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PubMed2006

A-to-I pre-mRNA editing of the serotonin 2C receptor: comparisons among inbred mouse strains.

The serotonin receptor 5HT2CR pre-mRNA is subject to adenosine deamination (RNA editing) at five residues located within a 15 nucleotide stretch of the coding region. Such changes of adenosine to inosine (A-to-I) can produce 32 mRNA variants, encoding 24 different protein isoforms, some of which vary in biochemical and pharmacological properties. Because serotonin mediates diverse neurological processes relevant to behavior and because inbred mouse strains vary in their responses to tests of learning and behavior, we have examined the A-to-I editing patterns of the 5HT2CR mRNA in whole brains from eight mouse strains. By sequencing approximately 100 clones from individual mice, we generated detailed information on levels of editing at each site and patterns of editing that identify a total of 28 mRNA and 20 protein isoforms. Significant differences between individuals from different strains were found in total editing frequency, in the proportion of transcripts with 1 and 4 edited sites, in editing frequency at the A, B, E and D sites, in amino acid frequencies at positions 157 and 161, and in subsets of major protein isoforms. Primer extension assays were used to show that individuals within strains (six C3H.B-+rd1 and four 129SvImrJ) displayed no significant differences in any feature. These findings suggest that genetic background contributes to subtle variation in 5HT2CR mRNA editing patterns which may have consequences for pharmacological treatments and behavioral testing.

Adenosine↗
PubMed2006

Mental health and the city: intra-urban mobility among individuals with schizophrenia.

Intra-urban residential mobility of a cohort with schizophrenia was compared to a matched cohort with no mental illness using population-based administrative data. The percentage of individuals with one or more changes in postal code in the three-year mobility study period was examined, along with measures of the movement between different intra-urban areas. The schizophrenia cohort was more likely to move than the matched cohort; however, this depends on their age, income level, and area of residence at baseline. Age, gender, marital status, income quintile, and use of physicians and hospitalizations were associated with mobility. Individuals in the schizophrenia cohort were significantly more likely to move from the suburb to the inner city, and significantly less likely to move from the inner city to the suburb than those with no mental illness. Implications of the findings and directions for future research are discussed, with particular attention paid to the utility of administrative data for further mental health research.

Adult↗
PubMed2004

Echo-enhanced duplex sonography of extracranial vertebral arteries.

We sought to investigate the potential benefit in examining extracranial vertebral arteries (ExVA) with an echo contrast agent. A total of 26 patients with insufficiently assessable ExVA underwent extracranial duplex sonography without and with an echo contrast medium. All examinations were recorded and analysed independently by two experienced sonographers. Interrater agreement was fair in assessment of B-mode quality, colour-coding, blooming artefacts, change of vmax, good to very good in all other rated categories. Using an echo contrast medium reduced overall inassessable ExVA by 48% and 36% according to the two raters, respectively. After contrast enhancement, diagnosis was clarified in ExVA formerly inassessable for hypoplasia in 60% vs. 56%, extracranial occlusion in 67% vs. 56% and resistance signal in 63% vs. 45%, respectively. Application of an echo contrast agent leads to clarification of ExVA sonographic diagnosis in approximately one third of poorly examinable patients (35% and 30%, respectively), and contributes in ruling out extracranial occlusion, hypoplasia and resistance signal.

Arterial Occlusive Diseases↗
PubMed2006

Impaired nuclear import of mammalian Dlx4 proteins as a consequence of rapid sequence divergence.

Dlx genes encode a developmentally important family of transcription factors with a variety of functions and sites of action during vertebrate embryogenesis. The murine Dlx4 gene is an enigmatic member of the family; little is known about the normal developmental function(s) of Dlx4. Here, we show that Dlx4 is expressed in the murine placenta and in a trophoblast cell line where the protein localizes to both the nucleus and cytoplasm. Despite the presence of several leucine/valine-rich motifs that match known nuclear export sequences, cytoplasmic Dlx4 is not due to CRM-1-mediated nuclear export. Rather, nuclear import of Dlx4 is compromised by specific residues that flank the nuclear localization signal. One of these residues represents a novel conserved feature of the Dlx4 protein in placental mammals, and the second represents novel variation within mouse Dlx4 isoforms. Comparison of orthologous protein sequences reveals a particularly high rate of non-synonymous change in the coding regions of mammalian Dlx4 genes. Since impaired nuclear localization is unlikely to enhance the function of a nuclear transcription factor, these data point to reduced selection pressure as the basis for the rapid divergence of the Dlx4 gene within the mammalian clade.

