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At least 199 records · Page 11Linked to original sources
PubMed1994

Expression of NAD(P)H:quinone oxidoreductase and glutathione S-transferases alpha and pi in human renal cell carcinoma and in kidney cancer-derived cell lines.

NAD(P)H:quinone oxidoreductase (NQOR) and glutathione S-transferases (GST) are enzymes of interest in cell defence and drug resistance. Relative levels of NQOR mRNA in renal cell carcinomas were 28 +/- 24% (n = 21) of those in non-neoplastic tissue and the enzyme activity decreased from 41 +/- 39 to 18 +/- 27 mU/mg protein (n = 23). In three of the cases, there was no measurable NQOR enzyme activity at all, indicating a polymorphism in the population for this gene. Relative GST-alpha mRNA levels in the tumours were on average 6 +/- 6% (n = 22) of the control value, whereas for GST-pi mRNA smaller decreases as well as increases were found in the tumours as compared to control tissue, but, on average, the level remained unchanged. Overall GST activity measured with CDNB as a substrate was 152 +/- 157 mU/mg protein in tumour tissue and 342 +/- 177 mU/mg protein in non-neoplastic tissue (n = 23). In all kidney tumour-derived cell lines NQOR mRNA was strongly expressed and on a per protein basis NQOR activity was about 10-fold higher than in the kidney tumour samples. GST-pi but not GST-alpha mRNA was also present. Total GST enzyme activities in these cell lines were similar to those in kidney tumour samples. HepG2 cells exhibited expression of NQOR and GST-alpha; GST-pi was not detectable. NQOR activity in HepG2 was about four-fold higher than in kidney-derived cell lines. Thus, NQOR and GST-alpha are both down-regulated in renal carcinoma, but their expression diverges in carcinoma cell lines.

Aged↗
PubMed2006

The natural history of the WRKY-GCM1 zinc fingers and the relationship between transcription factors and transposons.

WRKY and GCM1 are metal chelating DNA-binding domains (DBD) which share a four stranded fold. Using sensitive sequence searches, we show that this WRKY-GCM1 fold is also shared by the FLYWCH Zn-finger domain and the DBDs of two classes of Mutator-like element (MULE) transposases. We present evidence that they share a stabilizing core, which suggests a possible origin from a BED finger-like intermediate that was in turn ultimately derived from a C2H2 Zn-finger domain. Through a systematic study of the phyletic pattern, we show that this WRKY-GCM1 superfamily is a widespread eukaryote-specific group of transcription factors (TFs). We identified several new members across diverse eukaryotic lineages, including potential TFs in animals, fungi and Entamoeba. By integrating sequence, structure, gene expression and transcriptional network data, we present evidence that at least two major global regulators belonging to this superfamily in Saccharomyces cerevisiae (Rcs1p and Aft2p) have evolved from transposons, and attained the status of transcription regulatory hubs in recent course of ascomycete yeast evolution. In plants, we show that the lineage-specific expansion of WRKY-GCM1 domain proteins acquired functional diversity mainly through expression divergence rather than by protein sequence divergence. We also use the WRKY-GCM1 superfamily as an example to illustrate the importance of transposons in the emergence of new TFs in different lineages.

Amino Acid Sequence↗
PubMed2001

Gene genealogies, cryptic species, and molecular evolution in the human pathogen Coccidioides immitis and relatives (Ascomycota, Onygenales).

Previous genealogical analyses of population structure in Coccidioides immitis revealed the presence of two cryptic and sexual species in this pathogenic fungus but did not clarify their origin and relationships with respect to other taxa. By combining the C. immitis data with those of two of its closest relatives, the free-living saprophytes Auxarthron zuffianum and Uncinocarpus reesii, we show that the C. immitis species complex is monophyletic, indicating a single origin of pathogenicity. Cryptic species also were found in both A. zuffianum and U. reesii, indicating that they can be found in both pathogenic and free-living fungi. Our study, together with a few others, indicates that the current list of known fungal species might be augmented by a factor of at least two. However, at least in the C. immitis, A. zuffianum, and U. reesii complexes, cryptic species represent subdivisions at the tips of deep monophyletic clades and thus well within the existing framework of generic classification. An analysis of silent and expressed divergence and polymorphism values between and within the taxa identified by genealogical concordance did not reveal faster evolution in C. immitis as a consequence of adaptation to the pathogenic habit, nor did it show positive Darwinian evolution in a region of a dioxygenase gene (tcrP gene coding for 4-HPPD) known to cause antigenic responses in humans. Instead, the data suggested relative stasis, indicative of purifying selection against mostly deleterious mutations. Two introns in the same gene fragment were considerably more divergent than exons and were unalignable between species complexes but had very low polymorphism within taxa.

