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PubMed1984

Kappa-chain constant-region gene sequences in genus Rattus: coding regions are diverging more rapidly than noncoding regions.

We have determined the nucleotide sequence of a 1,200-base pair (bp) genomic fragment that includes the kappa-chain constant-region gene (C kappa) from two species of native Australian rodents, Rattus leucopus cooktownensis and Rattus colletti. Comparison of these sequences with each other and with other rodent C kappa genes shows three surprising features. First, the coding regions are diverging at a rate severalfold higher than that of the nearby noncoding regions. Second, replacement changes within the coding region are accumulating at a rate at least as great as that of silent changes. Third, most of the amino acid replacements are localized in one region of the C kappa domain--namely, the carboxy-terminal "bends" in the alpha-carbon backbone. These three features have previously been described from comparisons of the two allelic forms of C kappa genes in R. norvegicus. These data imply the existence of considerable evolutionary constraints on the noncoding regions (based on as yet undetermined functions) or powerful positive selection to diversify a portion of the constant-region domain (whose physiological significance is not known). These surprising features of C kappa evolution appear to be characteristic only of closely related C kappa genes, since comparison of rodent with human sequences shows the expected greater conservation of coding regions, as well as a predominance of silent nucleotide substitutions within the coding regions.

Animals↗

PubMed1992

[Abortion in the penal code].

Before discussing the change of legal norms it is necessary to know the actual law. The paper shows the West-German penal code and it's application in respect of the pregnant women, the physician and third persons.

Abortion, Legal↗

PubMed2001

Mutations in the preproghrelin/ghrelin gene associated with obesity in humans.

Ghrelin and preproghrelin sequences were determined in 96 unrelated female subjects with severe obesity (mean body mass index (BMI) 42.3 +/- 3.4 kg/m(2)) and in 96 non-obese female controls (mean BMI 23.0 +/- 1.4 (kg/m2) of the Swedish Obese Subjects cohort. A mutation at amino acid position 51 (Arg51Gln) of the preproghrelin sequence that corresponds to the last amino acid in mature ghrelin product was identified in six (all heterozygotes) obese subjects (6.3%) but not among controls (p < 0.05). The self-reported weight at 20, 30, and 40 years of age tended to be 7.5, 4.7 and 6.4 kg lower, respectively, among obese Gln allele carriers versus obese non-carriers. In addition, a mutation at codon 72 of the preproghrelin gene (Leu72Met) was detected in 15 obese (12 hetero- and 3 homozygotes) and 12 control (all heterozygotes) subjects. This mutation outside the coding region of the mature ghrelin product tended to be associated with lower age of self-reported onset of obesity (15.6 +/- 7.9 vs. 20.5 +/- 10.5 years; p = 0.09). In addition to these two mutations in coding regions, a G274A base change in a non-coding region between exons one and two was found only in two obese individuals. The Arg51Gln amino acid substitution may alter the cleavage site of endoproteases and the length of the mature ghrelin product. The functional significance of the Leu72Met mutation and a G274A base change remains to be determined. In conclusion, the data provide evidence that a low frequency sequence variation in the ghrelin gene could play a role in the etiology of obesity.

Adult↗

PubMed1994

Receptor mutations and haplotypes in growth hormone receptor deficiency: a global survey and identification of the Ecuadorean E180splice mutation in an oriental Jewish patient.

Eight different mutations were detected in the growth hormone (GH) receptor gene of patients with inherited GH receptor deficiency (GHRD; Laron syndrome) from five continents. All the mutations are located in the extracellular domain of the receptor and are predicted to cause gross structural abnormalities and non-functional receptor molecules. They include three nucleotide changes in the coding region causing translational stop signals, including the newly identified E183X mutation; two nucleotide changes in introns that affect splice junctions; two dinucleotide deletions that result in stop codons downstream; and one single nucleotide change that activates a donor splice site within an exon and results in a transcript missing 24 nucleotides. This latter mutation (E180splice) was first identified in a cohort of patients with GHRD from southern Ecuador. Based on the fact that the E180splice mutation generates a new cleavage site for the restriction enzyme MnlI, a simple diagnostic test has been developed that can be carried out on dried blood spots collected on filter paper. A total of 55 affected individuals from Ecuador has been found to be homozygous for this mutation. Asymptomatic carriers can also be detected, and 104 of 150 individuals screened were found to be carriers. Using this test, the E180splice mutation has recently been detected in one of two oriental Jewish patients from Israel.

