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PubMed1981

A Rous sarcoma virus provirus is flanked by short direct repeats of a cellular DNA sequence present in only one copy prior to integration.

The Rous sarcoma virus (RSV)-transformed rat cell line RSV-NRK-2 contains a single complete RSV provirus. We have obtained recombinant lambda clones that contain both ends of the RSV provirus and the flanking rat sequences. The provirus is integrated in unique DNA and is present in only one of the two homologous chromosomes. The rat sequences into which the RSV provirus integrated were also cloned from the RSV-NRK-2 cell line. The sequences of the regions involved in the recombination event have been determined and compared. Our data suggest that, compared with the sequence of viral DNA in the large circular form of unintegrated viral DNA, the provirus lacks two base pairs at each end and that the provirus is flanked by a six-base-pair direct repeat of cellular DNA. This six-base-pair repeat was apparently created during the integration event because this sequence was present only once at the integration site before the provirus was inserted. A survey of eight other independent RSV transformed rat cell lines demonstrates that, in agreement with earlier results, the RSV proviruses have entered different segments of rat cell DNA. We have also determined the sequence of a second virus DNA-host cell DNA junction from a second RSV-transformed rat cell line (RSV-NRK-4) and find that there are no obvious similarities between the two integration sites or between the integration sites and the termini of viral DNA.

Avian Sarcoma Viruses↗
PubMed1984

The retrovirus pol gene encodes a product required for DNA integration: identification of a retrovirus int locus.

We mutagenized cloned spleen necrosis virus DNA to identify a region of the retrovirus genome encoding a polypeptide required for integration of viral DNA. Five plasmids bearing different lesions in the 3' end of the pol gene were examined for the ability to integrate or replicate following transfection of chicken embryo fibroblasts. Transfection with one of these DNAs resulted in the generation of mutant virus incapable of integrating but able to replicate at low levels; this phenotype is identical to that of mutants bearing alterations in the cis-acting region, att. To determine whether the 3' end of the pol gene encodes a protein that interacts with att, we did a complementation experiment. Cells were first infected with an att- virus and then superinfected with the integration-deficient virus containing a lesion in the pol gene and a wild-type att site. The results showed that the att- virus provided a transacting function allowing integration of viral DNA derived from the mutant bearing a wild-type att site. Thus, the 3' end of the pol gene serves as an "int" locus and encodes a protein mediating integration of retrovirus DNA through interaction with att.

Animals↗
PubMed1989

Retroviral integration: structure of the initial covalent product and its precursor, and a role for the viral IN protein.

An essential step in the life cycle of a retrovirus is the integration of a DNA copy of the viral genome into a host cell chromosome. We have analyzed the structure of the initial covalent product of an in vitro retroviral integration reaction and determined the structure of the ends of the unintegrated linear viral DNA molecules present in vivo in cells infected with murine leukemia virus (MLV). Our results lead to the following conclusions: (i) Circularization of viral DNA plays no role in integration. The direct precursor to the integrated MLV provirus is a linear molecule. (ii) The initial step in the integration reaction is probably a cleavage that removes the terminal 2 bases from each 3' end of the viral DNA. This cleavage depends on a virally encoded protein, IN, that has previously been shown genetically to be required for integration. (iii) The resulting viral 3' ends are joined to target DNA to form the initial recombination intermediate.

Cell Transformation, Viral↗
PubMed1991

Preferential integration of marker DNA into the chromosomal fragile site at 3p14: an approach to cloning fragile sites.

Fragile sites are specific regions of chromosomes that are prone to breakage. In cells cultured under conditions that induce fragile site expression, high levels of inter- and intrachromosomal recombination have been observed involving chromosomal bands containing fragile sites. To determine whether expression of specific fragile sites would facilitate preferential integration of exogenous DNA at these recombination hot spots, the vector pSV2Neo was transfected into a Chinese hamster-human somatic cell hybrid containing a derivative chromosome 3 as its only human component. Chromosome 3 contains a common fragile site at band 3p14.2 (FRA3B) that is induced by aphidicolin. Both cells induced to express FRA3B and the uninduced control cells were transfected with the pSV2Neo selectable plasmid. In situ hybridization of a biotin-labeled pSV2Neo probe to metaphase chromosomes revealed one to three integration sites in each stably transfected clone. Four of 13 clones transfected under conditions of FRA3B induction showed integration of pSV2Neo at 3p14; these clones also showed specific integration into hamster chromosome 1 and a rearranged chromosome characteristic of CHO cells (mar2). The 7 control clones, however, showed an apparently random pattern of pSV2Neo integration. Significant hybridization of pSV2Neo to both FRA3B and Chinese hamster chromosomes 1 and mar2 was seen in 100 cells from pooled colonies transfected after treatment with aphidicolin. These results suggest that preferential integration of marker DNA into human and Chinese hamster fragile sites occurs with exposure to aphidicolin. The nature of the DNA sequences at fragile sites is unknown and, despite a number of approaches, these sequences have not yet been isolated; our procedure may represent an approach to the cloning of fragile sites.

