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PubMed1987

Nucleotide sequence of the insecticidal protein gene of Bacillus thuringiensis strain aizawai IPL7 and its high-level expression in Escherichia coli.

A DNA fragment carrying the insecticidal protein gene of Bacillus thuringiensis subsp. aizawai IPL7 was cloned from a 78-kb plasmid. The nucleotide sequence revealed that the cloned DNA fragment contained a 3465-bp protein-coding region with 156-bp 5'-flanking, and 168-bp 3'-flanking regions. The open reading frame encoded a 130,690 Da protein consisting of 1155 amino acid residues. Nucleotide sequence comparison of the aizawai gene with the published berliner 1715 gene showed only 8 nt changes in the coding regions. It was found that 72 bp of the 5'-flanking sequence of the cloned aizawai gene was responsible for constitutive expression of the 130-kDa protein gene in Escherichia coli. The expression was greatly enhanced by introducing the tac promoter upstream from the 72-bp 5'-flanking region of the aizawai gene. Under optimal conditions, the 130-kDa insecticidal protein amounted to 38% of the total cellular protein.

Amino Acid Sequence↗
PubMed1999

The role of ethical principles in health care and the implications for ethical codes.

A common ethical code for everybody involved in health care is desirable, but there are important limitations to the role such a code could play. In order to understand these limitations the approach to ethics using principles and their application to medicine is discussed, and in particular the implications of their being prima facie. The expectation of what an ethical code can do changes depending on how ethical properties in general are understood. The difficulties encountered when ethical values are applied reactively to an objective world can be avoided by seeing them as a more integral part of our understanding of the world. It is concluded that an ethical code can establish important values and describe a common ethical context for health care but is of limited use in solving new and complex ethical problems.

Codes of Ethics↗
PubMed1984

Expression of the mouse dihydrofolate reductase cDNA in B. subtilis: a system to select mutant cDNAs coding for methotrexate resistant enzymes.

With the aim to obtain a cDNA coding for a mammalian methotrexate resistant dihydrofolate reductase (Dhfr) a plasmid ( pQS1 ) harboring the mouse wild type Dhfr cDNA was constructed and used to transform a methotrexate sensitive bacteria: B. subtilis. A plasmid, pQS4 , expressing large amount of Dhfr in both E. coli and B. subtilis was isolated through a two steps selection with two substrate analogues, trimethoprim followed by methotrexate. This new plasmid has a 54 bp duplication including the beta-lactamase promoter and a deletion of 564 bp removing the 5' end of the beta-lactamase coding region. These changes create a new -35 region TTGAAA and a potentially stronger binding site for both E. coli and B. subtilis 16S ribosomal RNA. pQS4 transformed B. subtilis were then grown in the presence of high level of methotrexate and resistant mutants isolated. One of them, pQS6 , which codes for an enzyme about 50 times more resistant to methotrexate than the wild type Dhfr was sequenced. It shows that a point mutation replaces the glutamine residue at position 35 by a proline.

Animals↗
PubMed1991

Impaired expression of glycogen synthase mRNA in skeletal muscle of NIDDM patients.

Based on recent studies of the abnormal physiology and biochemistry of the glycogen synthesis in skeletal muscle of non-insulin-dependent diabetes mellitus (NIDDM) patients and their first-degree relatives, the key enzyme of this pathway, glycogen synthase (GS), is considered a candidate gene in the pathogenesis of insulin resistance. Comparing matched groups of 14 NIDDM patients with 14 control subjects, we found that impaired insulin-stimulated nonoxidative glucose metabolism of peripheral tissue (P less than 0.02) and reduced total GS activity (P less than 0.05) of vastus lateralis muscle from patients with NIDDM were accompanied by a 39% reduction (P less than 0.02) in the steady state level of GS mRNA per microgram DNA of muscle. In both diabetic and control subjects, the mRNA expression of GS was unaffected after euglycemic-hyperinsulinemic clamp for 4 h. With single-stranded conformation polymorphism analysis of the entire coding sequence of the GS gene, we were unable to detect any genetic variants in a subset of eight NIDDM patients. We conclude that abnormal pretranslational regulation of the GS gene may contribute to impaired glycogen synthesis of muscle in NIDDM. Our studies give no evidence for structural changes in the coding region of the GS gene, and it is unknown if the decreased mRNA expression is due to impaired transcription or accelerated degradation of the transcript.