Base Sequence↗

PubMed2003

Personality assessment in neuropsychology: the nonspecificity of MMPI-2 neurocorrection methods.

Three established methods of neurocorrection claim to improve Minnesota Multiphasic Personality Inventory (MMPI)/MMPI-2 validity with closed-head injury (CHI) patients. These methods (which suggest removing "neurological" items from scoring) were employed here comparing 35 CHI patients with 35 psychiatric patients with elevated profiles. The 14-item correction changed 2-point codes for 41% of CHI and 31% of psychiatric profiles, the 30-item system changed 77% of CHI and 71% of psychiatric profiles, whereas the 37-item system changed 80% of CHI and 71% of psychiatric profiles. There were no significant differences between the two groups in number of profiles changed or number of neurocorrective items endorsed. Using each of the three correction systems, the following percentage of profiles remained elevated: 99%, 87%, and 89%, respectively.

Adult↗

PubMed1990

How much change in the case mix index is DRG creep?

We re-abstracted a nationally representative sample of 7,887 Medicare charts to determine how much of the change in Medicare's Case Mix Index between 1986 and 1987 was true change in the complexity of cases and how much was upcoding or 'DRG creep'. About two-thirds of the change is true. Most of the remaining third is attributable to a general change in the completeness of coding; some is attributable to changes in the Grouper program. Thus, most of the additional $1 billion paid to hospitals because of the Case Mix Index change appears justified by the additional complexity of patients hospitalized.

Abstracting and Indexing↗

PubMed1986

Cloning and expression of human lymphotoxin mRNA derived from a human T cell hybridoma.

We cloned human lymphotoxin (LT) cDNA from a cDNA library prepared from phorbol myristate acetate (PMA) and Con A-stimulated human T cell hybridoma (AC5-8) cells, The nucleotide sequence of the cDNA insert in the plasmid, pLT13, was determined and compared with those of peripheral blood mononuclear cell derived LT cDNA and the LT gene. Four stretches, containing 14 nucleotides in total, were different among the three sequences. The differences included one base change from C to A in the coding region. Because this change was expected to result in a change in the amino acid at position 26 from Thr to Asn, we constructed an E. coli expression plasmid (pLT13tac6-8.2) and a mammalian cell expression plasmid (pSV2-LT) in order to confirm that pLT13 contains the coding sequence of human LT. Both plasmids were found to synthesize active LT molecules after transfection into JM105 and COS-1 cells, respectively, and their lytic activities were found to be completely neutralized by anti human LT serum. Using an insertion mutant and a deletion mutant, we examined the role of the C terminal domain in the LT activity. The results obtained strongly suggested that the intactness of the C terminal less than 10 residues is required for the LT activity.

Amino Acid Sequence↗

PubMed1994

tRNA structure and ribosomal function. II. Interaction between anticodon helix and other tRNA mutations.

