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At least 937 records · Page 52Linked to original sources
PubMed2006

Cooperative sequence modules determine replication initiation sites at the human beta-globin locus.

The human beta globin locus contains two adjacent replicators, each capable of initiating DNA replication when transferred from its native locus to ectopic sites. Here, we report a detailed analysis of the sequence requirements for replication initiation from these replicators. In both replicators, initiation required a combination of an asymmetric purine:pyrimidine sequence and several AT-rich stretches. Modules from the two replicators could combine to initiate replication. AT-rich sequences were essential for replicator activity: a low frequency of initiation was observed in DNA fragments that included a short stretch of AT-rich sequences, whereas inclusion of additional AT-rich stretches increased initiation efficiency. By contrast, replication initiated at a low level without the asymmetric purine:pyrimidine modules but they were required in synergy to achieve efficient initiation. These data support a combinatorial model for replicator activity and suggest that the initiation of DNA replication requires interaction between at least two distinct sequence modules.

Base Sequence↗
PubMed2006

Different post-Pleistocene histories of Eurasian parids.

Previous phylogeographic studies of the great tit (Parus major) and the willow tit (Parus montanus) found a general absence of phylogeographic structure for both species and suggested that each species underwent range contraction during the last Ice Age and survived in relatively low numbers, P. major in southern Europe and P. montanus in southeastern Asia. However, prior studies did not sample the entire range of either species. We analyzed sequence data for the complete mitochondrial ND2 gene from 87 P. major and 139 P. montanus from 15 new Eurasian localities, both to test prior conclusions and to provide better coverage of each species' range. Our analyses confirmed the absence of phylogeographic structure in P. major and P. montanus and supported the prior refuge hypothesis for P. major. For P. montanus, we concluded that besides surviving the Ice Age in southeastern Asia, as previously hypothesized, it apparently sustained a relatively large population in northern Eurasian riverine thickets and then expanded eastward. Genetic diversity was low in P. major (pi = 0.0012, h = 0.64) and moderate in P. montanus (pi = 0.0021, h = 0.88), suggesting higher long-term effective population sizes and the older ages of populations in P. montanus. If molecular substitution rates are similar, P. montanus colonized its current Eurasian range earlier than P. major. Differences between prior studies and ours likely result from sampling gaps in earlier studies.

Animals↗
PubMed2006

Transcriptional organization, regulation and role of the Porphyromonas gingivalis W83 hmu haemin-uptake locus.

Porphyromonas gingivalis, an oral bacterium associated with periodontal disease, requires haemin for growth. Although several multigenic clusters encoding haemin-uptake systems are present on the genome of P. gingivalis, little is known regarding their transcriptional organization and expression. This study identified a 23 kDa iron-regulated haemin-binding protein encoded by a larger than previously reported variant of hmuY. It was shown that the hmu locus is larger than previously reported and is composed of six genes, hmuYRSTUV, encoding a novel hybrid haemin-uptake system. The locus has an operonic organization and the transcriptional start site is located 292 bp upstream of hmuY. The data indicate that the regulation of the operon is iron-dependent. Interestingly, differential regulation within the operon was demonstrated, resulting in excess of the hmuYR message encoding the outer-membrane proteins when compared to the full-length transcript. In addition, the hmuY transcript is more prevalent than the hmuR transcript. Secondary structure analysis of the hmuYRSTUV mRNA predicted the formation of several potential stem-loops in the 5' ends of hmuR- and hmuS-specific mRNAs, consistent with the differential regulation observed. Finally, it was demonstrated that haemin binding and uptake are elevated in iron-depleted conditions and are reduced 45 % and 70 %, respectively, in an hmu-deficient strain when compared to the parental strain, indicating that the hmu locus plays a major role in haemin acquisition in P. gingivalis. Since homologues of the hmu locus were also found in Bacteroides fragilis, Bacteroides thetaiotaomicron and Prevotella intermedia, these findings may have implications for a better understanding of haemin acquisition in those organisms as well.

Amino Acid Sequence↗
PubMed2006

HLA-DQB1 locus and gastric cancer in Helicobacter pylori infection.

BACKGROUND AND AIMS: It has been suggested that the incidence of digestive diseases associated with Helicobacter pylori is influenced by the strain diversity of H. pylori, factors involving the host or environment, and the duration of infection. The authors have previously reported that human leukocyte antigen (HLA)-DQB1*0401 plays an important role in the development of atrophic gastritis in H. pylori infected patients. The aim of the present study was to investigate the relationship between HLA-DQB1 genotype and cancer development. METHODS: HLA-DQB1 genotyping was performed by the PCR-RFLP method on 122 H. pylori-infected non-ulcer dyspepsia (NUD) patients, 53 gastric cancer patients and 28 uninfected controls. To reliably estimate the grade of atrophic gastritis, histological evaluation was performed. RESULTS: The allele frequency of DQB1*0401 was significantly higher in intestinal type cancer patients compared with age- and sex-matched H. pylori-infected NUD patients. There was no significant difference in the mean atrophic scores of the biopsy samples from the lesser curvature of the mid-corpus between these groups. CONCLUSIONS: HLA-DQB1*0401 is a useful marker for determining susceptibility to intestinal type gastric cancer.

