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PubMed1983

Nucleotide sequence analysis of human c-myc locus, chicken homologue, and myelocytomatosis virus MC29 transforming gene reveals a highly conserved gene product.

We have determined the complete nucleotide sequence of human cellular c-myc, which is homologous to the transforming gene, v-myc, of myelocytomatosis virus MC29. Analysis of the genetic information and alignment with the known sequence of chicken c-myc and v-myc indicates: (i) An intervening sequence can be identified by consensus splice signals. The unique 5' sequence of c-myc and its junction with the v-myc region may be a canonical 3' splice acceptor. (ii) The c-myc locus can generate a mRNA whose termination signals are downstream from the translational termination signal. (iii) The three myc genes share the same reading frame, including translational termination signals. (iv) The homology is conserved only in the coding region. (v) Most changes at the nucleotide level result in no change in the amino acid. (vi) There are two distinct domains--the 5' unique domain, which is different from the viral, and the 3' coding domain, which contains amino acids coded by the two exons whose sequences have been determined here. In the latter domain, the amino acid variation between v-myc and chicken c-myc is less than 2%, whereas that between the chicken v-myc and the human is 27%, with the variation concentrated in the region that flanks the splicing points.

Alpharetrovirus↗
PubMedDate not supplied

Consistency of reporting endocervical cells. An intralaboratory and interlaboratory assessment.

A study of the intralaboratory and interlaboratory consistency of reporting endocervical cells on cytologic smears is presented. Two sets of 40 slides were compiled from previously reported material. Twenty-two laboratories each reported one set of the slides according to a single coding schedule. The intralaboratory agreement on the endocervical cell code was 80%. Considerable variation was evident between laboratories. While only 14% of the 80 slides received a unanimous endocervical code across the 11 reviewing laboratories, 73 of the 80 slides had agreement by at least 7 of the 11 reviewing laboratories. If the coding option "minor reactive and inflammatory changes in endocervical cells" was amalgamated with the coding option "normal endocervical cells present," a substantial improvement in the level of agreement resulted. The probability of agreement between laboratories did not vary according to whether the subsequent histology/cytology was reported as negative or as a low grade abnormality.

Adenocarcinoma↗
PubMed2005

CPT coding and reimbursement issues in dermatology.

In the past 6 years, significant changes have been made in Current Procedural Terminology codes, descriptors, and guidelines affecting dermatologists. These changes involved excision, repair, measuring excised diameter, measuring flap defects, skin biopsy and Mohs surgery guidelines, KOH examination, and fungus cultures. New codes were introduced for photodynamic therapy, laser treatment, and whole-body photography. Reimbursement issues affecting dermatologists are also discussed, including inappropriate bundling of separate services, failure to recognize modifiers, and unfair multiple procedure reduction. The successes of the American Academy of Dermatology Association advocacy efforts with insurance carriers are summarized, with an update on the current status of these issues. Physician responsibilities, documentation requirements, and expectations are also outlined.

Current Procedural Terminology↗
PubMed1990

Insertion in the mRNA of a metachromatic leukodystrophy patient with sphingolipid activator protein-1 deficiency.

The lysosomal catabolism of sulfatide requires arylsulfatase A and a specific sphingolipid activator protein, SAP-1. While most patients with metachromatic leukodystrophy have mutations in the gene for arylsulfatase A, some patients have deficient SAP-1, as determined by immunological techniques. We now describe the molecular findings in a patient who died at 22 years of age with SAP-1 deficiency. The DNA polymerase chain reaction was used to amplify regions of cDNA which were subcloned in M13 phage DNA and sequenced by the dideoxy chain-termination method. The patient was found to have a 33-base-pair insertion between nucleotides 777 and 778 (numbered from the A of the ATG initiation codon). No other changes were found in the coding sequence of the cDNA from this patient. At the site of the insertion some normal people have an additional 9 base pairs, which correspond to the last 9 nucleotides at the 3' end of the insertion. The cDNAs from the second-cousin parents were amplified and sequenced, and in both two alleles were identified, one with the 33-base-pair insertion and one with no insertion. Two brothers were found to have only the normal alleles and a sister was found to have the 33-base-pair insertion and a normal allele. The findings confirm studies performed on leukocyte extracts demonstrating normal antigen levels in the two brothers and a lower level in the sister. The presence of 11 additional amino acids in the coding region of mature SAP-1 in this patient causes significant changes in the hydropathy profile compatible with the previous findings at the protein level.