4-Hydroxyphenylpyruvate Dioxygenase↗
PubMed2025

Interspecies Organoids Reveal Human-Specific Molecular Features of Dopaminergic Neuron Development and Vulnerability.

The disproportionate expansion of telencephalic structures during human evolution involved tradeoffs that imposed greater connectivity and metabolic demands on midbrain dopaminergic neurons. Despite the central role of dopaminergic neurons in human-enriched disorders, molecular specializations associated with human-specific features and vulnerabilities of the dopaminergic system remain unexplored. Here, we establish a phylogeny-in-a-dish approach to examine gene regulatory evolution by differentiating pools of human, chimpanzee, orangutan, and macaque pluripotent stem cells into ventral midbrain organoids capable of forming long-range projections, spontaneous activity, and dopamine release. We identify human-specific gene expression changes related to axonal transport of mitochondria and reactive oxygen species buffering and candidate cis- and trans-regulatory mechanisms underlying gene expression divergence. Our findings are consistent with a model of evolved neuroprotection in response to tradeoffs related to brain expansion and could contribute to the discovery of therapeutic targets and strategies for treating disorders involving the dopaminergic system.

Brain evolution↗
PubMed2004

Perceptions on the standardization of psychiatric work: development of a care pathway.

Policy development and practice for hospital care has shifted towards a more deterministic approach. Crucial within this development is the assumption that interventions can be standardized to fit within the confines of a practice framework. A system to deliver standardized approaches to care is a care pathway. A research study was carried out to determine how care could be standardized to fit within a care pathway for people diagnosed with schizophrenia. A range of interviews with the multidisciplinary team and observations of the working group process was the data collection technique. Analysis was driven by emergent themes across the data set. Clinicians expressed divergent views on the nature of standardized care for people with schizophrenia. Respondents also offered a deeper understanding of standardized care by arguing for a sense of flexibility to be built into care systems. Findings from this study have implications for the introduction of NICE core standards for people with schizophrenia. For example, clinicians may be so opposed to such structures as to work against them. By understanding different views on standardized care, it may ultimately support their introduction into practice.

Attitude of Health Personnel↗
PubMed1989

Regulation of enterobacterial cephalosporinase production: the role of a membrane-bound sensory transducer.

In clinical isolates of Enterobacter cloacae, resistance to the newer beta-lactam antibiotics often results from overproduction of a cephalosporinase encoded by the beta-lactam-inducible ampC gene. Regulation of ampC is controlled by the divergently expressed activator gene, ampR, and a second unlinked locus. In this presentation we show that although Escherichia coli has lost its ampR gene it has retained the second regulatory locus and that this comprises the bicistronic ampDE operon. Genetic and biochemical studies define the ampD gene as encoding a repressor for ampC transcription whereas the ampE gene product is a cytoplasmic membrane protein. Inactivation of the AmpD protein by mutation causes massive overproduction of cephalosporinase which, in E. cloacae, can terminate in therapeutic failure. In contrast, loss of AmpE results in a total block in induction, despite the presence of the activator, AmpR.

Amino Acid Sequence↗
PubMed1991

The cephamycin biosynthetic genes pcbAB, encoding a large multidomain peptide synthetase, and pcbC of Nocardia lactamdurans are clustered together in an organization different from the same genes in Acremonium chrysogenum and Penicillium chrysogenum.