Blotting, Northern↗
PubMedDate not supplied

Asymptomatic coronary heart disease detected on epidemiological survey of urban population of Delhi.

A community based epidemiological study of coronary heart disease (CHD) was carried out in a random sample of 13723 adults in the age group of 25-64 years in the urban population of Delhi. The electrocardiogram (ECG) of all clinically detected CHD cases and of a sample of 5621 persons (selected on the basis of alternate household screened) without clinical manifestations of CHD, was obtained. Out of 5621 persons labelled as asymptomatic, CHD evidence of Q wave myocardial infarction (MI) was present in 80 ECGs (1.4%). Another 296 ECGs had ST & T changes vide Minnesota Code 4-1-1, 4-1-2, 5-1 and 5-2 acceptable as evidence of probable CHD. The overall prevalence rate of asymptomatic CHD was 6.7% (male 5.6%, female 7.6%). Silent MI was more common in the male patients (1.7% vs 1.1%, p < 0.001). However, ST-T changes were more common in female patients (6.5% vs 3.9%, p < 0.001). The ST-T changes showed a steady factor in asymptomatic CHD cases was hypertension in both sexes (male-45.2%, female-43.5%) p = NS. Obesity was present in 24% of male & 46.1% of female patients (p < 0.001). Family history was found in 20% cases of both sexes. Smoking was recorded in 34.9% male and 10.9% female patients with asymptomatic CHD (p < 0.001).

Adult↗
PubMed1998

Extracting findings from narrative reports: software transferability and sources of physician disagreement.

While natural language processing systems are beginning to see clinical use, it remains unclear whether they can be disseminated effectively through the health care community. MedLEE, a general-purpose natural language processor developed for Columbia-Presbyterian Medical Center, was compared to physicians' ability to detect seven clinical conditions in 200 Brigham and Women's Hospital chest radiograph reports. Using the system on the new institution's reports resulted in a small but measurable drop in performance (it was distinguishable from physicians at p = 0.011). By making adjustments to the interpretation of the processor's coded output (without changing the processor itself), local behavior was better accommodated, and performance improved so that it was indistinguishable from the physicians. Pairs of physicians disagreed on at least one condition for 22% of reports; the source of disagreement appeared to be interpretation of findings, gauging likelihood and degree of disease, and coding errors.

Diagnosis, Computer-Assisted↗
PubMed1994

The regularity of changes of the Chou-Fasman parameters within the genetic code.

It has been shown that Chou-Fasman conformational parameters of amino acids, which reflect their ability to adopt a definite conformation within the peptide chain, change very regularly within the genetic code, arranged in the manner discussed recently by Siemion and Stefanowicz (1992a) (BioSystems 27, 77-84). Two mutually perpendicular C2 axes of pseudosymmetry appear in the center of the diagrams (between ACY and ACR threonine codons) presenting the changes of P alpha and P beta parameters. The left and right parts of diagrams superimpose on each other quite well when the symmetry operation involving a proper axis is performed. This phenomenon is due, in our opinion, to the regular arrangement of equivalent codons in the 'one-step mutation' ring formed by 64 triplets of the genetic code.

Amino Acid Sequence↗
PubMed2002

Unusual splice-site mutations in the RSK2 gene and suggestion of genetic heterogeneity in Coffin-Lowry syndrome.