Animals↗
PubMed1991

Influence of chromosomal integration on glucocorticoid-regulated transcription of growth-stimulating papillomavirus genes E6 and E7 in cervical carcinoma cells.

In most cervical carcinoma cells the E6 and E7 genes of specific human papillomaviruses are transcribed from viral sequences integrated into host cell chromosomes. Glucocorticoids activate the promoter elements of various human papillomaviruses in transient-expression assays. We have analyzed the effect of dexamethasone on the transcription rate of human papillomavirus 18 E6 and E7 genes integrated at different chromosomal sites in four cervical cancer cell lines. Dexamethasone led to an increase in the transcription rate of the integrated E6-E7 sequences in C4-1 and C4-2 cells but led to a decrease in SW 756 cells and did not affect the transcription rate in HeLa cells. However, when the viral promoter elements derived from HeLa or SW 756 cells, in which dexamethasone does not activate transcription of the integrated E6-E7 sequences, were tested in transient-expression assays within the same cell lines, dexamethasone consistently activated the viral promoter. It thus appears that dominant regulatory mechanisms presumably depending on the chromosomal integration site are able to override the response of the viral promoter to steroid hormones. The growth rate of all dexamethasone-treated cell lines correlated consistently with the expression of the papillomavirus E6 and E7 genes, supporting their role in the maintenance of the proliferative phenotype of cervical carcinoma cells. Since human papillomaviruses are integrated into the host cell genome at variable, presumably randomly selected chromosomal loci, regulatory mechanisms that influence viral gene expression, and hence cell growth, may differ among cancers of independent clonal origin.

Cell Line↗
PubMed1994

Eye position and eye velocity integrators reside in separate brainstem nuclei.

Two types of central nervous system integrators are critical for oculomotor performance. The first integrates velocity commands to create position signals that hold fixation of the eye. The second stores relative velocity of the head and visual surround to stabilize gaze both during and after the occurrence of continuous self and world motion. We have used recordings from single neurons to establish that the "position" and "velocity" integrators for horizontal eye movement occupy adjacent, but nonoverlapping, locations in the goldfish medulla. Lidocaine inactivation of each integrator results in the eye movement deficits expected if horizontal eye position and velocity signals are processed separately. These observations also indicate that each brainstem compartment generates and stores these signals. Consequently, each integrator exhibits functional autonomy. Therefore, we propose that the intrinsic electrophysiological properties of the constituent neurons in each brainstem subnucleus may be sufficient for producing integrator rhythmicity.

Animals↗
PubMed2000

An Arabidopsis histone H2A mutant is deficient in Agrobacterium T-DNA integration.

Agrobacterium tumefaciens genetically transforms plant cells by transferring a portion of the bacterial Ti-plasmid, the T-DNA, to the plant and integrating the T-DNA into the plant genome. Little is known about the T-DNA integration process, and no plant genes involved in integration have yet been identified. We characterized an Arabidopsis mutant generated by T-DNA insertional mutagenesis, rat5, that is resistant to Agrobacterium root transformation. rat5 contains two copies of T-DNA integrated as a tandem direct repeat into the 3' untranslated region of a histone H2A gene, upstream of the polyadenylation signal sequence. Transient and stable beta-glucuronidase expression data and assessment of the amount of T-DNA integrated into the genomes of wild-type and rat5 Arabidopsis plants indicated that the rat5 mutant is deficient in T-DNA integration. We complemented the rat5 mutation by expressing the RAT5 histone H2A gene in the mutant plant. Overexpression of RAT5 in wild-type plants increased Agrobacterium transformation efficiency. Furthermore, transient expression of a RAT5 gene from the incoming T-DNA was sufficient to complement the rat5 mutant and to increase the transformation efficiency of wild-type Arabidopsis plants.

