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PubMed2006

[Sequence analysis of integration sites of reticuloendotheliosis virus LTR in fowlpox vaccine virus genomes].

By use of genomic DNA prepared from 5 fowlpox virus (FPV) vaccines made in China (from Shandong, Beijing, Liaoning, Zhejing and Shanghai respectively) as the templates, reticuloendotheliosis virus (REV) LTR was amplified in PCR with a pair of primers synthesized according to the sequences flanking the integrated REV-5'LTR in FPV genomes published in US and Australia. Sequence analysis indicated that the REV-5'LTR integration sites in genomes of all 5 Chinese PFV vaccine products were identical to American and Australian FPV vaccines with integrated REV-5' LTR. Among the 5 FPV vaccine products made in China, 3 productes Vac-B-Ch, Vac-D-Ch and Vac-E-Ch had the integrated REV-5' LTR sequences of 223bp with 100% homology to that in American vaccine Vac-3-Am and Australian vaccine Vac-M3-Au. The integrated 505bp REV-LTR sequences in another Chinese products Vac-A-Ch and Vac-C-Ch had 99.6% homology to the integrated REV-LTR of American vaccine Vac-1-Am and Australian vaccine Vac-S-Au. However, REV-5'LTR integrated in all 5 FPV vaccines made in China gave only 75.4%-91.5% homology to LTR of a Chinese field strain HA9901 of REV. Based on the above results, it is reasonable to speculate that the virus stocks for the 5 Chinese FPV vaccine products were rather originally imported with their integrated REV LTR than recombinated with LTR of REV local field strains in China.

China↗

PubMed1984

Some subjective and objective prerequisites to educational integration of handicapped children.

The success of educational integration of handicapped children is dependent upon, inter alia, the attitudes of social groups involved in the integration (subjective prerequisites) and from certain characteristics of the schools in which they are being integrated (objective prerequisites). In the latter case, an investigation was carried out on the attitudes of teachers at regular and special schools, of handicapped and non-handicapped school-children and the parents of both samples of children by means of the Lickert-type questionnaires, and the data processed by means of the multivariate analysis method. In the case of regular school teachers, an analysis was made also of the relationship between their concept of integration and their attitude towards the educational role of the school as an institution and towards their socioeconomic status. The objective prerequisites of integration were estimated by investigating in loco the conditions in regular schools, and through interviews with the responsible school staff. The factor analysis of the random samples investigated enabled factors to be extracted which, in respect to the integration, proved to be favorable to unfavorable. Some of these factors are of a general nature, in the sense that they refer to all the children, whereas other factors are specific, i. e. they refer to the type of disability. An examination of the objective prerequisites of integration produced findings which could lead to a suitable policy in preparing objective conditions for integration. The whole of this investigation was carried out within the framework of a research project of the Faculty of Defectology in Zagreb, lead by Prof. Dr. Franjo Tonković.

Adult↗

PubMed1982

Early infantile development as reflected in the psychoanalytical process: steps in integration.

The contention of this paper is that early infantile development is reflected in the infantile part of the transference. When it is well integrated it gives rise to an underlying non-verbal communication which gives a depth to other communications. When not integrated it gives rise to acting in as a primitive mode of communication. When this is understood the primitive experience can be integrated, symbolized and partly at least verbalized. The development of the infantile part can be followed in the fluctuating moves towards integration. Two examples are given. In one case I show how many analytical understanding leads to the integration of a split off primitive pre-verbal experience and the connexion of such integration with the development of speech. I also show how a failure of understanding on the analyst's part, repeating a developmental failure can affect this process adversely. In the second case I show integrative processes connected with weaning and the integration of the weaning process with genital sexuality.

Adult↗

PubMed1994

Primary and secondary care integration.