Coffin-Lowry syndrome (CLS) is a syndromic form of X-linked mental retardation that is characterized, in male patients, by psychomotor and growth retardation and various skeletal anomalies. Typical facial changes and specific clinical and radiological hand aspects exhibited by patients are essential clues for the diagnosis. CLS is caused by mutations in a gene that is located in Xp22.2 and that encodes RSK2, a growth-factor-regulated protein kinase. RSK2 mutations are extremely heterogeneous and lead to premature termination of translation and/or loss of phosphotransferase activity. Surprisingly, among a series of 250 patients screened by single-strand conformation polymorphism (SSCP) analysis, in whom a clinical diagnosis of CLS was made, no mutations were detected in 66% (165) of the patients. To determine what proportion of these latter patients have a RSK2 mutation that has not been detected and what proportion have different disorders that are phenotypically similar to CLS, we have, in the present article, investigated, by western blot analysis and in vitro kinase assay, cell lines from 26 patients in whom no mutation was previously identified by SSCP analysis. This approach allowed us to identify seven novel RSK2 mutations: two changes in the coding sequence of RSK2, one intragenic deletion, and four unusual intronic nucleotide substitutions that do not affect the consensus GT or AG splice sites. We have also determined the nucleotide sequence of the promoter region of the RSK2 gene, and we have screened it for mutations. No disease-causing nucleotide change was identified, suggesting that mutations affecting the promoter region are unlikely to account for a large number of patients with CLS. Finally, our results provide evidence that some patients have a disease that is phenotypically very similar to CLS, which is not caused by RSK2 defects. This suggests that there are defects in either additional genes or combinations of genes that may result in a CLS-like phenotype.

Base Sequence↗
PubMed2000

Polyamine regulation of ornithine decarboxylase synthesis in Neurospora crassa.

Ornithine decarboxylase (ODC) of the fungus Neurospora crassa, encoded by the spe-1 gene, catalyzes an initial and rate-limiting step in polyamine biosynthesis and is highly regulated by polyamines. In N. crassa, polyamines repress the synthesis and increase the degradation of ODC protein. Changes in the rate of ODC synthesis correlate with similar changes in the abundance of spe-1 mRNA. We identify two sequence elements, one in each of the 5' and 3' regions of the spe-1 gene of N. crassa, required for this polyamine-mediated regulation. A 5' polyamine-responsive region (5' PRR) comprises DNA sequences both in the upstream untranscribed region and in the long 5' untranslated region (5'-UTR) of the gene. The 5' PRR is sufficient to confer polyamine regulation to a downstream, heterologous coding region. Use of the beta-tubulin promoter to drive the expression of various portions of the spe-1 transcribed region revealed a 3' polyamine-responsive region (3' PRR) downstream of the coding region. Neither changes in cellular polyamine status nor deletion of sequences in the 5'-UTR alters the half-life of spe-1 mRNA. Sequences in the spe-1 5'-UTR also impede the translation of a heterologous coding region, and polyamine starvation partially relieves this impediment. The results show that N. crassa uses a unique combination of polyamine-mediated transcriptional and translational control mechanisms to regulate ODC synthesis.

5' Untranslated Regions↗
PubMed1975

The ontogeny of auditory frequency generalization in the chicken.

To determine if there is an ontogenetic change in stimulus coding, chickens between the day of hatching and 9-10 days old were tested using a habituation-generalization paradigm. Experiment 1 indicated that 1 day-old and 3--4-day-old chicks show similar habituation of an eye-opening response to auditory stimuli in the 800--1,200-Hz range. In Experiment 2 the eye-opening response to a 1,000-Hz stimulus was habituated and then immediately tested using stimuli which varied between 800 and 1,200 Hz. Each age-group (1 day, 3--4 days, and 9--10 days) showed a symmetrical stimulus generalization gradient around the 1,000-Hz stimulus and the 1-day-old chicks displayed a reliably flatter gradient than either of the older groups, which did not differ. In a third experiment, the position of the gradients relative to the baseline was shifted without altering the relative shapes. These results allow general arousal, general auditory responsiveness, overall error rate, and metric characteristics of the independent and dependent variables to be eliminated as possible sources of the age differences in gradient shape. The changes in stimulus generalization, therefore, support the view that during normal development there is a sharpening of perceptual coding processes.