Agrobacterium tumefaciens↗
PubMed2000

Both the structure and DNA binding function of the barrier-to-autointegration factor contribute to reconstitution of HIV type 1 integration in vitro.

Retroviral integration is mediated by viral preintegration complexes (PICs), and human immunodeficiency virus type 1 (HIV-1) PICs treated with high salt lose their in vitro integration activity. Barrier-to-autointegration factor (BAF) is a host protein that efficiently restores PIC activity, but the mechanism(s) by which BAF participates in HIV-1 integration remains largely unknown. Here we developed a gel shift assay to study BAF DNA binding, and analyzed 14 mutant proteins containing substitutions of conserved residues for binding and PIC reconstitution activities. Although wild-type BAF efficiently bound double-stranded DNA, binding to single-stranded DNA, RNA, or an RNA/DNA hybrid was not detected, suggesting that BAF associates with retroviral cDNA relatively late during reverse transcription. Although some of the BAF mutant proteins efficiently bound DNA, others were defective for binding. Mutants that bound DNA efficiently reconstituted HIV-1 integration, even though in one case binding was just 0.2% of wild-type BAF. Although misfolded mutants did not reconstitute integration, a structurally intact DNA binding-defective mutant displayed partial activity at high BAF concentration. We therefore conclude that both BAF protein structure and its DNA binding activity play roles in reconstituting HIV-1 integration in vitro.

Amino Acid Sequence↗
PubMed2006

A derivative of lipid A is involved in signal recognition particle/SecYEG-dependent and -independent membrane integrations.

A cell-free system was developed that allows the correct integration of single and multispanning membrane proteins of Escherichia coli into proteoliposomes. We found that physiological levels of diacylglycerol were required to prevent spontaneous integration into liposomes even of the polytopic mannitol permease. Using diacylglycerol-containing proteoliposomes, we identified a novel integration-stimulating factor. Integration of mannitol permease was dependent on both the SecYEG translocon and this factor and was mediated by signal recognition particle and signal recognition particle receptor. Integration of M13 procoat, which is independent of both signal recognition particle/signal recognition particle receptor and SecYEG, was also promoted by this factor. Furthermore, the factor stimulated the post-translational translocation of presecretory proteins, suggesting that it also mediates integration of a signal sequence. This factor was found to be a lipid A-derived membrane component possessing a peptide moiety.

Bacterial Outer Membrane Proteins↗
PubMed1998

Competence in discourse as a measure of social integration and quality of life in persons with traumatic brain injury.

Persisting difficulties in communication are a serious handicap faced by many after traumatic brain injury (TBI) and a major barrier to community reintegration. Conventional approaches to the study of communication problems after TBI have focused on the form of language production and expression, usually in terms of phonological, semantic, and syntactical features. Most TBI patients, however, perform overall within normal ranges on these conventional indicators. More recently, attention has focused on language in its naturally-occurring form, that is, discourse, which is heavily influenced by linguistic, cognitive and social skills. Because most TBI patients are left with residual deficits in these areas, study of discourse abilities seem to be particularly suited to understanding their problems in communication and facilitating eventual reintegration into the community. This study was designed to determine if and how the conversational discourse of TBI patients differs from a matched non-TBI group and whether any identified variables are related to measures of outcome as measured by community integration and quality of life. Additionally, the study was designed to explore the relationship between TBI and features of discourse across conversational, narrative, procedural genres. TBI patients (n = 30) from an out-patient brain injury programme were compared to matched controls (n = 10) in the three discourse genres. Bivariate and multivariate analyses evaluated 23 measures of discourse efficiency, complexity, topic management, information and pragmatic behaviours in each genre as well as measures of psychosocial adjustment, particularly social integration and quality of life. Results indicated that TBIs were significantly different from controls on several measures of discourse and psychosocial adjustment. A number of other features of discourse were found to correlate significantly with social integration and quality of life. Interestingly, discourse variables appeared to correlate with social integration more strongly than age, gender, education, and other conventional psychosocial factors. Contrary to prediction, features of conversational discourse did not correlate more strongly than other types of discourse with social integration and quality of life. Discussion centred on the apparent comorbidity of features in everyday discourse and psychosocial determinants that were associated with quality of life and social integration.