Amino Acid Sequence↗
PubMed2004

cis-Regulatory and protein evolution in orthologous and duplicate genes.

The relationship between protein and regulatory sequence evolution is a central question in molecular evolution. It is currently not known to what extent changes in gene expression are coupled with the evolution of protein coding sequences, or whether these changes differ among orthologs (species homologs) and paralogs (duplicate genes). Here, we develop a method to measure the extent of functionally relevant cis-regulatory sequence change in homologous genes, and validate it using microarray data and experimentally verified regulatory elements in different eukaryotic species. By comparing the genomes of Caenorhabditis elegans and C. briggsae, we found that protein and regulatory evolution is weakly coupled in orthologs but not paralogs, suggesting that selective pressure on gene expression and protein evolution is quite similar and persists for a significant amount of time following speciation but not gene duplication. Additionally, duplicates of both species exhibit a dramatic acceleration of both regulatory and protein evolution compared to orthologs, suggesting increased directional selection and/or relaxed selection on both gene expression patterns and protein function in duplicate genes.

Animals↗
PubMed2004

Enhanced cytoplasmic sequestration of the nuclear export receptor CRM1 by NS2 mutations developed in the host regulates parvovirus fitness.

To investigate whether a DNA virus can evade passive immunotherapy with a polyclonal antiserum, we analyzed the protection of a neutralizing capsid antiserum against a lethal infection of the immunosuppressive strain of the parvovirus minute virus of mice (MVMi) in 42 immunodeficient mice over a period of 200 days. A few mice were effectively protected, but most developed a delayed lethal leukopenic syndrome during the treatment or weeks afterwards. Unexpectedly, viruses isolated from treated but also from control leukopenic mice showed no amino acid changes throughout the entire capsid coding region, although the viral populations were genetically heterogeneous, mainly in the second exon of the coding sequence of the NS2 nonstructural protein. The NS2 point amino acid changes (T88A, K96E, L103P, and L153 M) that were consistently selected in several mice clustered within the nuclear exportin CRM1 binding domain, in a reading frame that did not alter the overlapping NS1 coding region. These mutations endowed emerging viruses with an increased fitness that was demonstrable by their relative resistance to the neutralizing capsid antiserum in a postentry plaque-forming assay, the rapid overgrowth of a competing wild-type (wt) population in culture, and a larger yield of infectious particles. Mutant NS2 proteins interacted with a higher affinity and sequestered CRM1 in the perinuclear region of the cytoplasm more efficiently than the wt. Correspondingly this phenomenon, as well as the following timely ordered release of the NS1 nonstructural protein and the empty capsid from the nucleus to the cytoplasm, occurred markedly earlier in the infection cycle of the mutant viruses. We hypothesize that the enhanced cytoplasmic sequestration of CRM1 by the NS2 mutations selected in mice may trigger pleiotropic effects leading to an accelerated MVMi life cycle and thus to increased fitness. These results strengthen our earlier report on the rapid evolutionary capacity of this mammalian-specific DNA virus in vivo and indicate that the NS2-CRM1 interaction is an important determinant of parvovirus virulence that can be modulated in nature, hampering the effectiveness of passive antibody therapies in the long term.

Amino Acid Substitution↗
PubMed2000

Selection against frameshift mutations limits microsatellite expansion in coding DNA.