Integration of primary and secondary health care is a goal of the 1993 New Zealand health reforms. Focus groups were selected to raise options and stimulate improved integration between primary and secondary care in the Auckland metropolitan and rural areas. Cooperation, communication, coordination, were considered relevant. Several detailed recommendations were produced. They fell into six groups; (1) liaison committees or meetings, (2) communication, (3) referral admission discharge, (4) joint ventures, (5) horizontal integration and (6) general. A key recommendation was that regional health authorities should fund liaison committees or functions to promote inter provider integration. The findings of the focus groups are placed in context of the wider requirements for integration. These are integrated funding, integrated information systems, integrated purchasing and utilisation management.

Communication↗

PubMed1994

The essential role of integrative biomedical sciences in protecting and contributing to the health and well-being of our nation.

The biomedical sciences in the United States are currently experiencing the effects of an increased emphasis on in vitro models of biological and disease processes. Advances in cellular and subcellular biology have been a driving force in the funding of new research, the training of new scientists, and new drug discovery and development. The importance of new findings at the cellular and subcellular levels is not disputed. However, the corresponding decline in funding and training opportunities for biologically relevant investigations at the level of the intact animal (including humans; hereafter designated as integrative biology) is a serious threat to continued biomedical advances. The lack of resources for integrative biology has far-reaching negative consequences in 1) the development and utilization of whole animal models of disease and dysfunction; 2) assessing the relevancy of in vitro studies to physiological mechanisms; 3) the evaluation of the scientific merit of whole animal investigations and their relevancy to the nation's scientific imperatives; 4) the instruction of young scientists in the technology and especially in the methods of integrative biology, including how to develop appropriate experimental hypotheses; 5) the instruction of graduate, medical, dental, pharmacy, and nursing students in drug and disease processes in the intact human; and 6) the ability of the pharmaceutical manufacturers, the FDA, the EPA and academia to hire scientists who can develop drugs and evaluate the effects of exogenous agents on the intact animal. These negative consequences can be alleviated in a variety of ways. These include 1) increasing the availability of funding for research in integrative biology, 2) increasing the opportunities for training in integrative biology, and 3) instituting grant reviews of integrative biomedical research by peers in integrative biomedical sciences. These measures can revitalize integrative biomedical research, help ensure the continued advancement of biomedical understanding, and consequently contribute to the alleviation of human suffering.

Animals↗

PubMed1993

Characterization of the forward and reverse integration reactions of the Moloney murine leukemia virus integrase protein purified from Escherichia coli.

The forward and reverse reactions for integration were characterized for the Moloney murine leukemia virus integrase (M-MuLV IN) protein. The M-MuLV IN was recombinantly produced in Escherichia coli, and was purified to greater than 90% homogeneity by a one-step affinity purification scheme. M-MuLV IN was highly active for integration as measured by in vitro cleavage and strand transfer assays. Furthermore, the integration of a model viral substrate into lambda concatamers by IN correctly produced the flanking 4-base pair duplications characteristic of M-MuLV IN. The reverse reaction of integration, disintegration, was also catalyzed by the recombinant M-MuLV IN. Two products were generated, a 3'-recessed long terminal repeat and a ligated target DNA, from a model integration-intermediate substrate in the presence of M-MuLV IN. The requirements and optimal conditions for maximal integration and disintegration activity for M-MuLV IN were determined. The forward and reverse reactions required different concentrations of manganese ion and reductant. Salt was also titrated for the forward and reverse reactions. Sodium chloride inhibited integration, but had little affect on disintegration. Low concentrations of potassium chloride enhanced integration, but had no affect on disintegration. The dinucleotide cleavage, strand transfer, and the disintegration reactions each had a unique pH profile of activity.

Base Sequence↗

PubMed1998

Integral and shell-MIP display algorithms in MR and CT three-dimensional models of the brain surface.

