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PubMed1984

Vesicular stomatitis virus mutants resistant to defective-interfering particles accumulate stable 5'-terminal and fewer 3'-terminal mutations in a stepwise manner.

We have studied the evolution of sequences which include the RNA polymerase binding sites at the 5' and 3' termini of vesicular stomatitis virus mutants (Sdi-) resistant to defective-interfering particles. We observed a striking stepwise accumulation of stable base substitutions within the area of replication initiation at the 5'-terminal 54 nucleotides of Sdi- mutants isolated at intervals from persistent infections and undiluted lytic passage series. Fewer mutations accumulated in the region of transcription initiation at the 3' end and in those portions of the N and L protein coding cistrons examined. The termini changes are not strictly required to obtain the Sdi- phenotype. However, it is possible that they represent stepwise compensatory changes to accommodate Sdi- mutations affecting viral replication or encapsidation gene products or both. These results have important implications for RNA virus genome evolution.

Base Sequence↗
PubMed1987

A temperature-sensitive mutant of the myeloproliferative sarcoma virus, altered by a point mutation in the mos oncogene, has been modified as a selectable retroviral vector.

The myeloproliferative sarcoma virus (MPSV) is a mos-oncogenic retrovirus which induces an acute myeloproliferative disease in adult mice. The isolation and molecular cloning of two mutants of MPSV temperature sensitive (ts) for mos transformation (Kollek et al., J. Virol. 50:717-724, 1984) have been described previously. In this report, we describe the biological activity of these clones, the molecular basis of the ts lesion of one clone, and the construction of a selectable vector based on the MPSV ts genome. Both molecular clones, ts159 and ts124, proved to have retained the ts phenotype, the former being tighter for the induction and maintenance of the transformed phenotype. A single transition (G----A) at position 1888 in the mos coding region, resulting in the change of Gly to Arg at position 307, was responsible for the ts phenotype of clone ts159. Substitution of sequences carrying this mutation with the corresponding sequences of the wild-type virus generated a virus that was ts for transformation. Insertion of the dominant selectable marker gene for geneticin resistance (neor) into ts159 did not disrupt mos expression or its ts phenotype. neor-ts159 facilitates the study of mos action by allowing the selection of infected cells at the nonpermissive temperature before mos transformation has been induced. Furthermore, infected cells which show no obvious phenotype alteration due to mos expression can be identified by their Neor phenotype.

Base Sequence↗
PubMed1991

RNA editing intermediates of cox2 transcripts in maize mitochondria.

Eighteen cytidines are changed to uridines in the coding sequence of transcripts for cytochrome c oxidase subunit 2 (cox2) in maize mitochondria. The temporal relationship of editing and splicing was examined in cox2 transcripts by sequence analysis of spliced and unspliced cDNAs. Cloned cDNAs of unspliced cox2 transcripts ranged from clones with no edited nucleotides to completely edited forms, while spliced cDNAs were nearly completely edited. Incompletely edited transcripts in the nascent pool of unspliced transcripts represent intermediates of the editing process. These results indicate that editing proceeds without a strong directional bias and suggest that RNA editing is a posttranscriptional process.

Amino Acid Sequence↗
PubMed1987

Independent regulation of transcription of the two strands of the c-myc gene.

Previously we demonstrated the existence of transcripts from the noncoding strand of a rearranged, truncated c-myc gene in murine plasmacytomas in which this oncogene is translocated to an immunoglobulin constant-region gene element (M. Dean, R. B. Kent, and G. E. Sonenshein, Nature [London] 305:443-446, 1983). Here we report on the transcription of the two strands of a normal, unrearranged c-myc gene. We examined the effects of gene rearrangements, growth state transitions, and differentiation on the relative levels of usage of the two strands. Transcription from intron 1 to exon 3 of the murine c-myc gene was studied in in vitro nuclear runoff assays. The level of transcription of the noncoding strand across this region of a germ line c-myc gene in a murine B-cell lymphoma line was comparable to the level observed in plasmacytomas with translocated c-myc genes. Rapid changes in transcription of the coding strand of the c-myc gene could be seen during growth arrest of WEHI 231 cells and during activation of splenic T lymphocytes. Transcription of the noncoding strand was constitutive during these growth state transitions and during activation of primary cultures of quiescent calf aortic smooth muscle cells as well. In contrast, differentiation of murine erythroleukemia cells was accompanied by an early drop in transcription of the two strands of this gene. The ramifications of these findings with respect to measurements of c-myc gene transcription and to the regulation of this gene are discussed.