A 34 kb fragment of the Nocardia lactamdurans DNA carrying the cluster of early cephamycin biosynthetic genes was cloned in lambda EMBL3 by hybridization with probes internal to the pcbAB and pcbC genes of Penicillium chrysogenum and Streptomyces griseus. The pcbAB and pcbC genes were found to be closely linked together in the genome of N. lactamdurans. The pcbAB gene of N. lactamdurans showed the same orientation as the pcbC gene, in contrast to the divergent expression of the genes in the pcbAB-pcbC cluster of P. chrysogenum and Acremonium chrysogenum. The pcbAB gene encodes a large (3649 amino acids) multidomain delta-(L-alpha-aminoadipyl)-L-cysteinyl-D-valine synthetase with a deduced Mr of 404,134. This enzyme contains three repeated domains and a consensus thioesterase active-site sequence. The pcbC gene encodes a protein of 328 amino acids with a deduced Mr of 37,469, which is similar to other isopenicillin N synthases except that it lacks one of two cysteine residues conserved in all other isopenicillin N synthases. The different organization of the pcbAB-pcbC gene cluster in N. lactamadurans and Streptomyces clavuligerus relative to P. chrysogenum and A. chrysogenum is intriguing in relation to the hypothesis of horizontal transference of these genes from actinomycetes to filamentous fungi by a single transfer event.

Acremonium↗
PubMed2000

Sharing obstetric care: barriers to integrated systems of care.

OBJECTIVES: To map the provision of shared obstetric care in Victoria, and investigate the views of care providers about the ways in which current practice could be improved. METHOD: All Victorian public hospitals with > or = 300 births per annum and a purposive sample of hospitals with < 300 births per annum were mailed a questionnaire seeking information about current practice. Interviews with key informants (n = 32) were conducted at four case study sites. RESULTS: The response rate to the hospital survey was 98% (42/43). Fourteen different models of shared care were identified. Two-thirds of hospitals with > or = 300 births per annum (16/28) had three or more different models of shared care. Six hospitals (15%) had written guidelines for all models of shared care offered; 13 (32%) had written guidelines covering some models. Practice varied considerably in relation to: exclusion criteria, recommended schedule of visits and use of patient-held records. There was little consensus about the content of visits and responsibility for covering particular aspects of care. Few hospitals (6/42) had written information for women about shared care. Care providers expressed divergent views regarding the question of where ultimate responsibility lies for individual patient care and for the overall management of shared care. CONCLUSIONS: Current funding arrangements provide strong incentives to expand enrollment in shared obstetric care. Expansion of shared care has occurred without the development of formal, consultative and agreed arrangements between providers, or adequate provision for monitoring, evaluation and review. The variety, complexity and fluidity of models of shared care and lack of agreed procedures contribute to difficulties experienced by both providers and women participating in shared care. IMPLICATIONS: Detailed evidence-based agreed guidelines developed in consultation with hospital and community providers, and provision of improved information to women about what to expect in shared care arrangements are urgently required.

Attitude of Health Personnel↗
PubMed1996

Multiple antibiotic resistance (mar) locus protects Escherichia coli from rapid cell killing by fluoroquinolones.

The multiple antibiotic resistance (mar) locus in Escherichia coli consists of two divergently expressed operons (marC and marRAB), both of which contribute to the Mar phenotype. Overexpression of the marRAB operon protected E. coli against rapid cell killing by fluoroquinolones. Inactivation of the operon in mar mutants restored a wild-type bactericidal susceptibility. Both operons of the locus were required for protection from the quinolone-mediated bactericidal activity in mar locus deletion mutants. The effect was lost at high concentrations of fluoroquinolones, unlike the case for the previously described genes hipA and hipQ. The inducible mar locus appears to specify a novel antibactericidal mechanism which may play a role in the emergence of fluoroquinolone-resistant clinical E. coli isolates.

Anti-Infective Agents↗
PubMed2001

Integration of matrix-assisted laser desorption ionization-time of flight mass spectrometry and molecular cloning for the identification and functional characterization of mobile ortho-halobenzoate oxygenase genes in Pseudomonas aeruginosa strain JB2.