Adult↗
PubMedDate not supplied

Adult age differences in memory and linguistic integration revisited.

In recent studies questioning whether linguistic integration of semantic information declines with age, the performance measures were based on recognition of related sentences in the Bransford/Franks paradigm; and the conclusions about age differences in linguistic integration were based on equivalent recognition performance of young and old adults. In the current study, the measure of linguistic integration was based on inference in a linear ordering task. Subjects were students at the University of Maryland - 34 between 18 and 23 years of age and 33 between 60 and 72. Recognition performance was equivalent for old and young groups, but linguistic integration was age related. Young subjects inferred the truth status of more sentences than did old subjects. These findings indicate that linguistic integration based on inference is age related and that equivalent recognition performance is not adequate evidence for equivalent linguistic integration. Furthermore, recent findings indicate that age deficits in making inferences using new information presented auditorily are due to deficits in memory for facts and in working memory. This study supports those findings and indicates that they can be generalized to information presented visually.

Adolescent↗
PubMed1998

A survey of persons who use integrated control devices.

Integrated devices allow users to operate multiple pieces of assistive technology items from a single input device. Through this single input device, users with severe physical limitations are able to operate several other devices such as a wheelchair, telephone, computer, and communication aid. Twenty-four integrated control users completed a telephone survey to ascertain consumer satisfaction with integrated controls. Eighteen were either satisfied or very satisfied with the evaluation for an integrated control, one was neither satisfied nor dissatisfied, two were very dissatisfied, and three did not respond to the question. Twenty were very satisfied or satisfied and four were either dissatisfied or very dissatisfied with the training they received. Twenty-two respondents indicated they were either very satisfied or satisfied with their integrated control device, one was neither satisfied nor dissatisfied, and one was very dissatisfied. In general, respondents were satisfied with their integrated control devices. Specifically, respondents were satisfied with the increase in independence and the ability to control other equipment such as television sets and computers. Simplicity, touch sensitivity, and visual/auditory feedback appeared to play important roles in satisfaction.

Adolescent↗
PubMed1991

Crossmodal integration in the identification of consonant segments.

Although speechreading can be facilitated by auditory or tactile supplements, the process that integrates cues across modalities is not well understood. This paper describes two "optimal processing" models for the types of integration that can be used in speechreading consonant segments and compares their predictions with those of the Fuzzy Logical Model of Perception (FLMP, Massaro, 1987). In "pre-labelling" integration, continuous sensory data is combined across modalities before response labels are assigned. In "post-labelling" integration, the responses that would be made under unimodal conditions are combined, and a joint response is derived from the pair. To describe pre-labelling integration, confusion matrices are characterized by a multidimensional decision model that allows performance to be described by a subject's sensitivity and bias in using continuous-valued cues. The cue space is characterized by the locations of stimulus and response centres. The distance between a pair of stimulus centres determines how well two stimuli can be distinguished in a given experiment. In the multimodal case, the cue space is assumed to be the product space of the cue spaces corresponding to the stimulation modes. Measurements of multimodal accuracy in five modern studies of consonant identification are more consistent with the predictions of the pre-labelling integration model than the FLMP or the post-labelling model.

Attention↗
PubMed1998

Variations in gene expression and genomic stability of human hepatoma cells integrated with hepatitis B virus DNA.

The association of hepatitis B virus (HBV) infection with human hepatoma is well established. However, no consensus regarding the etiology of hepatocellular carcinoma was elucidated. In this paper, the genomic stability and gene expression of HBV DNA-integrated and non-integrated hepatoma cells by Transcript Profile (TP)-PCR and RT-PCR are characterized. The additional DNA bands generated from TP-PCR of HBV integrated genomes were not correlated with the sequence of HBV, suggesting that the variations may result from genomic instability of the host cells. Moreover, differential genes expressed in HBV DNA-integrated cells were sequenced. A cDNA generated from the integrated cells exhibited 99.3% homology with the sequences of ATP synthase 6 and cytochrome C oxidase III, but the sequences were abnormally linked together. Since HBV infection may alter the energy metabolism of the cell, the results suggest that the integration may cause mitochondriae defects in the ATP synthase 6 and cytochrome C oxidase III genes.

ATP Synthetase Complexes↗
PubMedDate not supplied

Bottom-up and top-down integration of human and ecological risk assessment.