Animals↗
PubMed1986

Diet and coronary heart disease in England and Wales during and after the second world war.

During the second world war there were large changes in consumption of fats, fibre, and sugar in Britain. These changes matched recent recommendations made by the Committee on Medical Aspects of Food Policy (COMA) with the object of reducing the incidence of coronary heart disease (CHD). It is widely believed that CHD mortality fell during the war. This paper re-examines CHD mortality among middle-aged people in England and Wales from 1931 to 1967. After allowance for changes in the rules for coding cause of death, and for the sharp increase in all-causes mortality in 1940, there is little to suggest that time trends in CHD were much influenced by the war. Because of confounding variables, this does not argue against the COMA report. However, it gives no support to the view that compliance with the recommendations on fat, fibre, and sugar will lead, by itself, to an appreciable fall in CHD mortality in middle-aged people.

Coronary Disease↗
PubMed2000

An ethical paradox: the effect of unethical conduct on medical students' values.

OBJECTIVE: To report the ethical development of medical students across four years of education at one medical school. DESIGN AND SETTING: A questionnaire was distributed to all four classes at the Wake Forest University School of Medicine during the Spring of 1996. PARTICIPANTS: Three hundred and three students provided demographic information as well as information concerning their ethical development both as current medical students and future interns. MAIN MEASUREMENTS: Results were analyzed using cross-tabulations, correlations, and analysis of variance. RESULTS: Results suggested that the observation of and participation in unethical conduct may have disparaging effects on medical students' codes of ethics with 35% of the total sample (24% of first years rising to 55% of fourth years) stating that derogatory comments made by residents/attendings, either in the patient's presence or absence, were "sometimes" or "often" appropriate. However, approximately 70% of the sample contended that their personal code of ethics had not changed since beginning medical school and would not change as a resident. CONCLUSIONS: Results may represent an internal struggle that detracts from the medical school experience, both as a person and as a doctor. Our goal as educators is to alter the educational environment so that acceptance of such behaviour is not considered part of becoming a physician.

Adult↗
PubMed2004

Low-dose furosemide modulates taste responses in the nucleus of the solitary tract of the rat.

Taste-evoked neural responses in the nucleus of the solitary tract (NST) are subject to both excitatory and inhibitory modulation by physiological conditions that influence ingestion. Treatments that induce sodium appetite predominantly reduce NST gustatory responsiveness to sapid stimuli. When sodium appetite is aroused with 10 mg of the diuretic furosemide (Furo), however, NST gustatory neurons exhibit an enhanced responsiveness to NaCl. In addition to inducing a sodium appetite, 10 mg Furo supports a conditioned taste aversion (CTA). A lower, 2-mg dose of Furo induces an equivalent sodium appetite, but not a CTA. To determine whether the anomalous electrophysiological results reflected the adverse effects of the 10-mg dose, we replicated the original experiment but instead used 2 mg of Furo. In chronically prepared, lightly anesthetized rats, the responses of 49 single NST neurons to 12 taste stimuli were recorded after subcutaneous injections of either 2 mg Furo or saline. There was no effect of treatment on NST neural responses to the four standard taste stimuli. In the NaCl concentration series, however, 2 mg Furo evoked significantly higher responses to the two highest concentrations of NaCl. There was no effect of treatment in the sucrose concentration series. Thus, unlike other methods that induce a sodium appetite, Furo increases NST neural responsiveness to NaCl. At least as far as the first central relay, sodium appetite apparently does not depend on specific changes in the sensory neural code for taste.

Animals↗
PubMed1994

Spatiotemporal response properties of direction-selective neurons in the nucleus of the optic tract and dorsal terminal nucleus of the wallaby, Macropus eugenii.