Active Transport, Cell Nucleus↗
PubMed1987

Air pollution and hospital admissions in Southern Ontario: the acid summer haze effect.

Air pollution data from 17 sampling stations between Windsor and Peterborough in Southern Ontario, for January, February, July, and August in 1974 and 1976 to 1983, have been analyzed. Each station reported O3, NO3, SO2, and the coefficient of haze (COH) every hour and aerosol sulfates for a 24-hr period every sixth day using glass-fiber filters. Data on mean daily temperature and relative humidity for the region were also recorded. It is shown that there are high correlations between different pollutants and between these and temperature in the summer. In the summer, sulfate levels were significantly correlated with relative humidity. In winter, the highest correlation was between COH and NO2. Over the 9-year period, SO2 levels in both winter and summer have fallen considerably; there have been no significant trends in O3, NO3, or COH data. Aerosol sulfates increased between 1976 and 1980 in both summer and winter and have since declined slightly. Hospital admission data for the 79 acute care hospitals serving the region, which contains about 5.9 million people, have been analyzed on a daily basis for the same months of the same years. Total admissions and total respiratory admissions have declined about 15% over the period, but asthma admissions appear to have risen. The asthma category of admissions is complicated by the effects of a change in ICD coding in 1979. It has been shown that significant correlations exist between O3, SO4, SO2, and temperature, on the one hand, and deviations from the mean respiratory admissions for that day of the week, for that season, for that year, on the other. These correlations exist if asthma is excluded from the diagnoses. In winter, asthma admissions are correlated with temperature only. A group of nonrespiratory conditions showed no correlations with air pollutants in winter or summer. Stepwise multiple regression analysis based on each year considered individually indicates that in summer SO4 and temperature account for about 5% of the variance in respiratory or asthma admissions. It is shown that the mean of the hourly ozone maxima has a high correlation with the maximal 8-hr average for ozone, and that using this index instead of the mean of the hourly maxima does not increase the correlation coefficient with respiratory disease. Another analysis has been performed by grouping the hospitals and sampling stations into nine separate regions.(ABSTRACT TRUNCATED AT 400 WORDS)

Air Pollutants, Occupational↗
PubMed2001

Yeast chromatin structure and regulation of GAL gene expression.

Yeast genomic DNA is covered by nucleosome cores spaced by short, discrete length linkers. The short linkers, reinforced by novel histone properties, create a number of unique and dynamic nucleosome structural features in vivo: permanent unpeeling of DNA from the ends of the core, an inability to bind even full 147 bp core DNA lengths, and facility to undergo a conformational transition that resembles the changes found in active chromatin. These features probably explain how yeast can maintain most of its genome in a transcribable state and avoid large-scale packaging away of inactive genes. The GAL genes provide a closely regulated system in which to study gene-specific chromatin structure. GAL structural genes are inactive without galactose but are highly transcribed in its presence; the expression patterns of the regulatory genes can account for many of the features of GAL structural gene control. In the inactive state, GAL genes demonstrate a characteristic promoter chromosomal organization; the major upstream activation sequence (UASG) elements lie in open, hypersensitive regions, whereas the TATA and transcription start sites are in nucleosomes. This organization helps implement gene regulation in this state and may benefit the organism. Induction of GAL expression triggers Gal4p-dependent upstream nucleosome disruption. Disruption is transient and can readily be reversed by a Gal80p-dependent nucleosome deposition process. Both are sensitive to the metabolic state of the cell. Induction triggers different kinds of nucleosome changes on the coding sequences, perhaps reflecting the differing roles of nucleosomes on coding versus promoter regions. GAL gene activation is a complex process involving multiple Gal4p activities, numerous positive and negative cofactors, and the histone tails. DNA bending and chromosomal architecture of the promoter regions may also play a role in GAL regulation. Regulator-mediated competition between nucleosomes and the TATA binding protein complex for the TATA region is probably a central aspect of GAL regulation and a focal point for the numerous factors and processes that contribute to it.