Microsatellite enrichment is an excess of repetitive sequences characteristic to all studied eukaryotes. It is thought to result from the accumulated effects of replication slippage mutations. Enrichment is commonly measured as the ratio of the observed frequency of microsatellites to the frequency expected to result from random association of nucleotides. We have compared enrichment of specific types of microsatellites in coding sequences with those in noncoding sequences across seven eukaryotic clades. The results reveal consistent differences between coding and noncoding regions, in terms of both the quantity of repetitive DNA and the types present. In noncoding regions, all types of microsatellite (mono-, di-, tri-, tetra-, penta-, and hexanucleotide repeats) are found in excess, and in all cases, these excesses scale in a similar exponential fashion with the length of the microsatellite. This suggests that all types of noncoding repeats are subject to similar mutational and selective processes. Coding repeats, however, appear to be under much stronger and more specific constraints. Tri- and hexanucleotide repeats are found in consistent and significant excess over a wide range of lengths in both coding and noncoding sequences, but other repeat types are much less frequent in coding regions than in noncoding regions. These findings suggest that the differences between coding and noncoding microsatellite frequencies arise from specific selection against frameshift mutations in coding regions resulting from length changes in nontriplet repeats. Furthermore, the excesses of tri- and hexanucleotide coding repeats appear to be controlled primarily by mutation pressure.

Animals↗
PubMed1990

Ethical issues associated with managed care pharmacy services.

The authors' purpose in raising these issues and questions is not to provide answers for the profession. We recognize that answers must be derived from a process that includes input from many individuals, and from many sectors of the profession. We also recognize that the pharmacist practicing today realizes that the health care system is changing. We believe that the code of ethics supporting our profession must be revised to reflect these changes to provide more meaningful guidance for pharmacists confronting difficult contemporary issues and dilemmas. We have tried to show that pharmacists working in the HMO setting may face unique problems that must be considered by a revised code of ethics. We are pleased that APhA has begun this process of revision.

Codes of Ethics↗
PubMed2004

Gonadotrophin-induced gene regulation in human granulosa cells obtained from IVF patients. Modulation of steroidogenic genes, cytoskeletal genes and genes coding for apoptotic signalling and protein kinases.

Gonadotrophins exert a major effect on ovarian development and on the control of fertilization. By stimulating cells with forskolin (FK), it is possible to study which genes are activated by gonadotrophins via the cAMP cascade, and which by alternative pathways. Using RNA isolated from stimulated cells, we found that 59% of the total genes modulated by LH were also modulated by FK, while 69% of the genes modulated exclusively by FSH were also modulated by FK. Gene transcripts involved in steroidogenesis/progesterone production were highly elevated, while 17beta-hydroxysteroid dehydrogenase was down-regulated. This suggests that a decrease in the conversion of androstenedione to testosterone and estrone to estradiol occurs during luteinization. Down-regulation of genes coding for actin cytoskeleton proteins and cytokeratin 18 was observed in response to gonadotrophin and cAMP stimulation. Several of the genes coding for the microtubule network were also modulated, implying that rearrangement of the cytoskeletal proteins permits better coupling between organelles involved in steroidogenesis. A dramatic change in gene transcripts coding for signalling enzymes was observed following LH stimulation. This includes the down-regulation of adenylyl cyclase 7 and 9, elevation of cAMP-dependent phosphodiesterase, and the up-regulation of a negative regulator of G-protein signalling (RGS16) that may negate gonadotrophin signalling via guanine nucleotide binding proteins. Thus luteinized cells, despite increased gene transcripts to LH/chorionic gonadotrophin (CG) receptors, respond inefficiently to gonadotrophin stimulation, due to attenuation of signal transduction in the cAMP cascade at multiple steps. Novel genes involved in the regulation of apoptosis were found for the first time to be up-regulated by gonadotrophin stimulation, including: BAX inhibitor-1, granulysin and apoptosis repressor with caspase recruitment domain (ARC). These proteins may be involved in a unique alternative pathway of ovarian cell death. Such a pathway could temporarily preserve the mitochondria and progesterone production during the initial stages of granulosa cell apoptosis.

