of mouse lactate dehydrogenase-B protein. The nucleotide sequence of the mouse coding region for lactate dehydrogenase B shows 86% identity with that of the human isoenzyme, and only eight of the 139 nucleotide differences resulted in amino acid substitutions at residues 10, 13, 14, 17, 52, 132, 236 and 317. The rates of nucleotide substitutions at synonymous and nonsynonymous sites in the mammalian lactate dehydrogenase genes are calculated. The rates of synonymous substitutions for lactate dehydrogenase genes A (muscle) and B (heart) are considerably higher than the average rate computed from human and rodent genes. The rates of nonsynonymous substitutions for lactate dehydrogenase genes A (muscle) and B (heart), particularly the latter, are highly conservative. The rates of synonymous and nonsynonymous substitutions for the lactate dehydrogenase-C gene are about the same as the average rates for mammalian genes. A phylogenetic tree of vertebrate lactate dehydrogenase protein sequences is constructed. In agreement with the previous results, this analysis further indicates that lactate dehydrogenase-C gene branched off earlier than did lactate dehydrogenase-A and lactate dehydrogenase-B genes.

Amino Acid Sequence↗
PubMed1996

Homozygous expression of a missense mutation at nucleotide 385 in the FUT2 gene associates with the Le(a+b+) partial-secretor phenotype in an Indonesian family.

A new point mutation was found in the coding sequence of the secretor FUT2 gene. This missense mutation with an A-->T substitution at nucleotide 385 resulted in an amino acid change of Ile129 to Phe129. This mutation showed a clear genetic trait in an Indonesian pedigree and, when appearing in a homozygous form, it was associated with the red cell Le(a+b+) and salivary partial-secretor phenotype. This result suggests that the molecular basis for the Le(a+b+) and associated partial-secretor phenotype is caused by a partially inactivating amino acid change in the alpha(1,2)fucosyltransferase coded for by this new FUT2 allele.

Base Sequence↗
PubMed1992

Twenty year trends in hospital discharges for asthma among members of a health maintenance organization.

We examined trends in hospitalizations for asthma from 1967 to 1987 among members of a large health maintenance organization. During this time asthma discharges increased significantly among children, and especially among boys under the age of 5 years. Ninety-five percent of the increase in discharges among boys was explained by a corresponding increase in the number of boys who were hospitalized. Increased readmissions did not account for the rise. Changes in the International Classification of Diseases coding of asthma and diagnostic shift by physicians accounted for only part of the increase. A decline in hospitalizations since 1984 may reflect changes in the management of asthma in the emergency room and not a decline in severe asthma episodes.

Adolescent↗
PubMed2006

Developing an ethical code for engineers: the discursive approach.

From the Hippocratic Oath on, deontological codes and other professional self-regulation mechanisms have been used to legitimize and identify professional groups. New technological challenges and, above all, changes in the socioeconomic environment require adaptable codes which can respond to new demands. We assume that ethical codes for professionals should not simply focus on regulative functions, but must also consider ideological and educative functions. Any adaptations should take into account both contents (values, norms and recommendations) and the drafting process itself. In this article we propose a process for developing a professional ethical code for an official professional association (Colegio Oficial de Ingenieros Industriales de Valencia (COIIV) starting from the philosophical assumptions of discursive ethics but adapting them to critical hermeneutics. Our proposal is based on the Integrity Approach rather than the Compliance Approach. A process aiming to achieve an effective ethical document that fulfils regulative and ideological functions requires a participative, dialogical and reflexive methodology. This process must respond to moral exigencies and demands for efficiency and professional effectiveness. In addition to the methodological proposal we present our experience of producing an ethical code for the industrial engineers' association in Valencia (Spain) where this methodology was applied, and we evaluate the detected problems and future potential.

Codes of Ethics↗
PubMed2004

Beyond Arabidopsis. Translational biology meets evolutionary developmental biology.

Developmental processes shape plant morphologies, which constitute important adaptive traits selected for during evolution. Identifying the genes that act in developmental pathways and determining how they are modified during evolution is the focus of the field of evolutionary developmental biology, or evo-devo. Knowledge of genetic pathways in the plant model Arabidopsis serves as the starting point for investigating how the toolkit of developmental pathways has been used and reused to form different plant body plans. One productive approach is to identify genes in other species that are orthologous to genes known to control developmental pathways in Arabidopsis and then determine what changes have occurred in the protein coding sequence or in the gene's expression to produce an altered morphology. A second approach relies on natural variation among wild populations or crop plants. Natural variation can be exploited to identify quantitative trait loci that underlie important developmental traits and, thus, define those genes that are responsible for adaptive changes. The possibility of applying comparative genomics approaches to Arabidopsis and related species promises profound new insights into the interplay of evolution and development.