Chromatin↗
PubMed1998

Pathogenicity and immunogenicity of different isolates of Teladorsagia circumcincta.

The effects on liveweight gain and development of immunity were studied in lambs trickle infected for 8 weeks with either a benzimidazole-resistant isolate (Moredun ovine resistant isolate, MORI), a multiple benzimidazole + ivermectin-resistant isolate (Moredun caprine resistant isolate, MCRI) or an unselected susceptible isolate (Moredun ovine susceptible isolate, MOSI) of Teladorsagia circumcincta. Plasma pepsinogen concentrations of infected groups were significantly elevated compared to an uninfected control group (P < 0.001) by day 14. The liveweight gains varied markedly but there were no statistical differences between the infected and uninfected control groups at any point in time during the study. Lambs infected with the MORI had significantly lower faecal consistency scores than the other challenged groups on days 7 and 14 (P < 0.05) but from day 21 onwards, faecal consistencies were similar in all of the groups. There was a notable difference in the pre-patent periods of the different isolates with the MOSI producing positive faecal egg counts (FECs) by day 14 of the study. The FECs remained reasonably low once infections had reached patency and there were no further differences between the groups. Following administration of anthelmintic to remove residual worms from the trickle infection, no differences between the infected groups in terms of worm burden or mucosal mast cell numbers were evident as a consequence of a single challenge infection. The changes in genetic code associated with enhanced resistance against anthelmintics do not appear to have resulted in any fundamental alteration of the pathogenicity and immunogenicity of these three isolates of Teladorsagia.

Animals↗
PubMed2001

Nitric oxide in the afferent synaptic transmission of the axolotl vestibular system.

This study was performed using intracellular and multiunit extracellular recording techniques in order to characterize the role of nitric oxide in the afferent synaptic transmission of the vestibular system of the axolotl (Ambystoma tigrinum). Bath application of nitric oxide synthase inhibitors N(G)-nitro-L-arginine (0.01microM to 10microM) and N-nitro-L-arginine methyl ester hydrochloride (0.1microM to 1000microM) elicited a dose-dependent decrease in the basal discharge of the semicircular canal afferent fibers. N(G)-Nitro-L-arginine also diminished the response to mechanical stimuli. Moreover, N(G)-nitro-L-arginine (1microM) produced a hyperpolarization associated with a decrease in the spike discharge and diminished the frequency of the excitatory postsynaptic potentials on afferent fibers recorded intracellularly. Nitric oxide donors were also tested: (i) S-nitroso-N-acetyl-DL-penicillamine (0.1microM to 100microM) increased the basal discharge and the response to mechanical stimuli. At the maximum effective concentration (100microM) this drug affected neither the amplitude nor the frequency of the excitatory postsynaptic potentials. However, it slightly depolarized the afferent neurons and decreased their input resistance. (ii) 3-Morpholino-sydnonimine hydrochloride did not significantly affect the basal discharge or the mechanically evoked peak response of afferent neurons at any of the concentrations used (1microM to 1000microM). However, after 10min of perfusion in the bath, 1microM and 10microM 3-morpholino-sydnonimine hydrochloride significantly modified the baseline of the mechanically evoked response, producing an increase in the mean spike discharge of the afferent fibers. These results indicate that nitric oxide may have a facilitatory role on the basal discharge and on the response to mechanical stimuli of the vestibular afferent fibers. Thus, nitric oxide probably participates in the sensory coding and adaptative changes of vestibular input in normal and pathological conditions.

Action Potentials↗
PubMed2002

Genetic characterization of Drosophila Mi-2 ATPase.