Acoustic Stimulation↗
PubMed1982

An immunoglobulin promoter region is unaltered by DNA rearrangement and somatic mutation during B-cell development.

The V1 gene encodes the heavy chain variable region of antibodies that bind to phosphorylcholine in the Balb/c mouse. V1 genes have been cloned from mouse sperm DNA, an IgM-producing tumor HPCM2 and an IgA-producing tumor M167. The transcription start site of the V1 gene has been mapped 63 +/- 1 base pairs from the coding sequence for both alpha and mu transcripts. Comparison of flanking DNA sequence 574 base pairs 5' to the V1 transcription start site in sperm, HPCM2 and M167 DNA reveals that sperm and HPCM2 sequences are completely identical in this region and the M167 sequence differs from them by a single base change. Although the coding region of the V1 gene has undergone a high (4%) rate of somatic mutation in M167 we demonstrate that the somatic mutation mechanism stops near the transcription start site. These results demonstrate that initiation of V1 gene transcription remains unchanged with respect to location and 5' sequences throughout B-cell development.

Animals↗
PubMed1985

Ontogeny of tonotopic organization of brain stem auditory nuclei in the chicken: implications for development of the place principle.

The morphological development of the cochlea begins in the base or midbasal region and spreads toward the apex. In adults, the base responds maximally to high-frequency sounds and lower frequencies are represented progressively toward the apex. This predicts that responses to sound should occur initially to high frequencies and gradually change to include lower frequencies. Paradoxically, animals respond first to relatively low frequencies and last to high frequencies. We have previously proposed that this discrepancy results from an ontogenetic change in spatial coding of frequency along the cochlea (Rubel et al., '76). According to this model, only the basal end of the cochlea transduces sound early in development but it responds to low frequencies. During maturation the representation of low and midrange frequencies shifts apically and the base becomes responsive to high frequencies. This hypothesis predicts that the tonotopic organization within the central nervous system should change during development; neurons at any given location within an auditory nucleus should become maximally responsive to successively higher frequency sounds during development. In the present study this prediction was tested by using microelectrode recording procedures to map the tonotopic organization of nucleus magnocellullaris (NM) and nucleus laminaris (NL), first- and second-order auditory nuclei, in chickens at three ages: embryonic day 17, 1 day posthatch, and 2-4 weeks posthatch. The characteristic frequencies of neurons having the same anatomical location were quantitatively compared across ages. The tonotopic order in NM and NL was similar at all ages; responses to high-frequency sounds were recorded anteromedially and lower frequencies were located progressively more caudolaterally. However, there was a striking quantitative change in tonotopic organization. Neurons at a given location in both nuclei became maximally responsive to progressively higher frequencies during development. The characteristic frequencies of neurons in embryos and newly hatched chicks averaged, respectively, 1.00 (+/- 0.06, S.E.M.) and 0.34 (+/- 0.04) octaves lower than their predicted adult values. All regions in both nuclei showed a statistically significant increase in characteristic frequency during development except the most posterolateral (low-frequency) sector. Too few neurons were recorded from this region to be able to reliably estimate characteristic frequency. These results support the hypothesis that the spatial coding of frequency along the cochlea shifts during development.(ABSTRACT TRUNCATED AT 400 WORDS)

Age Factors↗
PubMed2001

Prevalence, phenotypic spectrum, and modes of inheritance of gonadotropin-releasing hormone receptor mutations in idiopathic hypogonadotropic hypogonadism.