Arabidopsis↗
PubMed2006

Nonlinearities in color coding: compensating color appearance for the eye's spectral sensitivity.

Most wavelengths change hue when mixed with white light. These changes, known as the Abney effect, have been extensively studied to characterize nonlinearities in the neural coding of color, but their potential function remains obscure. We measured the Abney effect in a new way--by varying the bandwidth of the spectrum rather than mixing with white--and this leads to a new interpretation of the role of nonlinear responses in color appearance. Because of the eye's limited spectral sensitivity, increasing the bandwidth of a spectrum changes the relative responses in the three classes of cone receptor and thus would change hue if the percept were tied to a fixed cone ratio. However, we found that hue is largely independent of bandwidth and thus constant for a constant peak wavelength for stimuli with Gaussian spectra. This suggests that color appearance is compensated for the eye's spectral filtering, and that this compensation embodies specific perceptual inferences about how natural spectra vary. When a wavelength is instead diluted with white light--which does not bias the cone ratios--then the same compensation predicts changes in hue because the "right" response is made to the "wrong" stimulus. This model generates constant hue loci that are qualitatively consistent with measures of the Abney effect and provides a novel functional account of such effects in color appearance, in which postreceptoral responses are adjusted so that constant hue percepts are tied to consistent physical properties of the environment rather than consistent physiological properties such as the cone ratios.

Adaptation, Physiological↗
PubMed2002

Coding of pediatric behavioral and mental disorders.

BACKGROUND: In response to changing reimbursement and other pressures in the health care environment, many physicians have reported the use of alternate coding to substitute for certain clinical diagnoses. However, very little information is available on how physicians who care for children approach diagnosis and coding dilemmas for behavioral and mental disorders, which often present unique additional challenges. OBJECTIVE: Our study sought to describe the frequency of alternate coding, different approaches to coding, and attitudes toward diagnosis and coding practices by physician specialty. METHODS: We conducted a mail survey of 1492 physicians--497 developmental/behavioral pediatricians (DBP), 500 pediatricians (PED), and 495 child and adolescent psychiatrists (PSY). The main outcomes were survey items on frequency of alternate coding (never, rarely, monthly, weekly, daily), use of different coding strategies (use of somatic symptoms, modifiers, and substitution with other terms), and attitudes on coding practices (Likert scales of agreement). We analyzed outcomes by physician specialty and demographics using Pearson's chi2 and multivariate logistic regression. RESULTS: Overall response rate was 62% (787 of 1269 eligible physicians). The majority of physicians had used an alternate code (DBP 83%, PED 68%, PSY 58%), and many respondents reported monthly-daily alternate coding (DBP 60%, PED 36%, PSY 27%). Physicians used multiple approaches to diagnosis and a variety of coding options, which varied by physician specialty. Financial issues were commonly cited reasons for alternate coding--both to obtain patient services and to receive physician reimbursement. However, challenges of diagnostic classification and coding subthreshold symptoms were cited as frequently as reimbursement issues. Stigmatization, confidentiality, and parental acceptance were mentioned, but reported less frequently. Very few practices and providers have organized administrative methods of alternate coding (26%) or receive feedback on denied claims (46%). Most physicians believe that alternate coding is justified in the present system; however, some physicians expressed concerns that these practices may contribute to stigmatization or lead to improper management decisions. CONCLUSIONS: Alternate coding is commonly reported; however, approaches to diagnostic coding vary by provider specialty. Reimbursement issues are important, but other challenges in diagnosis and classification hold special relevance to children with behavioral and mental disorders. There seems to be a great need to reconsider the separate goals and uses of clinical diagnosis and administrative coding. Additional study is needed to assess how reported coding practices may affect administrative data, patient care, and health care economics.

Adolescent Psychiatry↗
PubMed1980

The evolution of genes: the chicken preproinsulin gene.