Mammalian Mi-2, an auto-antigen for dermatomyositis, is known to be an adenosine triphosphate (ATP)-dependent nucleosome remodelling factor. The Drosophila homologue of Mi-2 (dMi-2) gene is located at 76D5-6 on the left arm of the third chromosome and is transcribed into two alternate transcripts (dMi-2a and dMi-2b). Both transcripts are present at high levels in the ovary and during the first 8 h of embryogenesis when detected by Northern blot analysis. The localization of protein was nuclear, which is consistent with its proposed function as a component of the chromatin remodelling complex. Several lines of recessive mutants including mutations in dMi-2 were isolated and classified into four different complementation groups. Four alleles of dMi-2 mutants were further characterized in molecular nature; dMi-2(BL1) was found to have a mutation in the ATP-binding motif of the ATPase domain, dMi-2(BL7) in the core histidine of the first plant homeodomain zinc finger and dMi-2(BL12) in a conserved serine in the chromodomain. On the other hand, dMi-2(BL3) did not have any change in the coding region. The expression pattern of dMi-2 and the embryonic lethal phenotypes of mutants indicate that dMi-2 is essential for embryonic development in Drosophila melanagaster.

Adenosine Triphosphatases↗
PubMed2001

Subcortical neural coding mechanisms for auditory temporal processing.

Biologically relevant sounds such as speech, animal vocalizations and music have distinguishing temporal features that are utilized for effective auditory perception. Common temporal features include sound envelope fluctuations, often modeled in the laboratory by amplitude modulation (AM), and starts and stops in ongoing sounds, which are frequently approximated by hearing researchers as gaps between two sounds or are investigated in forward masking experiments. The auditory system has evolved many neural processing mechanisms for encoding important temporal features of sound. Due to rapid progress made in the field of auditory neuroscience in the past three decades, it is not possible to review all progress in this field in a single article. The goal of the present report is to focus on single-unit mechanisms in the mammalian brainstem auditory system for encoding AM and gaps as illustrative examples of how the system encodes key temporal features of sound. This report, following a systems analysis approach, starts with findings in the auditory nerve and proceeds centrally through the cochlear nucleus, superior olivary complex and inferior colliculus. Some general principles can be seen when reviewing this entire field. For example, as one ascends the central auditory system, a neural encoding shift occurs. An emphasis on synchronous responses for temporal coding exists in the auditory periphery, and more reliance on rate coding occurs as one moves centrally. In addition, for AM, modulation transfer functions become more bandpass as the sound level of the signal is raised, but become more lowpass in shape as background noise is added. In many cases, AM coding can actually increase in the presence of background noise. For gap processing or forward masking, coding for gaps changes from a decrease in spike firing rate for neurons of the peripheral auditory system that have sustained response patterns, to an increase in firing rate for more central neurons with transient responses. Lastly, for gaps and forward masking, as one ascends the auditory system, some suppression effects become quite long (echo suppression), and in some stimulus configurations enhancement to a second sound can take place.

Animals↗
PubMed2001

The neural basis of perceptual learning.

Perceptual learning is a lifelong process. We begin by encoding information about the basic structure of the natural world and continue to assimilate information about specific patterns with which we become familiar. The specificity of the learning suggests that all areas of the cerebral cortex are plastic and can represent various aspects of learned information. The neural substrate of perceptual learning relates to the nature of the neural code itself, including changes in cortical maps, in the temporal characteristics of neuronal responses, and in modulation of contextual influences. Top-down control of these representations suggests that learning involves an interaction between multiple cortical areas.

Action Potentials↗
PubMed1998

Nickel subsulfide is genotoxic in vitro but shows no mutagenic potential in respiratory tract tissues of BigBlue rats and Muta Mouse mice in vivo after inhalation.