Adenocarcinoma↗
PubMed2006

Locus of control predicts appraisals and cardiovascular reactivity to a novel active coping task.

These two studies investigated the influence of dispositional locus of control (LOC) on subjective and physiological responses to a novel laboratory stressor task. Across two studies, 64 healthy undergraduate students, ages 18-22, completed Levenson's (LOC) scales for internal, powerful others, and chance prior to performing a video-game task. Participants rated pretask and posttask stressfulness and coping ability (i.e., measures of primary and secondary appraisal). Cardiovascular measures (heart period, HP; preejection period, PEP; respiratory sinus arrhythmia, RSA; cardiac output, CO; systolic blood pressure, SBP; diastolic blood pressure, DBP & total peripheral resistance, TPR) were recorded during 4-minute baseline and 4-minute stressor task periods. The internal LOC factor predicted pretask reports of coping ability as well as posttask reports of stressfulness. In contrast, the powerful-others LOC factor predicted cardiac changes (HP, PEP, and RSA) during the task but not cardiac output or any other vascular change measure. These results underscore the importance of using the three subscales of the Levenson LOC to assess relationships between dispositional LOC and the response to stressors because self-reported appraisals of a task are predicted by a different component of dispositional LOC than are task-related cardiovascular functions.

Adaptation, Physiological↗
PubMed2003

The wbiA locus is required for the 2-O-acetylation of lipopolysaccharides expressed by Burkholderia pseudomallei and Burkholderia thailandensis.

Burkholderia pseudomallei and Burkholderia thailandensis express similar O-antigens (O-PS II) in which their 6-deoxy-alpha-L-talopyranosyl (L-6dTalp) residues are variably substituted with O-acetyl groups at the O-2 or O-4 positions. In previous studies we demonstrated that the protective monoclonal antibody, Pp-PS-W, reacted with O-PS II expressed by wild-type B. pseudomallei strains but not by a B. pseudomallei wbiA null mutant. In the present study we demonstrate that WbiA activity is required for the acetylation of the L-6dTalp residues at the O-2 position and that structural modification of O-PS II molecules at this site is critical for recognition by Pp-PS-W.

Acetylation↗
PubMed2001

Correction of sickle cell disease in transgenic mouse models by gene therapy.

Sickle cell disease (SCD) is caused by a single point mutation in the human betaA globin gene that results in the formation of an abnormal hemoglobin [HbS (alpha2betaS2)]. We designed a betaA globin gene variant that prevents HbS polymerization and introduced it into a lentiviral vector we optimized for transfer to hematopoietic stem cells and gene expression in the adult red blood cell lineage. Long-term expression (up to 10 months) was achieved, without preselection, in all transplanted mice with erythroid-specific accumulation of the antisickling protein in up to 52% of total hemoglobin and 99% of circulating red blood cells. In two mouse SCD models, Berkeley and SAD, inhibition of red blood cell dehydration and sickling was achieved with correction of hematological parameters, splenomegaly, and prevention of the characteristic urine concentration defect.

Anemia, Sickle Cell↗
PubMed1998

Going the distance: a current view of enhancer action.

In eukaryotes, transcription of genes by RNA polymerase II yields messenger RNA intermediates from which protein products are synthesized. Transcriptional enhancers are discrete DNA elements that contain specific sequence motifs with which DNA-binding proteins interact and transmit molecular signals to genes. Here, current models regarding the role of enhancers in the regulation of transcription by RNA polymerase II are presented.

Animals↗
PubMed2006

Tissue-specific chromatin modifications at a multigene locus generate asymmetric transcriptional interactions.

Random assortment within mammalian genomes juxtaposes genes with distinct expression profiles. This organization, along with the prevalence of long-range regulatory controls, generates a potential for aberrant transcriptional interactions. The human CD79b/GH locus contains six tightly linked genes with three mutually exclusive tissue specificities and interdigitated control elements. One consequence of this compact organization is that the pituitary cell-specific transcriptional events that activate hGH-N also trigger ectopic activation of CD79b. However, the B-cell-specific events that activate CD79b do not trigger reciprocal activation of hGH-N. Here we utilized DNase I hypersensitive site mapping, chromatin immunoprecipitation, and transgenic models to explore the basis for this asymmetric relationship. The results reveal tissue-specific patterns of chromatin structures and transcriptional controls at the CD79b/GH locus in B cells distinct from those in the pituitary gland and placenta. These three unique transcriptional environments suggest a set of corresponding gene expression pathways and transcriptional interactions that are likely to be found juxtaposed at multiple sites within the eukaryotic genome.