Using multiply mutated tRNA genes, we have studied unusual coding by tRNAs that have altered nucleotides (nt) 27-43, which normally form the top base-pair of the anticodon helix. In vivo, nt 27-43 mutations accelerate non-canonical C-A coding at the third (3') codon position 14-fold, similar to the 40-fold stimulation originally shown for first (5') codon position non-canonical G-U pairing. Thus the effects of nt 27-43 generalize to a second type of unusual coding. Nt 27-43 changes have a similar relative effect on tRNA level, aminoacylation, and ribosomal activity, despite concurrent changes of the 3' anticodon nucleotide which alter coding. However, under conditions of efficient aminoacylation, only a fraction of these (potential missense) anticodon changes can be recovered, suggesting toxicity. Available data support the idea that the effects of nt 27-43 are not particular to one codon. A previously isolated D-arm mutation (G24A) has a similar coding effect, enhancing both first position G-U wobble up to 130-fold, the third position C-A mispairing 40-fold. Anticodon helix mutations at 27-43 have little effect on 3' or 5' miscoding in the presence of the G24A D-arm mutation, and reciprocally, the D-arm's effects are much diminished in the presence of the anticodon helix mutations. Because these two tRNA loci alter both types of aberrant coding, and because they are highly interdependent, they may exploit a similar mechanism, dependent on a similar effect on tRNA conformation. We suggest a relatively non-specific decrease in the ribosomal rejection rates for tRNAs altered at anticodon helix nucleotides 27 and 43. Thus coding via non-canonical pairings at both 5' and 3' ends of the codon-anticodon helix has a measurable rate in vivo. However, we find that normal tRNA structure minimizes the efficiency of this aberrant translation. To put these same findings in another light, tRNAs bearing identical anticodons, if altered in structure elsewhere, may translate the genetic code differently.

Anticodon↗

PubMedDate not supplied

Changes in hepatic perfusion after administration of hydroxyethyl starch in intensive care patients assessed using color-coded Doppler sonography.

Using color-coded Doppler sonography (CCDS), changes in the resistance index of the hepatic artery (HA-RI) and in the velocities of the hepatic artery, portal and splenic vein (HA-V, PV-V, SV-V) were measured after administration of hydroxyethyl starch (HES) in 50 intensive care patients. PV-V and SV-V increased, whereas HA-V and HA-RI remained unchanged. CCDS is suitable to assess liver perfusion in intensive care patients. Since HES enhances splanchnic perfusion, its application improves hepatic perfusion in intensive care patients.

Blood Flow Velocity↗

PubMed2004

Enhanced motor unit rate coding with improvements in a force-matching task.

These data describe improved modulation of discharge rates (rate coding) of first dorsal interosseous motor units throughout the acquisition of a complex force-matching skill involving isometric index finger abduction. In each of 15 consecutive trials, subjects attempted to match their force to a trajectory consisting of the sum of two sine waves (0.15 and 0.5 Hz) and random oscillations (overall mean force level approximately 20% MVC). Reductions in root-mean-square (RMS) error of each subject's force relative to the trajectory indicated substantial improvements in force-matching ability (F = 33.8, p < 0.001). With the acquisition of this new skill, there was increased amplitude modulation of muscular force near both dominant frequencies of the force-matching trajectory (F = 10.6, p = 0.008). The standard deviation and coefficient of variation of motor unit inter-spike intervals both decreased with improved performance indicating a general reduction in the amplitude of firing rate modulations (SD: F = 18.69, p = 0.001; CV: F = 43.6, p < 0.001). After skill acquisition, there was decreased firing rate modulation outside of the two dominant frequencies and increased amplitude of firing rate modulation at the higher of the two dominant frequencies (0.5 Hz, F = 8.23, p = 0.015). These findings indicate that improved precision of rate coding was a contributor to the acquisition of the new force-matching task. That the change in rate coding was frequency dependent suggests that factors other than frequency coding may contribute to the improved force matching at 0.15 Hz.

Adult↗

PubMed1996

Amber suppression in mammalian cells dependent upon expression of an Escherichia coli aminoacyl-tRNA synthetase gene.

As an approach to inducible suppression of nonsense mutations in mammalian and in higher eukaryotic cells, we have analyzed the expression of an Escherichia coli glutamine-inserting amber suppressor tRNA gene in COS-1 and CV-1 monkey kidney cells. The tRNA gene used has the suppressor tRNA coding sequence flanked by sequences derived from a human initiator methionine tRNA gene and has two changes in the coding sequence. This tRNA gene is transcribed, and the transcript is processed to yield the mature tRNA in COS-1 and CV-1 cells. We show that the tRNA is not aminoacylated in COS-1 cells by any of the endogenous aminoacyl-tRNA synthetases and is therefore not functional as a suppressor. Concomitant expression of the E. coli glutaminyl-tRNA synthetase gene results in aminoacylation of the suppressor tRNA and its functioning as a suppressor. These results open up the possibility of attempts at regulated suppression of nonsense codons in mammalian cells by regulating expression of the E. coli glutaminyl-tRNA synthetase gene in an inducible, cell-type specific, or developmentally regulated manner.