Carcinogenic nickel compounds are known to induce promutagenic DNA lesions such as DNA strand breaks and DNA adducts in cultured mammalian cells. In standard mutation assays, in contrast, they were found to be either inactive or weakly active. In our in vitro mutation studies in a lacI transgenic embryonic fibroblast cell line, nickel subsulfide (Ni3S2) increased mutation frequency up to 4. 5-fold. We subsequently applied the comet assay and transgenic rodent mutation assays to investigate the DNA damaging effect and mutagenic potential of nickel subsulfide in target cells of carcinogenesis. A 2-h in vitro treatment of freshly isolated mouse nasal mucosa and lung cells with nickel subsulfide clearly induced DNA fragmentation in a concentration dependent manner. The strong effect was not seen in the same cell types following inhalative treatment of mice and rats, leading only in the mouse nasal mucosa to high DNA damage. When the same inhalative treatment was applied to lacZ and lacI transgenic mice and rats, the spontaneous mutation frequency of these target genes in the respiratory tissues was not increased. These results support a recently proposed non-genotoxic model of nickel carcinogenesis, which acts through gene silencing via DNA methylation and chromatin condensation. This model may also explain our in vitro mutation data in the lacI transgenic cell line, in which nickel subsulfide increased mutation frequency, but in about one-third of the mutants, molecular analysis did not reveal any DNA sequence change in the coding region of the lacI gene despite of the phenotypic loss of its function.

Administration, Inhalation↗
PubMed1990

Do statistics lie? Suicide in Kildare--and in Ireland.

This study, reporting a ten-year investigation of suicide in Kildare, found that the suicide rate based on clinical assessment of coroner's records was very close to the Central Statistics Office (CSO) figure for Kildare and for Ireland as a whole for the same period. Dublin data for 1977-1981 confirmed these findings. Since in the 1960s similar clinical assessment concluded that CSO rates underestimated suicide by a factor of two or over, we believe that changes in CSO coding procedures whereby more deaths are now coded to suicide than was the case in the past have resulted in current CSO data reflecting accurately the rate of clinical suicide. There has been more than a three-fold increase in CSO suicide rates in Ireland between 1968 and 1987. Even allowing for improved CSO practices there still remains a considerable excess of suicide deaths which indicates a doubling of 'real' suicide in Ireland over these twenty years.

Cause of Death↗
PubMed1991

Directive interactions and early vocabulary development: the role of joint attentional focus.

Maternal directiveness, assessed by the mother's use of prescriptives, is correlated with slow vocabulary development. As prescriptives are most often used to redirect a child's attention to a different object or activity, it is hypothesized that attentional regulation underlies this negative relationship. In the present study, twelve mothers were videotaped interacting with their children aged 1;1, and 100 maternal utterances were coded for pragmatic intent. Prescriptives were coded as either changing (leading) or following the child's focus of attention. Only the frequency of mothers' follow-prescriptives correlated significantly with a productive vocabulary measure taken at 1;10. This correlation was high and positive, indicating that, given joint focus, directing a 13-month-old's behaviour can have beneficial effects on subsequent vocabulary development.

Attention↗
PubMed2000

Nonsense-mediated decay mutants do not affect programmed -1 frameshifting.

Sequences in certain mRNAs program the ribosome to undergo a noncanonical translation event, translational frameshifting, translational hopping, or termination readthrough. These sequences are termed recoding sites, because they cause the ribosome to change temporarily its coding rules. Cis and trans-acting factors sensitively modulate the efficiency of recoding events. In an attempt to quantitate the effect of these factors we have developed a dual-reporter vector using the lacZ and luc genes to directly measure recoding efficiency. We were able to confirm the effect of several factors that modulate frameshift or readthrough efficiency at a variety of sites. Surprisingly, we were not able to confirm that the complex of factors termed the surveillance complex regulates translational frameshifting. This complex regulates degradation of nonsense codon-containing mRNAs and we confirm that it also affects the efficiency of nonsense suppression. Our data suggest that the surveillance complex is not a general regulator of translational accuracy, but that its role is closely tied to the translational termination and initiation processes.

Amino Acid Sequence↗
PubMed1991

Cloning and expression of complementary DNAs for multiple members of the human cytochrome P450IIC subfamily.