BACKGROUND AND PURPOSE: Our purpose was to demonstrate the use of integral and shell maximum intensity projection (shell-MIP) display algorithms in the 3-D CT and MR depiction of cerebral gyral and surface venous anatomy and disorders. These new algorithms are compared against MIP and shaded-surface-display (SSD) algorithms. METHODS: Integral and shell-MIP displays were generated from a specified number of proximal surface voxel layers in a 3-D model. Algorithmic models were compared on nine contrast-enhanced spoiled gradient-recalled acquisition in a steady state (SPGR) MR venograms for brain surface anatomic identification and detail. Seven CT venograms were compared for conspicuity of filling defects. Twelve contrast-enhanced preoperative planning 3-D MR models were rated for neurosurgical utility. RESULTS: A shell-MIP score of 7.00 and an integral score of 6.78 represented the highest mean subjective MR gyral quality (1-10 scale) followed by an SSD score of 3.89 and an MIP score of 1.06. Mean confidence scores for MR central sulcus identification (1-10 scale) were shell-MIP, 7.67; integral, 7.00; SSD, 3.22; and MIP, 1.00. Mean superficial venous quality MR ratings (1-10 scale) were shell-MIP, 8.22; MIP, 7.39; integral, 7.00; and SSD, 3.72. The mean number of cortical veins draining into each side of the superior sagittal sinus on MR was as follows: MIP, 6.19; integral, 6.06; shell-MIP, 5.94; and SSD, 3.81. Mean confidence scores for filling defect identification on CT venograms (1-5 scale) revealed a shell-MIP score of 4.36 and an integral score of 4.29 to be superior to a MIP score of 3.00. In selected cases, 3-D presurgical planning, prior to tumor resection, was clinically useful. CONCLUSION: Integral and shell-MIP are useful 3-D display algorithms for simultaneous display of superficial cerebral veins and gyri on MR images and of thrombosis on CT venograms.

Algorithms↗

PubMed1995

In vitro integration of human immunodeficiency virus type 1 cDNA into targets containing protein-induced bends.

Integration of human immunodeficiency virus type 1 cDNA into a target DNA can be strongly influenced by the conformation of the target. For example, integration in vitro is sometimes favored in target DNAs containing sequence-directed bends or DNA distortions caused by bound proteins. We have analyzed the effect of DNA bending by studying integration into two well-characterized protein-DNA complexes: Escherichia coli integration host factor (IHF) protein bound to a phage IHF site, and the DNA binding domain of human lymphoid enhancer factor (LEF) bound to a LEF site. Both of these proteins have previously been reported to bend DNA by approximately 140 degrees. Binding of IHF greatly increases the efficiency of in vitro integration at hotspots within the IHF site. We analyzed a series of mutants in which the IHF site was modified at the most prominent hotspot. We found that each variant still displayed enhanced integration upon IHF binding. Evidently the local sequence is not critical for formation of an IHF hotspot. LEF binding did not create preferred sites for integration. The different effects of IHF and LEF binding can be rationalized in terms of the different proposed conformations of the two protein-DNA complexes.

Bacterial Proteins↗

PubMedDate not supplied

Assessing the extent of integration achieved through physician-hospital arrangements.

In this article we examine management service organizations (MSOs), physician-hospital organizations (PHOs), hospital-affiliated independent practice associations (IPAs), and hospital-sponsored "group practices without walls" (GPWWs) that allow physicians to retain their practices and link hospitals and health systems to physicians through contractual arrangements. Also examined were medical foundations (MFs), integrated salary models (ISMs), and integrated health organizations (IHOs) that own the physical assets of physician practices and contract with payors for physician and hospital services. The research provides several new insights for understanding the structure and process of physician-hospital integration. It was found that the extent of processual integration in physician-hospital organizational arrangements can be measured along six dimensions: administrative and practice management services; physician financial risk-sharing; joint ventures to create new services; computer linkages; physician involvement in strategic planning; and salaried physician arrangements. These dimensions are consistent with the conceptual and empirical dimensions developed by others. These findings refute the notion raised by some industry observers that the new physician-hospital organizational models simply formalize integrative activities already in place. Earlier studies from the 1980s reported that hospitals integrated physicians through involvement in governance, capital planning, and the provision of practice management services. In contrast, we found that current integration.

American Hospital Association↗

PubMed2000

Integration of prevention and care of sexually transmitted infections with family planning services: what is the evidence for public health benefits?