Animals↗
PubMed1993

Purification of the human NF-E2 complex: cDNA cloning of the hematopoietic cell-specific subunit and evidence for an associated partner.

The human globin locus control region-binding protein, NF-E2, was purified by DNA affinity chromatography. Its tissue-specific component, p45 NF-E2, was cloned by use of a low-stringency library screen with murine p45 NF-E2 cDNA (N. C. Andrews, H. Erdjument-Bromage, M. B. Davidson, P. Tempst, and S. H. Orkin, Nature [London] 362:722-728, 1993). The human p45 NF-E2 gene was localized to chromosome 12q13 by fluorescent in situ hybridization. Human p45 NF-E2 and murine p45 NF-E2 are highly homologous basic region-leucine zipper (bZIP) proteins with identical DNA-binding domains. Immunoprecipitation experiments demonstrated that p45 NF-E2 is associated in vivo with an 18-kDa protein (p18). Because bZIP proteins bind DNA as dimers, we infer that native NF-E2 must be a heterodimer of 45- and 18-kDa subunits. Although AP-1 and CREB copurified with NF-E2, no evidence was found for heterodimer formation between p45 NF-E2 and proteins other than p18. Thus, p18 appears to be the sole specific partner of p45 NF-E2 in erythroid cells. Cloning of human p45 NF-E2 should permit studies of the role of NF-E2 in globin gene regulation and erythroid differentiation.

Amino Acid Sequence↗
PubMed2001

Position effects are influenced by the orientation of a transgene with respect to flanking chromatin.

We have inserted two expression cassettes at tagged reference chromosomal sites by using recombinase-mediated cassette exchange in mammalian cells. The three sites of integration displayed either stable or silencing position effects that were dominant over the different enhancers present in the cassettes. These position effects were strongly dependent on the orientation of the construct within the locus, with one orientation being permissive for expression and the other being nonpermissive. Orientation-specific silencing, which was observed at two of the three site tested, was associated with hypermethylation but not with changes in chromatin structure, as judged by DNase I hypersensitivity assays. Using CRE recombinase, we were able to switch in vivo the orientation of the transgenes from the permissive to the nonpermissive orientation and vice versa. Switching from the permissive to the nonpermissive orientation led to silencing, but switching from the nonpermissive to the permissive orientation did not lead to reactivation of the transgene. Instead, transgene expression occurred dynamically by transcriptional oscillations, with 10 to 20% of the cells expressing at any given time. This result suggested that the cassette had been imprinted (epigenetically tagged) while it was in the nonpermissive orientation. Methylation analysis revealed that the methylation state of the inverted cassettes resembled that of silenced cassettes except that the enhancer had selectively lost some of its methylation. Sorting of the expressing and nonexpressing cell populations provided evidence that the transcriptional oscillations of the epigenetically tagged cassette are associated with changes in the methylation status of regulatory elements in the transgene. This suggests that transgene methylation is more dynamic than was previously assumed.

Animals↗
PubMed2005

Status of the p53, p16, RB1, and HER-2 genes and chromosomes 3, 7, 9, and 17 in advanced bladder cancer: correlation with adjacent mucosa and pathological parameters.

AIMS: To evaluate a panel of well known genetic alterations for frequency of changes in bladder cancer that could be considered genomic instability determinants or adjunctive prognostic predictors. METHODS: Fluorescence in situ hybridisation analysis was performed to evaluate chromosomes 3, 7, 9, and 17 and the 9p21 (p16), 17p13.1 (p53), 13q14 (RB1), and 17q11.2 (HER-2) chromosomal loci in 48 muscle invasive bladder cancer specimens and the adjacent normal mucosa. RESULTS: There were significant differences between the frequency of chromosome 7 monosomy/polysomy and 17 monosomy in the two groups (tumours and adjacent mucosa) (p = 0.004, p = 0.037, and p = 0.015, respectively). There were no differences in the frequency of gene deletions between tumours and the adjacent mucosa. 17q11.2 amplification was found in 14.5% of tumours examined, but not in the non-malignant epithelium. Chromosome 3, 7, and 17 monosomy and the RB1 heterozygous deletion were significantly associated with stage T3-4 (p = 0.03, p = 0.04, p = 0.04, and p = 0.03, respectively). CONCLUSIONS: These results demonstrate the importance of chromosomes 3, 7, and 17 and gene alterations in bladder cancer progression, highlighting their usefulness as prognostic markers. Larger studies with longterm follow up of these patients are needed to determine the validity and clinical relevance of these genetic findings, and molecular prognostic markers should be incorporated into phase II and III trials to define their roles in predicting clinical outcome.