Mutations in the GnRH receptor (GNRHR) have been described as a cause of reproductive failure in a subset of patients with idiopathic hypogonadotropic hypogonadism (IHH). Given the apparent rarity of these mutations, we set out to determine the frequency and distribution of GNRHR mutations in a heterogeneous population of patients with IHH who were well characterized with respect to diagnosis, phenotype, and mode of inheritance and to define their distribution within the receptor protein. One hundred and eight probands with IHH were screened for mutations in the coding sequence of GNRHR. Forty-eight of the 108 patients had a normal sense of smell, whereas the remaining 60 had anosmia or hyposmia (Kallmann syndrome). Exon segments in the GNRHR were screened for mutations using temperature gradient gel electrophoresis, and all mutations were confirmed by direct sequencing. Five unrelated probands (3 men and 2 women), all normosmic, were documented to have changes in the coding sequence of the GNRHR. Two of these probands were from a subgroup of 5 kindreds consistent with a recessive mode of inheritance, establishing a GNRHR mutation frequency of 2 of 5 (40%) in patients with normosmic, autosomal recessive IHH. The remaining 3 probands with GNRHR mutations were from a subgroup of 18 patients without evidence of familial involvement, indicating a prevalence of 3 of 18 (16.7%) in patients with sporadic IHH and a normal sense of smell. Among the five individuals bearing GNRHR mutations, a broad spectrum of phenotypes was noted, including testicular sizes in the male that varied from prepubertal to the normal adult male range. Three probands had compound heterozygous mutations, and two had homozygous mutations. Of the eight DNA sequence changes identified, four were novel: Thr(32)Ile, Cys(200)Tyr, Leu(266)Arg, and Cys(279)TYR: COS-7 cells transiently transfected with complementary DNAs encoding the human GNRHR containing each of these four novel mutations failed to respond to GnRH agonist stimulation. We conclude that 1) the spectrum of phenotypes in patients with GNRHR mutations is much broader than originally anticipated; 2) the frequency of GNRHR mutations may be more common than previously appreciated in familial cases of normosmic IHH and infrequent in sporadic cases; and 3) functional mutations of the GNRHR are distributed widely throughout the protein.

Amino Acid Sequence↗
PubMed1991

[Value of color-coded duplex sonography in diagnosis of extracranial vascular changes].

72 patients at the age of 44 to 76 years with transitory ischaemic attacks which happened and for a short time reversible deficits, respectively, were diagnosed both conventionally duplex-sonographically and with the colour-coded duplex sonography under the question of vascular stenotic process in the region of the cervical vessels. After the ultrasound examination within two weeks an angiography was performed. As a result was shown that in 10 patients with an angiogram without pathological findings by means of the colour-coded duplex sonography in 3 cases plaque formations could be proved which could be clearly diagnosed only by colour marking.

Adult↗
PubMed1983

Code dependent conservation of the physico-chemical properties in amino acid substitutions.

The frequency of amino acid replacements in families of typical proteins has been elegantly analyzed by Argyle (1980) showing that the most frequent replacements involve a conservation of the amino acid chemical properties. The cyclic arrangement of the twenty amino acids resulting from the most frequent replacements has been described as an amino acid chemical ring. In this work, a novel amino acid replacement frequency ring is proposed, for which a conservation of over 90% of the most general physico-chemical properties can be deduced. The amino acid chemical similarity ring is also analyzed in terms of the genetic code base probability changes, showing that the discrepancy that exists between the standard deviation value of the amino acid replacement frequency matrix and its respective ideal value is almost equal to that deduced from the corresponding base codon replacement probability matrices. These differences are finally evaluated and discussed in terms of the restrictions imposed by the structure of the genetic code and the physico-chemical dissimilarities between some codons of amino acids which are chemically similar.

Amino Acid Sequence↗
PubMed1998

A mutation in guanylate cyclase activator 1A (GUCA1A) in an autosomal dominant cone dystrophy pedigree mapping to a new locus on chromosome 6p21.1.