It has been widely believed that, by combining the services for preventing and treating sexually transmitted infections (STI) with those for family planning (FP), STI coverage would increase and the combined service would be of higher quality and more responsive to the needs of women. So far, there is little concrete evidence that integration has had such an impact. Besides the absence of documentation, a clear definition of integration is lacking. We therefore carried out a comprehensive review of concrete experiences with integrated services, and present a summary of our findings in this article. The results indicate that the tasks of STI prevention, such as education for risk reduction and counselling, have been integrated into family planning services much more frequently than the tasks of STI diagnosis and treatment. Some STI/FP integration efforts appear to have been beneficial, for instance when the integration of STI/HIV prevention had a positive impact on client satisfaction, and on the acceptance of family planning. Less clear is whether STI prevention, when concentrated among traditional FP clients, is having a positive impact on STI risk behaviours or condom use. A few projects have reported increases in STI caseloads following integration. In some projects, FP providers were trained in STI case management, but few clients were subsequently treated.

Delivery of Health Care, Integrated↗

PubMed1998

Recurrent integration of papillomavirus DNA within the human 12q14-15 uterine breakpoint region in genital carcinomas.

Genital carcinomas are associated with human papillomaviruses, and the viral DNA is frequently integrated in the host cell genome. Recurrent chromosomal alterations are genetic markers for specific tumor phenotypes. To demonstrate that papillomavirus DNA integration is indeed a recurrent chromosomal aberration, we mapped two independent papillomavirus integration sites in the human 12q14-15 region, one containing HPV16 DNA and the other HPV18 DNA. The two HPV integration sites map approximately 10 kbp from each other within the cosmid LLNL12NCO1-196E1 clone. The integration site corresponding to HPV16 DNA in SK-v cells is proximal to the 5' end of a DNA segment known to be rearranged by integration of HPV18 DNA in another cervical carcinoma cell line, SW756. Both integrations are located in the PAL2 locus within the uterine leiomyoma cluster region of translocation.

Base Sequence↗

PubMed1992

Epstein-Barr virus integration in human lymphomas and lymphoid cell lines.

BACKGROUND: Epstein-Barr virus (EBV) is maintained as an episome in most infected cells. The presence of fused terminal restriction enzyme fragments distinguishes the circular DNA form from the linear virion form. METHODS: EBV genomic structure was analyzed in 8 lymphoid cell lines and 21 human lymphoma specimens by the Southern blot technique. RESULTS: Evidence of viral integration into host chromosomal DNA was identified in four cell lines. In the Namalwa and BL30-B95.8 cell lines, integration occurred through the terminal repeat (TR) sequences. In the BL41-P3HR1 and BL41-B95.8 cell lines, there was loss of left-end viral genomic sequences, including ori-P sequences required for episome maintenance, implying that integration was required for viral genome persistence. Integration was not detected in four other cell lines (Raji, Daudi, B95.8, and BL30-P3HR1). In 21 EBV-containing human lymphomas, including 18 immunodeficiency-related lymphomas, fused TR sequences were identified without evidence of viral genomic integration. CONCLUSIONS: These findings suggest that, although viral integration is common in Burkitt lymphoma cell lines infected in vitro, integration is not common in human lymphomas that develop in vivo in normal or immunodeficient people.

Adolescent↗

PubMed1991

Targeted integration of adeno-associated virus (AAV) into human chromosome 19.

A key feature in adeno-associated virus (AAV) replication is efficient integration of the viral genome into host cell DNA to establish latency when helper virus is absent. The steps involved in this process remain largely uncharacterized, even though AAV integration was first documented 20 years ago. Using a protein--DNA binding method we isolated AAV--cellular junction DNA sequences. The cellular component hybridized to a single restriction fragment in the virus-free parental cell line, and also co-migrated with AAV-specific sequences in numerous latently infected cell lines. Analysis of somatic cell hybrids indicated that this cellular sequence maps to the distal portion of the q arm of human chromosome 19. In situ hybridization of AAV DNA to chromosomes from latently infected cells confirms the physical location of AAV integrations to be q13.4-ter of chromosome 19. Sequence analysis of several independent integration sites shows breakpoints occurring within a 100 bp cellular region. This non-pathogenic parvovirus thus appears to establish viral latency by integrating its DNA specifically into one chromosomal region. Such specific integration is so far unique among the eukaryotic DNA viruses. The incorporation of site-specific integration into AAV vector schemes should make this vector system attractive for human gene therapy approaches.