Protein mass spectrometry and molecular cloning techniques were used to identify and characterize mobile o-halobenzoate oxygenase genes in Pseudomonas aeruginosa strain JB2 and Pseudomonas huttiensis strain D1. Proteins induced in strains JB2 and D1 by growth on 2-chlorobenzoate (2-CBa) were extracted from sodium dodecyl sulfate-polyacrylamide gel electrophoresis gels and analyzed by matrix-assisted laser desorption ionization-time of flight mass spectrometry. Two bands gave significant matches to OhbB and OhbA, which have been reported to be the alpha and beta subunits, respectively, of an ortho-1,2-halobenzoate dioxygenase of P. aeruginosa strain 142 (T. V. Tsoi, E. G. Plotnikova, J. R. Cole, W. F. Guerin, M. Bagdasarian, and J. M. Tiedje, Appl. Environ. Microbiol. 65:2151-2162, 1999). PCR and Southern hybridization experiments confirmed that ohbAB were present in strain JB2 and were transferred from strain JB2 to strain D1. While the sequences of ohbA from strains JB2, D1, and 142 were identical, the sequences of ohbB from strains JB2 and D1 were identical to each other but differed slightly from that of strain 142. PCR analyses and Southern hybridization analyses indicated that ohbAB were conserved in strains JB2 and D1 and in strain 142 but that the regions adjoining these genes were divergent. Expression of ohbAB in Escherichia coli resulted in conversion of o-chlorobenzoates to the corresponding (chloro)catechols with the following apparent affinity: 2-CBa approximately 2,5-dichlorobenzoate > 2,3,5-trichlorobenzoate > 2,4-dichlorobenzoate. The activity of OhbAB(JB2) appeared to differ from that reported for OhbAB(142) primarily in that a chlorine in the para position posed a greater impediment to catalysis with the former. Hybridization analysis of spontaneous 2-CBa(-) mutants of strains JB2 and D1 verified that ohbAB were lost along with the genes, suggesting that all of the genes may be contained in the same mobile element. Strains JB2 and 142 originated from California and Russia, respectively. Thus, ohbAB and/or the mobile element on which they are carried may have a global distribution.

Blotting, Southern↗
PubMed1996

Fis binding in the dnaA operon promoter region.

The region between the rpmH and dnaA genes contains five promoters that divergently express the ribosomal protein L34 and the proteins of the dnaA operon, including DnaA, the beta clamp of DNA polymerase III holoenzyme, and RecF. The DNA-binding protein Fis was shown by the band shift assay to bind near the rpmHp2 and dnaAp2 promoters and by DNase I footprinting to bind to a single site in the dnaAp2 promoter overlapping the -35 and spacer sequences. There were no observable differences in Fis affinity or the angle of bending induced by Fis between methylated and unmethylated DNA fragments containing the Fis binding site in the dnaAp2 promoter. Fis directly or indirectly represses the expression of DnaA protein and the beta clamp of DNA polymerase III. A fis null mutant containing a dnaA-lacZ in-frame fusion had twofold greater beta-galactosidase activity than a fis wild-type strain, and induced expression of Fis eliminated the increase in activity of the fusion protein. A two- to threefold increase in the levels of DnaA and beta clamp proteins was found in a fis null mutant by immunoblot gel analysis.

Bacterial Proteins↗
PubMed1996

The complex bet promoters of Escherichia coli: regulation by oxygen (ArcA), choline (BetI), and osmotic stress.

The bet regulon allows Escherichia coli to synthesize the osmoprotectant glycine betaine from choline. It comprises a regulatory gene, betI, and three structural genes: betT (choline porter), betA (choline dehydrogenase), and betB (betaine aldehyde dehydrogenase). The bet genes are regulated by oxygen, choline, and osmotic stress. Primer extension analysis identified two partially overlapping promoters which were responsible for the divergent expression of the betT and betIBA transcripts. The transcripts were initiated 61 bp apart. Regulation of the promoters was investigated by using cat (chloramphenicol acetyltransferase) and lacZ (beta-galactosidase) operon fusions. Mutation of betI on plasmid F'2 revealed that BetI is a repressor which regulates both promoters simultaneously in response to the inducer choline. Both promoters remained inducible by osmotic stress in a betI mutant background. On the basis of experiments with hns and hns rpoS mutants, we conclude that osmoregulation of the bet promoters was hns independent. The bet promoters were repressed by ArcA under anaerobic growth conditions. An 89-bp promoter fragment, as well as all larger fragments tested, which included both transcriptional start points, displayed osmotic induction and BetI-dependent choline regulation when linked with a cat reporter gene on plasmid pKK232-8. Flanking DNA, presumably on the betT side of the promoter region, appeared to be needed for ArcA-dependent regulation of both promoters.