Amino Acyl-tRNA Synthetases↗

PubMedDate not supplied

Calcium regulation and contractile dysfunction of smooth muscle.

A brief overview of recent findings of abnormal contractile function of smooth muscle under several selected pathophysiological conditions is presented and related to the dysfunction of the control of cytosolic calcium ion concentration, [Ca2+]. In diabetes mellitus (DM), contractile abnormalities depend on the animal species, vascular segments, mode of the induction of DM, and the period after the induction of DM. The abnormal contractile responses are frequently related to altered Ca2+, membrane transduction and the production and action of intracellular second messengers. The hypertensitive and/or hyperreactive contractile responses of airway smooth muscle in asthma inflammation represent a complex chronic consequence of actions of many cells and mediators. Chronic asthmatic disease seems to be associated with altered Ca2+ handling via changes in gene coding for receptors, enzymes and regulatory proteins, thus contributing to abnormal responsiveness and cell growth. Similarly, changes of contractile function of vascular smooth muscle commonly observed in chronic hypertension have long been recognized to be intimately associated with abnormal handling of Ca2+ at the level of subcellular membranes, isolated cells and intact vascular tissues. However, the subcellular sites of membrane abnormalities remain disputable.

Animals↗

PubMed2005

Nucleotide and amino acid changes in West Nile virus strains exhibiting renal tropism in hamsters.

Recent studies have shown that West Nile virus (WNV) can induce an asymptomatic persistent infection in the kidneys of experimentally infected hamsters. The chronically infected rodents shed virus in their urine for up to 8 months, despite the disappearance of viremia and the development of high levels of neutralizing antibodies. WNV, like most members of the Japanese encephalitis virus complex (Flavivirus; Flaviviridae), is assumed to be mainly neurotropic; little is known about the genetic basis for its renal tropism. In this study, complete sequence analyses were done to compare four WNV isolates from the urines of persistently infected hamsters with the wild-type parent virus (NY 385-99). Nucleotide changes, ranging from 0.05% to 0.09%, were identified in all of the WNV isolates from urine; most of the changes were in coding regions, causing amino acid substitutions in the E, NS1, NS2B, and NS5 proteins. The genetic changes associated with renal tropism were also accompanied by a loss of virulence for hamsters and a change in plaque morphology.

Amino Acid Sequence↗

PubMed1985

A hardware interpretation of the evolution of the genetic code.

A quantitative rationale for the evolution of the genetic code is developed considering the principle of minimal hardware. This principle defines an optimal code as one that minimizes for a given amount of information encoded, the product of the number of physical devices used by the average complexity of each device. By identifying the number of different amino acids, number of nucleotide positions per codon and number of base types that can occupy each such position with, respectively, the amount of information, number of devices and the complexity, we show that optimal codes occur for 3, 7 and 20 amino acids with codons having a single, two and three base positions per codon, respectively. The advantage of a code of exactly 4 symbols is deduced, as well as a plausible evolutionary pathway from a code of doublets to triplets. The present day code of 20 amino acids encoded by 64 codons is shown to be the most optimal in an absolute sense. Using a tetraplet code further evolution to a code in which there would be 55 amino acids is in principle possible, but such a code would deviate slightly more than the present day code from the minimal hardware configuration. The change from a triplet code to a tetraplet code would occur at about 32 amino acids. Our conclusions are independent of, but consistent with, the observed physico-chemical properties of the amino acids and codon structures. These correlations could have evolved within the constrains imposed by the minimal hardware principle.

Amino Acids↗

PubMed1995

Molecular genetics of the ABO histo-blood group system.