Animals↗
PubMed1992

Geographical dependence of sequence variation in the E7 gene of human papillomavirus type 16.

We have determined nucleotide sequences of the E7 open reading frame (ORF) of human papillomavirus type 16 (HPV-16) isolates obtained from 32 genital tumours and two HPV-16-transformed human keratinocyte cell lines. In comparison to the prototype HPV-16 isolated from a German cervical cancer biopsy, no sequence variations were noticed in either the two cell lines or the 10 biopsies that were obtained from German patients. In contrast only three of 22 (13.6%) of Tanzanian isolates showed the prototype sequence. In 18 of these biopsies two alterations (T to C and T to G) not affecting the amino acid sequence were found within the HPV-16 E7 ORF (nucleotide positions 789 and 795) but eight of these isolates contained an additional change (nucleotide position 647) coding for serine instead of asparagine (amino acid position 29). One tumour harbours HPV-16 DNA with a mutation (C to T) at nucleotide 790 changing the E7 amino acid sequence (arginine to cysteine) at position 76. Our findings suggest that clustering of E7 sequence variants may occur in different geographical regions of the world.

Amino Acid Sequence↗
PubMed1998

Crystallography & NMR system: A new software suite for macromolecular structure determination.

A new software suite, called Crystallography & NMR System (CNS), has been developed for macromolecular structure determination by X-ray crystallography or solution nuclear magnetic resonance (NMR) spectroscopy. In contrast to existing structure-determination programs, the architecture of CNS is highly flexible, allowing for extension to other structure-determination methods, such as electron microscopy and solid-state NMR spectroscopy. CNS has a hierarchical structure: a high-level hypertext markup language (HTML) user interface, task-oriented user input files, module files, a symbolic structure-determination language (CNS language), and low-level source code. Each layer is accessible to the user. The novice user may just use the HTML interface, while the more advanced user may use any of the other layers. The source code will be distributed, thus source-code modification is possible. The CNS language is sufficiently powerful and flexible that many new algorithms can be easily implemented in the CNS language without changes to the source code. The CNS language allows the user to perform operations on data structures, such as structure factors, electron-density maps, and atomic properties. The power of the CNS language has been demonstrated by the implementation of a comprehensive set of crystallographic procedures for phasing, density modification and refinement. User-friendly task-oriented input files are available for nearly all aspects of macromolecular structure determination by X-ray crystallography and solution NMR.

Computer Simulation↗
PubMed2003

Diversity in coding tandem repeats in related Neisseria spp.

BACKGROUND: Tandem repeats contained within coding regions can mediate phase variation when the repeated units change the reading frame of the coding sequence in a copy number dependent manner. Coding tandem repeats are those which do not alter the reading frame with copy number, and the changes in copy number of these repeats may then potentially alter the function or antigenicity of the protein encoded. Three complete neisserial genomes were analyzed and compared to identify coding tandem repeats where the number of copies of the repeat will have some structural consequence for the protein. This is the first study to address coding tandem repeats that may affect protein structures using comparative genomics, combined with a population survey to investigate which show interstrain variability. RESULTS: A total of 28 genes were identified. Of these, 22 contain coding tandem repeats that vary in copy number between the three sequenced strains, three strain specific genes were included for investigation on the basis of having >90% identity between repeated units, and three genes with repeated elements of >250 bp were included although no length variations were seen in the genomes. Amplification, and sequencing of repeats showing altered copy number, of these 28 coding tandem repeat containing regions, from a set of largely unrelated strains, revealed further repeat length variation in several cases. CONCLUSION: Eighteen genes were identified which have variation in repeat copy number between strains of the same species, twelve of which show greater diversity in repeat copy number than is present in the sequenced genomes. In some cases, this may reflect a mechanism for the generation of antigenic variation, as previously described in other species. However, some of the genes identified encode proteins with cytoplasmic functions, including sugar metabolism, DNA repair, and protein production, in which repeat length variation may have other functions. Coding tandem repeats appear to represent a largely unexplored mechanism of generating diversity in the Neisseria spp.