We have characterized a clone carrying a chicken preproinsulin gene, which is present in only one copy in the chicken genome. The gene contains two introns: a 3.5 kb intron interrupting the region encoding the connecting peptide and a 119 bp intron interrupting the DNA corresponding to the 5' non-coding region of the mRNA. This is similar to the structure of rat insulin gene II; therefore it represents the common ancestor. Since the rat insulin gene I lacks a 499 bp intron in the coding region, the rat genes have evolved by a recent gene duplication followed by loss of this intron in one copy. The divergences between insulin gene sequences, and also between globin genes, show that changes at introns and silent positions in coding regions appear very rapidly (7 X 10(-9) substitutions per nucleotide site per year), but that the accumulation of changes in these sites saturates, although not completely, after about 100 million years. From this we conclude that not all of these sites are neutral and that they do not behave as accurate evolutionary clocks over long periods of time. However, nucleotide substitutions leading to amino acid replacements are an excellent clock. Our analysis indicates that this clock is driven by selection.

Animals↗
PubMed2005

The role of Dam methylation in phase variation of Haemophilus influenzae genes involved in defence against phage infection.

Haemophilus influenzae uses phase variation (PV) to modulate the activity of its defence systems against phage infection. The PV of the restriction-modification (R-M) system HindI, the main defence system against phage infection and incoming chromosomal and phage DNA in H. influenzae Rd, is driven by changes of the pentanucleotide repeat tract within the coding sequence of the hsdM gene and is influenced by lack of Dam methylation. Phase-variable resistance/sensitivity to phage infection correlates with changes in lipooligosaccharide (LOS) structure and occurs by slippage of tetranucleotide repeats within the gene lic2A, coding for a step in the biosynthesis of LOS. The lack of Dam activity destabilizes the tetranuclotide (5'-CAAT) repeat tract and increases the frequency of switching from sensitivity to resistance to phage infection more than in the opposite direction. The PV of the lgtC gene does not influence resistance or sensitivity to phage infection. Insertional inactivation of lic2A, but not lgtC or lgtF, leads to resistance to phage infection and to the same structure of the LOS as observed among phase-variable phage-resistant variants. This indicates that in the H. influenzae Rd LOS only the first two sugars (Glc-Gal) extending from the third heptose are part of bacterial phage receptors.

Bacterial Proteins↗
PubMed2004

Accuracy of Medicare claims-based diagnosis of acute myocardial infarction: estimating positive predictive value on the basis of review of hospital records.

BACKGROUND: Many cardiovascular epidemiologic studies rely on diagnosis codes in health care claims databases. Despite important changes in the care and diagnosis of acute myocardial infarction (AMI), the validity of hospital discharge diagnosis codes for AMI in the US Medicare system has not been recently examined. Our objective was to examine the accuracy of International Classification of Diseases--ninth revision--Clinical Modifications (ICD-9-CM) discharge diagnosis codes and diagnosis-related groups (DRG) codes for AMI in a Medicare claims database. METHODS: We sampled hospitalization episodes from Medicare beneficiaries in Pennsylvania during 1999, 2000, or both. We used Medicare data to identify patients with hospitalizations containing indicators of AMI (ICD-9-CM diagnosis codes 410.X0 and 410.X1 or DRG codes 121, 122, and 123). Hospital records for these episodes were reviewed by trained abstractors using World Health Organization criteria for diagnosing AMI. We then calculated the positive predictive value of Medicare claims-based definitions of AMI. RESULTS: Of 2200 hospitalization episodes with Medicare diagnosis codes suggestive of AMI, 2022 hospital records (91.9%) were obtained. The positive predictive value for a primary Medicare claims-based definition was 94.1% (95% CI, 93.0%-95.2%). Positive predictive values for alternative claims-based definitions ranged slightly, with the definition including DRG codes and length-of-stay restrictions yielding the highest positive predictive value, 95.4% (95% CI, 94.3%-96.4%). Subjects with a history of myocardial infarction had a significantly lower positive predictive value than subjects without a history of myocardial infarction (88.1% vs 94.6%, P <.001). CONCLUSIONS: In this study, we observed high positive predictive values for a Medicare claims-based diagnosis of AMI and a diagnosis based on structured hospital record review.

Aged↗
PubMed2004

Allelic diversification at the C (OsC1) locus of wild and cultivated rice: nucleotide changes associated with phenotypes.