We report a mutation (Y99C) in guanylate cyclase activator 1A (GUCA1A), the gene for guanylate cyclase activating protein (GCAP1), in a family with autosomal dominant cone dystrophy. Linkage analysis excluded all the known cone and cone-rod dystrophy loci, except the chromosome 6p21.1 region. This is known to contain the RDS gene, which is associated with dominant cone-rod dystrophy. Screening of the RDS gene by heteroduplex analysis and direct sequencing failed to demonstrate sequence changes in the coding region of this gene. The gene for GCAP1, a calcium binding protein which is highly expressed in photoreceptor outer segments, is also located in 6p21.1. It was screened for mutations, and all affected individuals showed a single base pair missense mutation (A-->G) at codon 99 in exon 2 of this gene generating a tyrosine-to-cysteine change in the GCAP1 protein. This change was absent from 206 unrelated normal controls. We propose that this change would at least disrupt the EF3handof GCAP1 thereby preventing calcium binding and consequently interfere with activation. The resulting effect on cGMP production would predictably modify the number of open cGMP gated cation channels, and could explain the ultimate demise of cone photoreceptor cells.

Amino Acid Sequence↗
PubMed1990

Perceived pitch of vibrotactile stimuli: effects of vibration amplitude, and implications for vibration frequency coding.

1. The effect of changes in amplitude on the perceived pitch of cutaneous vibratory stimuli was studied in psychophysical experiments designed to test whether the coding of information about the frequency of the vibration might be based on the ratio of recruitment of the PC (Pacinian corpuscle-associated) and RA (rapidly adapting) classes of tactile sensory fibres. The study was based on previous data which show that at certain vibration frequencies (e.g. 150 Hz) the ratio of recruitment of the PC and RA classes should vary as a function of vibration amplitude. 2. Sinusoidal vibration at either 30 Hz or 150 Hz, and at an amplitude 10 dB above subjective detection thresholds was delivered in a 1 s train to the distal phalangeal pad of the index finger in eight human subjects. This standard vibration was followed after 0.5 s by a 1 s comparison train of vibration which (unknown to the subject) was at the same frequency as the standard but at a range of amplitudes from 2 to 50 dB above the detection threshold. A two-alternative forced-choice procedure was used in which the subject had to indicate whether the comparison stimulus was higher or lower in pitch (frequency) than the standard. 3. Marked differences were seen from subject to subject in the effect of amplitude on perceived pitch at both 30 Hz and 150 Hz. At 150 Hz, five out of the eight subjects reported an increase in pitch as the amplitude of the comparison vibration increased, one experienced no change, and only two experienced the fall in perceived pitch that is predicted if the proposed ratio code contributes to vibrotactile pitch judgements. At 30 Hz similar intersubject variability was seen in the pitch-amplitude functions. 4. The results do not support the hypothesis that a ratio code contributes to vibrotactile pitch perception. We conclude that temporal patterning of impulse activity remains the major candidate code for pitch perception, at least over a substantial part of the vibrotactile frequency bandwidth.

Female↗
PubMed1996

Large T antigen coding sequences of two DNA tumor viruses, BK and SV40, and nonrandom chromosome changes in two glioblastoma cell lines.

The T antigen (TAg) coding sequences of two DNA tumor viruses, BKV and SV40, were detected by Polymerase Chain Reaction (PCR) amplification followed by Southern-blot hybridization in two human glioblastoma multiforme derived cell lines. RT-PCR analysis indicated that these two TAg coding sequences were expressed in both tumor cell lines carrying the viral early region DNAs. Moreover, analytical polyacrylamide gel electrophoresis (PAGE) and DNA sequence analyses showed that the amplified PCR products are indistinguishable from the TAg coding sequences of BKV and SV40 wildtype strains. Cytogenetic study performed in the two cell lines showed unbalanced changes, mainly gains of chromosomes 3p, 5, 6, 7, and 19 and losses of chromosomes 3, 3q, 16, 9p22-->pter, 18, and 20. Excess of chromosomes 6 and 7 are common to the two cell lines. The putative role of the TAg of the two DNA tumor viruses in transformation and karyotype changes is discussed.

Antigens, Viral, Tumor↗