Adhesins, Bacterial↗
PubMed2003

Rearrangements between differently replicating DNA strands in asymmetric bacterial genomes.

Many bacterial genomes are under asymmetric mutational pressure which introduces compositional asymmetry into DNA molecule resulting in many biases in coding structure of chromosomes. One of the processes affected by the asymmetry is translocation changing the position of the coding sequence on chromosome in respect to the orientation on the leading and lagging DNA strand. When analysing sets of paralogs in 50 genomes, we found that the number of observed genes which switched their positions on DNA strand is lowest for genomes with the highest DNA asymmetry. However, the number of orthologs which changed DNA strand increases with the phylogenetic distance between the compared genomes. Nevertheless, there is a fraction of coding sequences that stay on the leading strand in all analysed genomes, whereas there are no sequences that stay always on the lagging strand. Since sequences diverge very fast after switching the DNA strand, this bias in mobility of sequences is responsible, in part, for higher divergence rates among some of coding sequences located on the lagging DNA strand.

Chromosomes, Bacterial↗
PubMed2006

Abnormal histone acetylase and deacetylase expression and function in lung inflammation.

Post-translational modifications in DNA and histone proteins are heritable changes that are not coded for in the DNA sequence itself but play an important role in the control of gene expression. These modifications include histone acetylation, methylation, ubiquitination, sumoylation and phosphorylation. These changes are not only critical for generating diversity of cell types during mammalian development, but are also important for maintaining the stability and integrity of the expression profiles of different cell types. Until recently, the study of human disease has focused on genetic mechanisms rather than on non-coding events. However, it is becoming increasingly clear that altered patterns of histone modifications can lead to several major pathologies. This review focuses on histone acetylation and its role in inflammatory gene expression. Interestingly, the expression and activity of enzymes that regulate this modification have been reported to be abnormal in the airways of patients with respiratory disease. Histone modifications, despite being heritable and stably maintained, are also potentially reversible and there is scope for the development of "epigenetic therapies" for disease.

Animals↗
PubMed1979

Visual persistence and code selection in short-term memory for letters.

Four experiments were conducted to examine temporal changes in visual and name codes and the relationship between them. Unlike earlier studies, the design included (a) several levels of visual similarity in addition to the conventional same case and different case conditions and (b) physical- as well as name-match tasks to provide direct evidence about subjects' retention of form information. The main results were as follows: First, the presence of multiple typefonts in the stimulus set does not eliminate convergence between the reaction time functions for the physical- and name-match conditions in a name-match task. Second, inclusion of a physical-match task, requiring subjects to retain form information, does not necessarily eliminate convergence in a primary, name-match task. When the secondary task does reduce convergence, however, the results suggest that it does this through its effect on the name-match function rather than on the physical-match function. Third, apart from difficulties with within-cluster typefont combinations, particularly at long interstimulus intervals, subjects can generally retain and use reliable information about letter form over the ISI range (.5--4.0 sec) used in the experiments. The results were thought to be consistent with the conclusion that convergence results from a combination of (a) a nonoptional decrease in the accessibility of the visual code as a function of increasing ISI and (b) an optional increase in the accessibility of the name code. Under ISI conditions at least, convergence cannot be attributed to either generation of a visual code of the alternative form of the target letter or to the absence of relevant form information.

Discrimination Learning↗
PubMed2002

[Mutation analysis of Cx26 gene in Chinese hereditary nonsyndromic deafness sufferers].