1. The spatial and temporal response characteristics of direction-selective neurons in the nucleus of the optic tract and dorsal terminal nucleus of the accessory optic system (NOT-DTN) of the wallaby were established using moving sinusoidal gratings. This is the first comprehensive investigation of the spatiotemporal response characteristics of NOT-DTN neurons in any species. 2. The analysis revealed two main classes of cells. The first class, referred to as slow neurons, are maximally sensitive to motion at low temporal frequencies (< 1 Hz) and high spatial frequencies (0.5-1.0 cpd). The second class, referred to as fast neurons, are most sensitive to motion at high temporal frequencies (> 10 Hz) and moderate to low spatial frequencies (0.1-0.5 cpd). The fast neurons also have a domain of high sensitivity at low temporal frequencies and high spatial frequencies. As the neurons are tuned to specific temporal frequencies of motion, rather than image velocities, it is suggested that the motion detectors are of the delay-and-compare type and code local motion-related changes in contrast or luminance. 3. Both classes of neuron are highly direction-selective in the midranges of their spatiotemporal tuning curves, i.e., the firing rates increase during motion in the preferred direction (temporonasal movement through the visual field of the contralateral eye) and decrease during motion in the opposite direction. At high temporal and low spatial frequencies, however, the slow neurons are inhibited by motion in both directions along their preferred axis. It is argued that this bidirectional inhibition at high speeds may act to inhibit ocular following during saccades and may act as a gain control mechanism preventing excessive overshoot in eye velocity at motion onset, when retinal-slip velocities are high. 4. The fast neurons probably have two functions. First, they are suited to initiating ocular following responses when image motion is quite fast. Second, their spatiotemporal tuning makes them candidates for supplying a velocity error signal into the velocity storage mechanism, which is most prominent at high stimulus speeds. 5. Fourier analysis of the peristimulus time histograms derived from the response of both the slow and fast neurons revealed that the main frequency components of the responses occurred at the fundamental and second harmonic frequencies of the input signal at low stimulus temporal frequencies (< 3.04 Hz). At higher stimulus frequencies, the responses contained significant frequency components at higher odd-harmonics of the input signal.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1999

Synchronization of local neural networks in the somatosensory cortex: A comparison of stationary and moving stimuli.

Spontaneous and stimulus-induced responses were recorded from neighboring groups of neurons by an array of electrodes in the primary (SI) somatosensory cortex of intact, halothane-anesthetized cats. Cross-correlation analysis was used to characterize the coordination of spontaneous activity and the responses to peripheral stimulation with moving or stationary air jets. Although synchronization was detected in only 10% (88 of 880) of the pairs of single neurons that were recorded, cross-correlation analysis of multiunit responses revealed significant levels of synchronization in 64% of the 123 recorded electrode pairs. Compared with spontaneous activity, both stationary and moving air jets caused substantial increases in the rate, proportion, and temporal precision of synchronized activity in local regions of SI cortex. Among populations of neurons that were synchronized by both types of air-jet stimulation, the mean rate of synchronized activity was significantly higher during moving air-jet stimulation than during stationary air-jet stimulation. Moving air jets also produced significantly higher correlation coefficients than stationary air jets in the raw cross-correlograms (CCGs) but not in the shift-corrected CCGs. The incidence and rate of stimulus-induced synchronization varied with the distance separating the recording sites. For sites separated by </=300 microm, 80% of the multiunit responses displayed significant levels of synchronization during both types of air-jet stimulation. For sites separated by >/=500 microm, only 37% of the multiunit responses were synchronized by discrete stimulation with a single air jet. Measurements of the multiunit CCG peak half-widths showed that the correlated activity produced by moving air jets had slightly less temporal variability than that produced by stationary air jets. These results indicate that moving stimuli produce greater levels of synchronization than stationary stimuli among local groups of SI neurons and suggest that neuronal synchronization may supplement the changes in firing rate which code intensity and other attributes of a cutaneous stimulus.

Animals↗
PubMed2001

Membrane properties of principal neurons of the lateral superior olive.