Molecular genetic study of the histo-blood group ABO system has elucidated the allelic basis of this genetic locus. Comparison of the nucleotide sequence has identified in the coding region differences which change amino acid sequences of the glycosyltransferases coded by these genes. Effects of the differences (mutations) on the specificity and activity of the glycosyltransferases have been examined.

ABO Blood-Group System↗

PubMed2002

[Site-directed mutation of PoIFN-alpha and its expression in Escherichia coli].

By using huge primer PCR Cys86 (TGC) of PoIFN-alpha was mutated to Tyr(TAC), and the first code TGT was simultaneously changed to TGC, which is a bias code of E. coli. The expression plasmid pGEX-IFN was constructed successfully. Recombinant porcine IFN alpha, which is expressed as inclusion bodies, was about 20% of the total proteins. The inclusion body was dissolved in 8 mol/L urea and subsequently renatured by dilution in refolding buffer. In order to obtain pure protein, the renatured IFN alpha was purified by FPLC, and the cytokine activity (5200 IU/mg) was verified by inhibiting the cytopathic effect.

Escherichia coli↗

PubMed1982

Variation of influenza A, B, and C viruses.

Influenza is caused by highly variable RNA viruses belonging to the orthomyxovirus group. These viruses are capable of constantly changing the genes coding for their surface proteins as well as for their nonsurface proteins. The mechanisms responsible for these changes in type A influenza viruses include recombination (reassortment) of genes among strains, deletions and insertions in genes, and, frequently, point mutations. In addition, old strains may reappear in the population. Influenza viruses of types B and C appear to vary to a lesser degree. The mechanisms responsible for changes in these viruses are not well characterized.

Genetic Variation↗

PubMed1994

The role of upstream U3 sequences in the pathogenesis of simian immunodeficiency virus-induced AIDS in rhesus monkeys.

The nef reading frame overlaps about 70% of the U3 region of the 3' long terminal repeat (LTR) in primate lentiviruses. We investigated the functional role of these overlapping U3 sequences by analyzing the properties of three mutant forms of the pathogenic SIVmac239 clone. In mutant UScon, 90 of 275 bp in the upstream sequences (US) of U3 were changed in a conservative fashion without changing the predicted nef coding sequence. In mutant USnon, 101 of 275 bp in this region were changed in a nonconservative fashion, again without changing the predicted nef coding sequence. In mutant delta US, 275 bp in this region were deleted. Full-size, immunoreactive nef protein was synthesized in cells infected with the UScon and USnon mutants. The USnon and delta US mutants replicated with similar kinetics and to similar extents as wild-type, parental SIVmac239 in primary rhesus monkey peripheral blood mononuclear cell (PBMC) cultures. The UScon mutant replicated with slightly delayed kinetics in rhesus monkey PBMC cultures. In the CEMx174 cell line, the delta US mutant replicated similarly to the wild type, but the UScon and USnon mutants replicated with significantly delayed kinetics. Analysis of LTR-driven chloramphenicol acetyltransferase (CAT) activity and the effects of 5-azacytidine on virus replication suggested that the growth defect of the point mutants in CEMx174 cells was due in whole or in part to the introduction of multiple CG methylation sites in proviral DNA. Rhesus monkeys were experimentally infected with the UScon and USnon mutants, and the characteristics of the infection were compared with those of the parental SIVmac239. Analysis of the levels of plasma antigenemia, virus load, and CD4+ cells in PBMC revealed no decreased virulence of the mutant viruses. Analysis of lymph node biopsies taken from animals that received mutant viruses revealed histologic changes and levels of virus expression indistinguishable from those of the wild type. Furthermore, the wild-type behavior of the mutant viruses in rhesus monkeys occurred without any specific reversional events through at least 20 weeks of infection. These results, and the recent results of Kirchhoff et al. (F. Kirchoff, H. W. Kestler III, and R. C. Desrosiers, J. Virol. 68:2031-2037, 1994), suggest that these upstream sequences in U3 are primarily or exclusively nef coding sequence.

Amino Acid Sequence↗