The present study characterizes the profile of cDNAs from the human P450IIC subfamily in a library from one individual, and it describes three new members of this subfamily (IIC17, IIC18, and IIC19) isolated from two human cDNA libraries. cDNA libraries were constructed from two human livers which differed phenotypically in the hepatic content of P450 HLx (IIC8). The library from the phenotypically low HLx individual was screened by using a cDNA for rat liver P450IIC13 and an oligonucleotide probe for human IIC8. One clone, 245c, was isolated which clearly represents a new member of the human P450IIC subfamily (IIC17). This clone lacked the first 358 nucleotides at the N-terminus but was only 91% homologous in its nucleic acid sequence to IIC9 and 79% homologous to IIC8. Near-full-length clones for IIC9 were also isolated from this library, but no clones for IIC8 were found. Northern blots indicated that the mRNA for IIC8 was low or absent in this individual. A second cDNA library (from a liver phenotypically high in HLx) was then screened. Eighty-three essentially full-length (greater than 1.8 kb) clones belonging to the IIC subfamily were isolated from this library. These include full-length clones for two additional new members of the IIC subfamily. Clones 29c and 6b appear to be allelic variants (IIC18), differing by one nucleotide (one amino acid change) in the coding region. Clone 11a represents a full-length clone for a third new P450 (IIC19).(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1990

Structure of the rabbit cytochrome P450IIC3 gene, a constitutive member of the P450IIC subfamily.

Fragments of rabbit DNA have been cloned which encompass the gene for rabbit cytochrome P450IIC3. Cytochrome P450IIC3 is a constitutive member of the cytochrome P450IIC subfamily which contains both constitutive and phenobarbital-responsive genes. The cytochrome P450IIC3 gene spans at least 25 kbp and contains 8 introns which have 5'GT's and 3'AG's and are located in the same positions as in other family II genes. The 5' flanking region contains a consensus TATA site about 25 bp from the RNA initiation site which was mapped by the primer extension method. Other potential regulatory sequences include a CCAAT sequence and sequences similar to binding sites for the liver-specific factor HNF-1 and the general transcription factors AP-1 and OCT. The gene sequence differs from the cytochrome P450IIC3 cloned cDNA sequence in only 2 of 1400 nucleotides, 1 of which results in an amino acid change. Since sequences coding for exon 1 and part of exon 2 were not present in the cloned cytochrome P450IIC3 cDNA, a 475-nucleotide fragment of the 5' end of the cDNA was amplified by the polymerase chain reaction, cloned, and sequenced. The sequence of this cDNA was identical with the gene exon sequence. The protein sequence derived from the gene differs in nine positions from that determined directly for the protein. A comparison of the amino acid sequence by exons with other cytochrome P450IIC proteins revealed that, in general, the similarity was greater in C-terminal exons than in N-terminal ones.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1990

Organization of the human protein S genes.

Human genomic clones that span the entire protein S expressed gene (PS alpha) and the 3' two-thirds of the protein S pseudogene (PS beta) have been isolated and characterized. The PS alpha gene is greater than 80 kilobases in length and contains 14 introns and 15 exons, as well as 6 repetitive "Alu" sequences. Exons I and XV contain 112 and 1139 bp 5' and 3' noncoding segments in addition to the amino and carboxyl termini, respectively. Exons I-VIII encode protein segments that are homologous to the vitamin K dependent clotting proteins and are bounded by introns whose position and type are identical with other members of this protein family. Exons IX-XV encode protein segments homologous to sex hormone binding globulin (SHBG) and are bounded by introns of identical type and position as in the SHBG gene. Genomic clones for the PS beta gene cover a distance of greater than 55 kilobases and contain segments corresponding to amino acids 46-635 of the mature protein and the 1.1-kb 3' noncoding region of the cDNA. The presence of multiple base changes in the coding portions of this gene, resulting in termination codons and frame shifts, suggests that it is a pseudogene. Comparison of DNA sequences for the two genes reveals 97% identity for coding and 3' noncoding, and 95.4% for intronic regions, suggesting divergence of the two genes is a relatively recent event.

Amino Acid Sequence↗