In the lateral superior olive (LSO) the firing rate of principal neurons is a linear function of inter-aural sound intensity difference (IID). The linearity and regularity of the "chopper response" of these neurons have been interpreted as a result of an integration of excitatory ipsilateral and inhibitory contralateral inputs by passive soma-dendritic cable properties. To account for temporal properties of this output, we searched for active time- and voltage-dependent nonlinearities in whole cell recordings from a slice preparation of the rat LSO. We found nonlinear current-voltage relations that varied with the membrane holding potential. Repetitive regular firing, supported by voltage oscillations, was evoked by current pulses injected from holding potentials near rest, but the response was reduced to an onset spike of fixed short latency when the pulse was injected from de- or hyperpolarized holding potentials. The onset spike was triggered by a depolarizing transient potential that was supported by T-type Ca(2+)-, subthreshold Na(+)-, and hyperpolarization-activated (I(H)) conductances sensitive, respectively, to blockade with Ni2+, tetrodotoxin (TTX), and Cs+. In the hyperpolarized voltage range, the I(H), was largely masked by an inwardly rectifying K+ conductance (I(KIR)) sensitive to blockade with 200 microM Ba2+. In the depolarized range, a variety of K+ conductances, including A-currents sensitive to blockade with 4-aminopyridine (4-AP) and additional tetraethylammonium (TEA)-sensitive currents, terminated the transient potential and firing of action potentials, supporting a strong spike-rate adaptation. The "chopper response," a hallmark of LSO principal neuron firing, may depend on the voltage- and time-dependent nonlinearities. These active membrane properties endow the LSO principal neurons with an adaptability that may maintain a stable code for sound direction under changing conditions, for example after partial cochlear hearing loss.

4-Aminopyridine↗
PubMed1988

A linear model for symmetric receptive fields: implications for classification tests with flashed and moving images.

The purpose of this study was to explore the effects of spatial and temporal properties on the expected responses of visual neurons that have linear receptive fields (RFs), particularly those having a mirror symmetric distribution of spatial subregions. Receptive fields that are symmetric in at least one spatial dimension occur in neurons of the retina, the lateral geniculate nucleus (LGN), and the visual cortex of mammals. Responses to flashing bars, moving bars, and moving edges were studied for different configurations of an analog RF model in which spatial and temporal aspects were varied independently. Responses of the model at intermediate stimulus speeds were found to agree with responses in the literature for X and Y units of the LGN and often for simple units of the visual cortex. In particular, having separated regions of response to light and dark edges, an identifying property of simple cells, was found to be a linear consequence of RF regions responding inversely to stimuli of opposite polarity. Model differences from responses of cortical complex units show that a linear model cannot mimic their responses, and imply that complex units employ major nonlinearities in coding image polarity (light vs dark), which signifies a nonlinearity in coding intensity. Because sudden flux changes inherent in flashing bars test mainly temporal RF properties, and slowly moving edges test mainly spatial properties, these two tests form a useful minimal set with which to describe and classify RFs. The usefulness of this set derives both from its sensitivity to spatial and temporal variables, and from the correlation between the linearity of a cell's processing of stimulus intensity and its RF classification.

Mathematics↗
PubMed2004

Base-By-Base: single nucleotide-level analysis of whole viral genome alignments.

BACKGROUND: With ever increasing numbers of closely related virus genomes being sequenced, it has become desirable to be able to compare two genomes at a level more detailed than gene content because two strains of an organism may share the same set of predicted genes but still differ in their pathogenicity profiles. For example, detailed comparison of multiple isolates of the smallpox virus genome (each approximately 200 kb, with 200 genes) is not feasible without new bioinformatics tools. RESULTS: A software package, Base-By-Base, has been developed that provides visualization tools to enable researchers to 1) rapidly identify and correct alignment errors in large, multiple genome alignments; and 2) generate tabular and graphical output of differences between the genomes at the nucleotide level. Base-By-Base uses detailed annotation information about the aligned genomes and can list each predicted gene with nucleotide differences, display whether variations occur within promoter regions or coding regions and whether these changes result in amino acid substitutions. Base-By-Base can connect to our mySQL database (Virus Orthologous Clusters; VOCs) to retrieve detailed annotation information about the aligned genomes or use information from text files. CONCLUSION: Base-By-Base enables users to quickly and easily compare large viral genomes; it highlights small differences that may be responsible for important phenotypic differences such as virulence. It is available via the Internet using Java Web Start and runs on Macintosh, PC and Linux operating systems with the Java 1.4 virtual machine.