Chromosomes, Human↗
PubMed2005

Understanding globin regulation in beta-thalassemia: it's as simple as alpha, beta, gamma, delta.

A vast excess of alpha-globin production and inadequate gamma-globin compensation lead to the development of severe anemia in human beta-thalassemia. Newly identified modifiers of alpha- and gamma-globin synthesis and insights into the mechanisms of globin regulation provide the tools for potential new approaches to treating this and other red blood cell disorders. In the study by Han and colleagues in this issue of the JCI, the activity of a heme-regulated protein, HRI, is shown to modulate the accumulation of excess alpha-globin chains in murine beta-thalassemia and to decrease the severity of the disease.

Animals↗
PubMed2005

Progress toward the genetic treatment of the beta-thalassemias.

The beta-thalassemias are congenital anemias that are caused by mutations that reduce or abolish expression of the beta-globin gene. They can be cured by allogeneic hematopoietic stem cell (HSC) transplantation, but this therapeutic option is not available to most patients. The transfer of a regulated beta-globin gene in autologous HSCs is a highly attractive alternative treatment. This strategy, which is simple in principle, raises major challenges in terms of controlling expression of the globin transgene, which ideally should be erythroid specific, differentiation- and stage-restricted, elevated, position independent, and sustained over time. Using lentiviral vectors, May et al. demonstrated in 2000 that an optimized combination of proximal and distal transcriptional control elements permits lineage-specific and elevated beta-globin expression, resulting in therapeutic hemoglobin production and correction of anemia in beta-thalassemic mice. Several groups have by now replicated and extended these findings to various mouse models of severe hemoglobinopathies, thus fueling enthusiasm for a potential treatment of beta-thalassemia based on globin gene transfer. Current investigation focuses on safety issues and the need for improved vector production methodologies. The safe implementation of stem cell-based gene therapy requires the prevention of the formation of replication-competent viral genomes and minimization of the risk of insertional oncogenesis. Importantly, globin vectors, in which transcriptional activity is highly restricted, have a lesser risk of activating oncogenes in hematopoietic progenitors than non-tissue-specific vectors, by virtue of their late-stage erythroid specificity. As such, they provide a general paradigm for improving vector safety in stem cell-based gene therapy.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Cladogenesis and loss of the marine life-history phase in freshwater galaxiid fishes (Osmeriformes: Galaxiidae).

Switches from migratory (diadromous) to nonmigratory (freshwater) life histories are known to have occurred repeatedly in some aquatic taxa. However, the significance of the loss of diadromy as an initiator for speciation remains poorly understood. The rivers of New Zealand's South Island house a species flock of recently derived nonmigratory galaxiid fishes known as the Galaxias vulgaris complex. Members of this complex are morphologically and genetically similar to the diadromous G. brevipinnis found in New Zealand and southeastern Australia. We hypothesised that South Island's G. vulgaris complex (at least 10 nonmigratory lineages) represents a number of independent radiations from a migratory G. brevipinnis stock, with repeated loss of diadromy. Sequence data were obtained for 31 ingroup samples (G. vulgaris complex and G. brevipinnis) plus four outgroup taxa. A well-resolved phylogeny based on 5039 base pairs of the mitochondrial genome suggests that diadromy has been lost on three separate occasions. Thus, speciation in these galaxiid fishes is partly an incidental phenomenon caused by switches from diadromous to nonmigratory strategies. However, much of the subsequent nonmigratory diversity is monophyletic, suggesting that drainage evolution (vicariance) has also played a major role in cladogenesis. Levels of sequence divergence among major ingroup lineages (1.6-12.7%) suggest that the radiation is considerably older relative to Northern Hemisphere (postglacial) complexes of salmonid, osmerid, and gasterosteid fishes. Sympatric taxa are not monophyletic, suggesting that their coexistence reflects secondary contact rather than sympatric speciation. The monophyly of New Zealand G. brevipinnis is well supported, but both mitochondrial DNA and nuclear sequences indicate that G. brevipinnis is paraphyletic on an intercontinental scale. The divergence (maximum 11.5%) between Tasmanian and New Zealand G. brevipinnis, although large, supports marine dispersal rather than vicariance as the principle biogeographic mechanism on an intercontinental scale.

Adenosine Triphosphatases↗