Bacterial Outer Membrane Proteins↗
PubMed2003

Targeted disruption of the murine Bin1/Amphiphysin II gene does not disable endocytosis but results in embryonic cardiomyopathy with aberrant myofibril formation.

The mammalian Bin1/Amphiphysin II gene encodes an assortment of alternatively spliced adapter proteins that exhibit markedly divergent expression and subcellular localization profiles. Bin1 proteins have been implicated in a variety of different cellular processes, including endocytosis, actin cytoskeletal organization, transcription, and stress responses. To gain insight into the physiological functions of the Bin1 gene, we have disrupted it by homologous recombination in the mouse. Bin1 loss had no discernible impact on either endocytosis or phagocytosis in mouse embryo-derived fibroblasts and macrophages, respectively. Similarly, actin cytoskeletal organization, proliferation, and apoptosis in embryo fibroblasts were all unaffected by Bin1 loss. In vivo, however, Bin1 loss resulted in perinatal lethality. Bin1 has been reported to affect muscle cell differentiation and T-tubule formation. No striking histological abnormalities were evident in skeletal muscle of Bin1 null embryos, but severe ventricular cardiomyopathy was observed in these embryos. Ultrastructurally, myofibrils in ventricular cardiomyocytes of Bin1 null embryos were severely disorganized. These results define a developmentally critical role for the Bin1 gene in cardiac muscle development.

Actins↗
PubMed2005

Compound genetic ablation of nidogen 1 and 2 causes basement membrane defects and perinatal lethality in mice.

Nidogen 1 and 2 are basement membrane glycoproteins, and previous biochemical and functional studies indicate that they may play a crucial role in basement membrane assembly. While they show a divergent expression pattern in certain adult tissues, both have a similar distribution during development. Gene knockout studies in mice demonstrated that the loss of either isoform has no effect on basement membrane formation and organ development, suggesting complementary functions. Here, we show that this is indeed the case. Deficiency of both nidogens in mice resulted in perinatal lethality. Nidogen 1 and 2 do not appear to be crucial in establishing tissue architecture during organ development; instead, they are essential for late stages of lung development and for maintenance and/or integrity of cardiac tissue. These organ defects are not compatible with postnatal survival. Ultrastructural analysis suggests that the phenotypes directly result from basement membrane changes. However, despite the ubiquitous presence of nidogens in basement membranes, defects do not occur in all tissues or in all basement membranes, suggesting a varying spectrum of roles for nidogens in the basement membrane.

Animals↗
PubMed2002

Alternative splicing yields novel BMAL2 variants: tissue distribution and functional characterization.

The BMAL2 gene encodes a member of the basic helix-loop-helix PER-ARNT-SIM family of transcription factors, which control diverse physiological processes including circadian rhythms. We identified four novel human BMAL2 transcripts that differ by alternative splicing within their NH2-terminal regions. Divergent expression of these and previously reported transcripts was observed among human tissues. The functional consequences of alternative splicing for transcriptional activation by CLOCK:BMAL2 heterodimers were assessed using luciferase reporter gene constructs that contained one of three diurnally regulated promoters, namely, those of the mouse period1, mouse vasopressin, and human plasminogen activator inhibitor-1 genes. These studies revealed that alternative splicing generates BMAL2 isoforms possessing high, medium, low, or no transcriptional activity. Similar results were obtained with each promoter, suggesting that alternative splicing may influence the amplitudes of both central and peripheral oscillators. Indeed, alternative splicing of BMAL2 may provide tissues with a rheostat capable of regulating CLOCK:BMAL2 heterodimer function across a broad continuum of potential transcriptional activities to accommodate varied metabolic demands and physiological roles.

ARNTL Transcription Factors↗
PubMed1994

Diverse G protein and beta-adrenergic receptor mRNA expression in normal and failing porcine hearts.