Base Composition↗
PubMed1998

High prevalence of T354P sodium/iodide symporter gene mutation in Japanese patients with iodide transport defect who have heterogeneous clinical pictures.

A missense and loss of function mutation of the Na+/I- symporter (NIS) gene, T354P [Thr354-->Pro (ACA-->CCA)], was found in the homozygous state in two unrelated Japanese patients with iodide transport defect. In this study we have identified the homozygous T354P NIS germline mutation in seven Japanese patients, including one previously reported, from five unrelated families. No other nucleotide changes were found in the coding regions and the exon-intron boundaries of the NIS gene in these seven patients. These results suggest a common prevalence of the T354P mutation in Japanese patients. Although these seven patients have the identical NIS mutation, T354P, marked heterogeneity in clinical pictures, especially concerning goiter and hypothyroidism, were noted among them. Therefore, another factor(s), but not the nature of the NIS mutation, may account for the clinical heterogeneity among patients with the iodide transport defect. We have previously reported that the NIS messenger ribonucleic acid was markedly increased in the thyroid of a patient with the homozygous T354P mutation. In this study we demonstrated that the NIS proteins in the patients' thyroids were significantly increased (approximately 10-fold) by Western blot analysis of integral membrane proteins using an antibody against the C-terminal peptide of the human NIS. Furthermore, we showed by immunohistochemical staining that the T354P mutant NIS proteins were overexpressed in the basal and lateral plasma membranes of patients' thyrocytes.

Adult↗
PubMed1998

Hemoglobins from bacteria to man: evolution of different patterns of gene expression.

The discovery of hemoglobins in virtually all kingdoms of organisms has shown (1) that the ancestral gene for hemoglobin is ancient, and (2) that hemoglobins can serve additional functions besides transport of oxygen between tissues, ranging from intracellular oxygen transport to catalysis of redox reactions. These different functions of the hemoglobins illustrate the acquisition of new roles by a pre-existing structural gene, which requires changes not only in the coding regions but also in the regulatory elements of the genes. The evolution of different regulated functions within an ancient gene family allows an examination of the types of biosequence data that are informative for various types of issues. Alignment of amino acid sequences is informative for the phylogenetic relationships among the hemoglobins in bacteria, fungi, protists, plants and animals. Although many of these diverse hemoglobins are induced by low oxygen concentrations, to date none of the molecular mechanisms for their hypoxic induction shows common regulatory proteins; hence, a search for matches in non-coding DNA sequences would not be expected to be fruitful. Indeed, alignments of non-coding DNA sequences do not reveal significant matches even between mammalian alpha- and beta-globin gene clusters, which diverged approximately 450 million years ago and are still expressed in a coordinated and balanced manner. They are in very different genomic contexts that show pronounced differences in regulatory mechanisms. The alpha-globin gene is in constitutively active chromatin and is encompassed by a CpG island, which is a dominant determinant of its regulation, whereas the beta-globin gene is in A+T-rich genomic DNA. Non-coding sequence matches are not seen between avian and mammalian beta-globin gene clusters, which diverged approximately 250 million years ago, despite the fact that regulation of both gene clusters requires tissue-specific activation of a chromatin domain regulated by a locus control region. The cis-regulatory sequences needed for domain opening and enhancement do show common binding sites for transcription factors. In contrast, alignments of non-coding sequences from species representing multiple eutherian mammalian orders, some of which diverged as long as 135 million years ago, are reliable predictors of novel cis-regulatory elements, both proximal and distal to the genes. Examples include a potential target for the hematopoietic transcription factor TAL1.

Amino Acid Sequence↗
PubMed1988

Contraction-induced potentiation of human motor unit discharge and surface EMG activity.