OBJECTIVE: To analyze the mutations in the code region of Cx26 gene in Chinese hereditary nonsyndromic hearing impairment (NSHI) sufferers. METHODS: Thirty-three cases (29 cases in the families of 8 students who were picked out from the Deafness and Muteness School of Tianjin, 2 cases as control and 2 normal cases of genetic counseling) were included in this study. The blood samples were obtained to distill the DNA templates. Using polymerase chain reaction (PCR), the code region of Cx26 gene was amplified. The mutations were screened by restriction endonucleases fingerprinting-single strand conformation polymorphism (REF-SSCP). Afterwards we inspected the polymorphous changes or mutations of these segments with DNA sequence. RESULTS: There were 30 cases with the nucleotide changes in the Cx26 code region. The rate was 90.9% (30/33). Eight kinds of mutations were found, 79G-->A, 109G-->A, 161A-->T, 235delC, 240G-->A, 341A-->G, 571T-->C and 608T-->C. 161A-->T, 240G-->A and 571T-->C were detected primarily. There were 3 cases with 235delC in 22 deafness sufferers and the rate was 13.64% (3/22). CONCLUSIONS: The 235delC of Cx26 gene is the main mutation in Chinese NSHI sufferers, and in NSHI cases many polymorphous changes exist.

Adolescent↗
PubMed1990

cDNA-derived amino acid sequences of choriocarcinoma alpha- and beta-subunits of human choriogonadotropin.

Although amino acid sequences of the alpha- and beta-subunits of human choriogonadotropin (hCG) are known, only limited information is available on the disease state hCG. We have examined the amino acid sequences of the alpha- and beta-subunits of hCG from choriocarcinoma BeWo cells. The amino acid sequences were derived from the nucleotide sequences of BeWo cDNA clones of hCG alpha- and beta-subunits and were found to be identical with those of the normal subunits. It appears that the differences between the normal and the choriocarcinoma alpha- and beta-subunits of hCG reside primarily in the carbohydrates rather than the amino acid sequences. It may be pointed out that although coding and non-coding regions of BeWo cDNA clones of CG alpha and CG beta had several base changes from the hCG alpha and hCG beta cDNAs, these changes did not result in the alteration of their amino acid sequences. The longest BeWo alpha and beta cDNAs were 719 and 878 base pairs (bp) in length and lacked only 16 and 7 bp from the transcription start sites respectively. BeWo CG alpha cDNA had two base changes in the non-coding regions, one insertion of C at position 39 and another substitution of T for A at position 651, the latter change deleted one HindIII polymorphous site. The BeWo CG beta cDNA also had two base substitutions, A for G at 131 in the non-coding region and T for C at 807 position in the coding region.

Amino Acid Sequence↗
PubMedDate not supplied

Pneumocystis and Trypanosoma cruzi: nomenclature and typifications.

Published phylogenetic reclassifications of Pneumocystis as a fungus resulted in a nomenclatural shift from the Zoological Code to the International Code of Botanical Nomenclature. The same may be true for all microsporidians and sundry other organisms. This resulted in the invalidation of names and subsequently precipitated changes to the botanical code to accommodate Pneumocystis and microsporidian names. The repercussions following application of the 2005 Vienna Code to Pneumocystis nomenclature are detailed. Validity of the name for the human pathogen, Pneumocystis jirovecii, is re-established from its 1976 publication under the Zoological Code, contrary to interpretation of validity under earlier botanical codes. Pneumocystis jirovecii is lectotypified and epitypified. The rat parasite, Pneumocystis carinii, is neotypified, separating it from Pneumocystis wakefieldiae. The original 1909 description of Trypanosoma cruzi, type species for Schizotrypanum, and causal agent of Chagas' disease, included parts of the life cycle of Pneumocystis. Trypanosoma cruzi is neotypified by the true Trypanosoma elements, thereby completing the nomenclatural separation from Pneumocystis and ensuring that Schizotrypanum is not applicable to Pneumocystis as an earlier name. The neotypes for P. carinii and T. cruzi represent the strains currently being investigated by their two respective genome projects. They were selected in light of their medical importance, physiological characterizations, and absence of lectotypifiable materials. The classification and nomenclature of Pneumocystis is reviewed and guidelines given for the publication of new species.

Animals↗