Base Sequence↗

PubMed1992

Retroviral integration into minichromosomes in vitro.

We describe here the use of chromatin as a target for retroviral integration in vitro. Extracts of cells newly infected with murine leukemia virus (MLV) provided the source of integration activity, and yeast TRP1ARS1 and SV40 minichromosomes served as simple models for chromatin. Both minichromosomes were used as targets for integration, with efficiencies comparable with that of naked DNA. In addition, under some reaction conditions the minichromosomes behaved as if they were used preferentially over naked DNAs in the same reaction. Mapping of integration sites by cloning and sequencing recombinants revealed that the integration machinery does not display a preference for nucleosome-free, nuclease-sensitive regions. The distributions of integration sites in TRP1ARS1 minichromosomes and a naked DNA counterpart were grossly similar, but in a detailed analysis the distribution in minichromosomes was found to be significantly more ordered: the sites displayed a periodic spacing of approximately 10 bp, many sites sustained multiple insertions and there was sequence bias at the target sites. These results are in accord with a model in which the integration machinery has preferential access to the exposed face of the nucleosomal DNA helix. The population of potential sites in chromatin therefore becomes more limited, in a manner dictated by the rotational orientation of the DNA sequence around the nucleosome core, and those sites are used more frequently than in naked DNA.

Chromosome Mapping↗

PubMed1993

Integration of murine leukemia virus DNA depends on mitosis.

In synchronized rat or mouse cells infected with Moloney murine leukemia virus (MLV), integration of viral DNA and production of viral proteins occur only after the cells traverse mitosis. Integration is blocked when cells are prevented from progressing through mitosis. Viral nucleoprotein complexes isolated from arrested cells contain full-length viral DNA and can integrate this viral DNA in vitro, showing that the block to integration in arrested cells is not due to a lack of mature integration machinery. When infected cells traverse mitosis, there is a sharp increase in nuclear accumulation of viral DNA. The dependence of integration on mitosis may therefore be due to a requirement for mitosis and nuclear envelope breakdown for entry of the viral integration complex into the nucleus.

Animals↗

PubMed2006

PhiC31 integrase mediates integration in cultured synovial cells and enhances gene expression in rabbit joints.

BACKGROUND: Gene transfer to synovium in joints has been shown to be an effective approach for treating pathologies associated with rheumatoid arthritis (RA) and related joint disorders. However, the efficiency and duration of gene delivery has been limiting for successful gene therapy for arthritis. The transient gene expression that often accompanies non-viral gene delivery can be prolonged by integration of vector DNA into the host genome. We report a novel approach for non-viral gene therapy to joints that utilizes phage phiC31 integrase to bring about unidirectional genomic integration. METHODS: Rabbit and human synovial cells were co-transfected with a plasmid expressing phiC31 integrase and a plasmid containing the transgene and an attB site. Cells were cultured with or without G418 selection and the number of neo-resistant colonies or eGFP cells determined, respectively. Plasmid rescue, PCR query, and DNA sequence analysis were performed to reveal integration sites in the rabbit and human genomes. For in vivo studies, attB-reporter gene plasmids and a plasmid expressing phiC31 integrase were intra-articularly injected into rabbit knees. Joint sections were used for histological analysis of beta-gal expression, and synovial cells were isolated to measure luciferase expression. RESULTS: We demonstrated that co-transfection of a plasmid expressing phiC31 integrase with a plasmid containing the transgene and attB increased the frequency of transgene expression in rabbit synovial fibroblasts and primary human RA synoviocytes. Plasmid rescue and DNA sequence analysis of plasmid-chromosome junctions revealed integration at endogenous pseudo attP sequences in the rabbit genome, and PCR query detected integration at previously characterized integration sites in the human genome. Significantly higher levels of transgene expression were detected in vivo in rabbit knees after intra-articular injection of attB-reporter gene plasmids and a plasmid expressing phiC31 integrase. CONCLUSION: The ability of phiC31 integrase to facilitate genomic integration in synovial cells and increase transgene expression in the rabbit synovium suggests that, in combination with more efficient DNA delivery methods, this integrase system could be beneficial for treatment of rheumatoid arthritis and other joint disorders.