In quadrupeds, an electrically induced, moderate to high intensity brief muscle contraction potentiates autogenetic excitation and leads to enhanced recruitment and/or tonic firing frequency of alpha-motor neurons. To determine if similar adaptations occur in humans, single motor units (SMUs) and surface electromyographic activity (EMG) were recorded from the right biceps brachii before and immediately after a 5-s 25% or 50% maximum voluntary contraction (MVC), while subjects held a handle (0-1% MVC) attached to a force transducer or maintained a 2% MVC for 30-60 s. Of 26 SMUs recorded, 15 increased, 4 decreased, and 7 showed no change in firing frequency (mean increase: 5 imp/s, P less than 0.01). Twelve SMUs had lower recruitment force thresholds after contraction. There was no significant treatment effect for the % MVC intensity. The postcontraction surface EMG power spectrum broadened, increased in amplitude, and contained a higher frequency component than the control contraction power spectrum. Changes in recruitment and/or frequency coding were reflected in the raw EMG records. Findings agree with previous reports in animals of contraction-induced potentiation of subsequent submaximal muscle contractions. Such acute adaptations in spinal neuromuscular pathways would function to optimize force output to a submaximal range of neural input frequencies.

Electromyography↗
PubMed2006

Functional analysis of an endo-1,6-beta-D-glucanase gene (neg-1) from Neurospora crassa.

The 1,6-beta-D-glucanase gene (neg1) of Neurospora crassa was disrupted by repeat-induced point mutations. Sequence analysis of the neg1 gene in the R12-1 mutant showed that 9 nucleotides within the coding region of the gene changed from GC to AT. The base transition of C to A at position 662 resulted in a codon. No apparent phenotypic changes were observed in the mutant, but Congo-red, SDS, and cetyltrimethyl ammonium bromide (CTAB), which affect fungal cell walls or membranes, markedly inhibited the hyphal growth of the mutant at a concentration that does not inhibit growth in the wild type.

Amino Acid Sequence↗
PubMed2005

Rapid and repeatable elimination of a parental genome-specific DNA repeat (pGc1R-1a) in newly synthesized wheat allopolyploids.

Recent work in the Triticum-Aegilops complex demonstrates that allopolyploidization is associated with an array of changes in low-copy coding and noncoding sequences. Nevertheless, the behavior and fate of repetitive DNA elements that constitute the bulk of nuclear DNA of these plant species is less clear following allopolyploidy. To gain further insight into the genomic events that accompany allopolyploid formation, we investigated fluorescence in situ hybridization (FISH) patterns of a parental-specific, tandem DNA repeat (pGc1R-1) on three sets of newly synthesized amphiploids with different parental species. It was found that drastic physical elimination of pGc1R-1 copies occurred in all three amphiploids in early generations. DNA gel-blot analysis confirmed the FISH data and estimates indicated that approximately 70-90% of the copies of the pGc1R-1 repeat family were eliminated from the amphiploids by the second to third selfed generations. Thus, allopolyploidy in Triticum-Aegilops can be accompanied by rapid and extensive elimination of parental-specific repetitive DNA sequences, which presumably play a role in the initial stabilization of the nascent amphiploid plants.

Electrophoresis↗
PubMed2000

Sodium butyrate/retinoic acid costimulation induces apoptosis-independent growth arrest and cell differentiation in normal and ras-transformed seminal vesicle epithelial cells unresponsive to retinoic acid.

Retinoic acid (RA) and sodium butyrate (NaB) are regulators of cell growth and differentiation. We studied their effect on normal (SVC1) or v-Ki-ras-transformed (Ki-SVC1) rat seminal vesicle (SV) epithelial cell lines. The treatment of these cells with 10(-((7( M RA did not produce significant changes in the morphological and biochemical parameters analyzed. When RA was used in combination with 2 mM NaB, the treatment induced substantial morphological changes, apoptosis-independent growth arrest, up-regulation of tissue transglutaminase (tTGase), and down-regulation of beta and gamma RA receptor (RAR) mRNA expression. The same cells did not express RAR alpha either before or after NaB/RA treatment. A similar treatment did not change the amount of mRNA coding for the protein SV-IV (a typical differentiation marker of the SV epithelium) in normal or ras-transformed cells nor the level of v-Ki-ras mRNA in Ki-SVC1 cells. These findings suggest that a defective RA/RARs signaling pathway is probably the biochemical condition that underlies the unresponsiveness to RA of our in vitro culture system, and indirectly points to the possibility that the NaB/RA-induced effects were brought about by a cooperation at the transcription level between the histone deacetylase inhibitory activity of NaB and the ability of RA/RAR to modulate the expression of various genes involved in the control of cell growth and differentiation.

Animals↗