Divergent phenotypes are often detected in domesticated plants despite the existence of invariant phenotypes in their wild forms. One such example in rice is the occurrence of varying degrees of apiculus coloration due to anthocyanin pigmentation, which was previously reported to be caused by a series of alleles at the C locus. The present study reveals, on the basis of comparison of its maps, that the C gene appears to be the rice homolog (OsC1) of maize C1, which belongs to the group of R2R3-Myb factors. Two different types of deletions causing a frameshift were detected in the third exon, and both of the deleted nucleotides corresponded to the positions of putative base-contacting residues, suggesting that the Indica and Japonica types carry loss-of-function mutations with independent origins. In addition, replacement substitutions were frequently detected in OsC1 of strains carrying the previously defined C alleles. Molecular population analysis revealed that 17 haplotypes were found in 39 wild and cultivated rices, and the haplotypes of most cultivated forms could be classified into one of three distinct groups, with few shared haplotypes among taxa, including Indica and Japonica types. The genealogy of the OsC1 gene suggests that allelic diversification causing phenotypic change might have resulted from mutations in the coding region rather than from recombination between preexisting alleles. The McDonald and Kreitman test revealed that the changes in amino acids might be associated with selective forces acting on the lineage of group A whose haplotypes were carried by most Asian cultivated forms. The results regarding a significant implication for genetic diversity in landraces of rice are also discussed.

Alleles↗
PubMed1993

Amplified genes in human gliomas.

The most common types of brain tumors in adults are collectively known as gliomas. The most common glioma is the most malignant, the glioblastoma. Double minute chromosomes, known to represent amplified genes, are found in 50% of glioblastomas. Four genes have been identified as being amplified in more than single cases of glioblastomas; MYCN, GLI, PDGFRA and EGFR. The first three have been reported in a few per cent of malignant gliomas, and EGFR in around 40% of glioblastomas. The latter two genes code for growth factor receptors. On amplification, the genes for these receptors frequently become rearranged, resulting in changes in the regions of their transcripts that code for the extra-cellular domains of these proteins. Such aberrant proteins may provide us with cell-surface, tumor-specific, epitopes. These findings provide simple examples of the impact the use of modern molecular biological techniques will have for our understanding and treatment of tumors in the future.

ErbB Receptors↗
PubMed1990

Extreme differences in charge changes during protein evolution.

The maintenance of a proper distribution of charged amino acid residues might be expected to be an important factor in protein evolution. We therefore compared the inferred changes in charge during the evolution of 43 protein families with the changes expected on the basis of random base substitutions. It was found that certain proteins, like the eye lens crystallins and most histones, display an extreme avoidance of changes in charge. Other proteins, like phospholipase A2 and ferredoxin, apparently have sustained more charged replacements than expected, suggesting a positive selection for changes in charge. Depending on function and structure of a protein, charged residues apparently can be important targets for selective forces in protein evolution. It appears that actual biased codon usage tends to decrease the proportion of charged amino acid replacements. The influence of nonrandomness of mutations is more equivocal. Genes that use the mitochondrial instead of the universal code lower the probability that charge changes will occur in the encoded proteins.

Biological Evolution↗
PubMed2001

REACTPOOL: a code implementing a new multi-compound pool model that accounts for chemical reactions and changing composition for spills of water reactive chemicals.

All chemicals that react violently with water or in contact with water liberate toxic gas are included in the list of substances covered by the majority of the international legislation on major hazards. This category includes a large number of chemicals that are used widely in the process industries. A survey of accidents that occurred in the last 10 years in the USA shows numerous major incidents that involved spillages of these substances. Even so, there are almost no experimental data on the behaviour of these chemicals on release. Furthermore, there are very few published studies on modelling the behaviour of such spillages, except in the case of hydrogen fluoride. In previous work we reported a new theoretical model [J. Haz. Mat. 62 (1998) 101-129, J. Haz. Mat. 62 (1998) 131-142, J. Haz. Mat. A67 (1999) 9-40], that describes accidental spills of SO(3) and oleum, which are substances with very complex behaviour that belong to this category. It describes both the pool [J. Haz. Mat. 62 (1998) 101-129, J. Haz. Mat. 62 (1998) 131-142] and the cloud behaviour [J. Haz. Mat. A67 (1999) 9-40]. In the work reported here the pool model was modified in a generic form in order to include other water reactive chemicals. REACTPOOL is a new code that can be used for both instantaneous and continuous liquid releases under a wide range of input parameters (steady or varying). It can be used for all liquids irrespective of their volatility and reactivity, and it describes pools consisting of more than one liquid that can have changing composition and properties. The purpose of this paper is to present the general procedure followed in REACTPOOL and to show how the new model has been modified and implemented for substances other than SO(3) and oleum. The modelling procedure has been implemented in a computer code written in Visual Basic, and results of the model have been generated using this code. It should be noted that this model requires validation data, but that the availability of such data awaits the performance of suitable experimental investigations.

Aerosols↗