Animals↗

PubMed1998

Identification of glucocorticoid receptor domains necessary for transcriptional activation of the mouse mammary tumor virus promoter integrated in the genome.

It has previously been determined that the mouse mammary tumor virus (MMTV) promoter when integrated in the genome assumes a defined chromatin structure which is disrupted upon addition of glucocorticoids. In contrast, a transiently introduced MMTV promoter has a random nucleoprotein structure. To reveal glucocorticoid receptor (GR) domains necessary for transcriptional activation of the MMTV promoter we compared the effects of mutations of the GR on transcriptional activation of the stably integrated versus transiently introduced MMTV promoter. For this purpose we generated a GR-negative cell line which has an MMTV promoter/reporter construct integrated in the genome and studied the transcriptional activation of this construct by different GR mutants introduced into the cells. Transcriptional activation of the integrated and transiently introduced promoter was achieved by the wild-type GR or a chimeric receptor in which the MR hormone-binding domain (HBD) replaced the GR HBD. In contrast, we found that deletion of the HBD of the GR or replacement of this region with the equivalent domain of the estrogen receptor produced receptors that were unable to activate the MMTV promoter integrated in the genome although these receptors efficiently activated the transiently introduced MMTV promoter. The HBD was not the sole determinant of MMTV transcriptional activation when integrated in the genome. Chimeric receptors which harbored the MR amino terminal domain or the wild-type MR were also unable to activate the integrated MMTV promoter. Taken together, these data indicate a rigid requirement for sequences in both the GR amino and the carboxy terminal domains for transcriptional activation of a hormone response element in the defined chromatin context of the MMTV promoter.

Aldosterone↗

PubMed1997

Site-specific in situ amplification of the integrated polyomavirus genome: a case for a context-specific over-replication model of gene amplification.

The fate of the genome of the polyoma (Py) tumor virus following integration in the chromosomes of transformed rat FR3T3 cells was re-examined. The viral sequences were integrated at a single transformant-specific chromosomal site in each of 22 transformants tested. In situ amplification of the viral sequences was observed in 24 of 34 transformants analyzed. Large T antigen, the unique viral function involved in initiating DNA replication from the viral origin, was essential for the amplification process. There was an absolute requirement for a reiteration of viral sequences and the extent of the reiteration affected the degree of amplification. The reiteration may be important for homologous recombination-mediated resolution of in situ amplified sequences. Among 11 transformants harboring a 1 to 2 kb repeat, the degree of amplification was transformant-specific and varied over a wide range. At the high end of the spectrum, the genome copy number increased 1300-fold at steady state, while at the low end, amplification was below twofold. Some aspect of the host chromatin at the site integration that affected viral gene expression, also directly or indirectly modulated the amplification. Use of high-resolution electrophoresis for the analysis of the integrated amplified sequences revealed a recurring novel pattern, consisting of a ladder with numerous bands separated by a constant distance approximately the size of the Py genome. We suggest that this pattern was generated by conversion of the amplified viral genomes to head to tail linear arrays with cell to cell variations in the number of genome repeats at single, transformant-specific, chromosomal sites. In light of the known "out of schedule" firing of the Py origin, we propose an "onion skin" structure intermediate and present a homologous recombination model for the conversion from onion skins to linear arrays. The relevance of the in situ amplification of the Py genome to cellular gene amplification is discussed. Finally, these results clarify our understanding of the integration of the Py genome in rat cells. They suggest that, in most cases, the multiple bands previously described in Py-transformants are likely to reflect genome amplification rather than multiple independent integration events, as assumed in the past. This interpretation is congruent with the accepted view that the integration of the Py genome is a rare and rate-limiting event in transformation.

Animals↗