Right atrial and left ventricular homogenates have similar protein composition and beta-adrenergic receptor (beta-AR) numbers, but the right atrium has > 58% less adenylyl cyclase activity than the left ventricle. Associated with distinctive patterns of adenylyl cyclase activities are differences in G protein regulation between the two chambers. Compared with the left ventricle, the right atrium has 74% less Gs alpha mRNA (P < 0.0001) and 83% less G alpha i-2 mRNA (P < 0.002). When hearts are rapidly paced to produce heart failure, the left ventricle shows significant reductions in mRNA expression for both Gs alpha and G alpha i-2. However, the right atrium shows increased Gs alpha and G alpha i-2 mRNA expression. Despite divergent mRNA expression, Gs alpha and G alpha i-2 protein expression is down-regulated in both chambers in heart failure. In contrast, both chambers have similar beta 1- and beta 2-adrenergic receptor mRNA contents, and there is a selective reduction of beta 1-adrenergic receptor protein and mRNA in response to heart failure. Thus G protein and beta-AR mRNA regulation is regionally diverse in the heart. Physiological and anatomic differences between the right atrium and the left ventricle may dictate distinct patterns of adrenergic signaling and adaptations to stress.

Adenylyl Cyclases↗
PubMed2005

Impaired flagellar regeneration due to uncoordinated expression of two divergent actin genes in Chlamydomonas.

Chlamydomonas has two actin genes: one encoding a conventional actin (90% amino acid identity with mammalian actin) and the other a highly divergent actin (NAP; 64% identity). The expression of the two genes is regulated in a mutually exclusive manner. Thus, ida5, a mutant that lacks the conventional actin (CrA) gene, expresses NAP abundantly, whereas wild-type cells express NAP only negligibly under normal conditions. To explore the physiological significance of the two actins, chimeric genes with the 5' upstream region of one gene replaced by that of the other were constructed and used to transform ida5. The transformant (TF5) with a chimeric clone comprising the 5'-untranslated region from the NAP gene and the CrA-encoding sequence recovered the dyneins missing in ida5 and showed almost normal motility. After deflagellation of this transformant, however, only about 30% of cells grew flagella, unlike wild-type cells, >80% of which displayed reflagellation. Transformant TF10, which contains the CrA upstream region and NAP coding region, underwent reflagellation normally, as did the parent strain, ida5. In TF5, the mRNA level of both CrA and NAP was increased greatly during reflagellation. In light of the recent finding that NAP mRNA is expressed transiently upon reflagellation in wild-type cells, the described results suggest that 1) the expression of NAP mRNA is indispensable for flagellation and 2) robust expression of CrA may inhibit proper flagellation by interfering with the function of NAP in the early stages of reflagellation.

Actins↗
PubMed1992

Regional cerebral perfusion in Landau-Kleffner syndrome and related childhood aphasias.

Assessment of cerebral perfusion may elucidate pathogenesis of Landau-Kleffner syndrome (LKS). We obtained 99mTc-HMPAO SPECT studies in five children with LKS and in three children with syndromes of verbal-auditory agnosia. In LKS, perfusion showed temporoparietal asymmetry (9.56% +/- 3.44%) (n = 4) or bilateral parietal abnormality (n = 1). SPECT in non-LKS patients was normal (n = 1), showed (n = 1) totihemispheral hypoperfusion accompanying structural abnormality or (n = 1) a pattern resembling but distinct from LKS. Seizures in LKS patients had never occurred (n = 1), were controlled satisfactorily (n = 2), or poorly (n = 2). Maximum EEG abnormality was left centrotemoral-occipital (n = 1), left frontocentral (n = 1), bitemporal/left central (n = 1), and left central/parasagittal (n = 1). Asymmetric temporoparietal perfusion appears characteristic of LKS, differing from findings in other childhood linguistic disturbances. This abnormality occurs across a spectrum of seizure expression, diverging from the distribution of EEG abnormalities. The SPECT abnormalities parallel PET-defined LKS metabolic abnormalities, and may indicate central pathogenetic features of the disorder.

Aphasia↗