The World Health Organization has published a framework for integrating human health and ecological risk assessments, and many others have argued for greater integration of health and environmental concerns in assessments. However, those who argue for integration do not agree on the expected benefits. This article provides a conceptual organization of the rationale for integration. The bottom-up line of argument begins with the premise that the mechanisms of transport, fate, exposure, and effects of chemicals on humans and nonhuman organisms are largely common. Therefore, integrated assessment should be more efficient and should employ the highest quality of science. The top-down line of argument begins with the premise that humans are organisms that reside in ecosystems. Therefore, changes in the environment imply changes in human health and welfare. These include changes in the many services of nature that contribute to human health, such as air and water purification, sentinel functions, and provision of recreation and food supplies. They also include the direct health benefits that have been associated with exposure of humans to plants, animals, and natural ecosystems. Integration should proceed from both the top and bottom.

Ecology↗
PubMed2005

Beam hardening artefacts in computed tomography with photon counting, charge integrating and energy weighting detectors: a simulation study.

Photon counting x-ray imaging provides efficient rejection of the electronics noise, no pulse height (Swank) noise, less noise due to optimal photon energy weighting and the possibility of energy resolved image acquisition. These advantages apply also to CT when projection data are acquired using a photon counting detector. However, photon counting detectors assign a weighting factor of 1 to all detected photons whereas the weighting factor of a charge integrating detector is proportional to the energy of the detected photon. Therefore, data collected by photon counting and charge integrating detectors represent the 'hardening' of the photon beam passed through the object differently. This affects the beam hardening artefacts in the reconstructed CT images. This work represents the first comparative evaluation of the effect of photon counting, charge integrating and energy weighting photon detectors on beam hardening artefacts in CT. Beam hardening artefacts in CT images were evaluated for 20 cm and 14 cm diameter water cylinders with bone and low contrast inserts, at 120 kVp and 90 kVp x-ray tube voltages, respectively. It was shown that charge integrating results in 1.8% less beam hardening artefacts from bone inserts (i.e., CT numbers in the 'shadow' of the bone are less by 1.8% as compared to CT numbers over the periphery of the image), as compared to photon counting. However, optimal photon energy weighting, which provides highest SNR, results in 7.7% higher beam hardening artefacts from bone inserts as compared to photon counting. The magnitude of the 'cupping' artefacts was lower by 1% for charge integrating and higher by 6.1% for energy weighting acquisitions as compared to photon counting. Only the photon counting systems provide an accurate representation of the beam hardening effect due to its flat energy weighting. Because of their energy dependent weighting factors, the charge integrating and energy weighting systems do not provide accurate representation of the beam hardening effect.

Computer Simulation↗
PubMed2004

An integrated probabilistic model for functional prediction of proteins.

We develop an integrated probabilistic model to combine protein physical interactions, genetic interactions, highly correlated gene expression networks, protein complex data, and domain structures of individual proteins to predict protein functions. The model is an extension of our previous model for protein function prediction based on Markovian random field theory. The model is flexible in that other protein pairwise relationship information and features of individual proteins can be easily incorporated. Two features distinguish the integrated approach from other available methods for protein function prediction. One is that the integrated approach uses all available sources of information with different weights for different sources of data. It is a global approach that takes the whole network into consideration. The second feature is that the posterior probability that a protein has the function of interest is assigned. The posterior probability indicates how confident we are about assigning the function to the protein. We apply our integrated approach to predict functions of yeast proteins based upon MIPS protein function classifications and upon the interaction networks based on MIPS physical and genetic interactions, gene expression profiles, tandem affinity purification (TAP) protein complex data, and protein domain information. We study the recall and precision of the integrated approach using different sources of information by the leave-one-out approach. In contrast to using MIPS physical interactions only, the integrated approach combining all of the information increases the recall from 57% to 87% when the precision is set at 57%-an increase of 30%.

Computational Biology↗
PubMed2025

Asymmetric integration of various cancer datasets for identifying risk-associated variants and genes.

MOTIVATION: Cancer genomic research provides an opportunity to identify cancer risk-associated genes, but often suffers from undesirable low statistical power due to a limited sample size. Integrated analysis with different cancers has the potential to enhance statistical power for identifying pan-cancer risk genes. However, substantial heterogeneity across various cancers makes this challenging. RESULTS: Recently, a novel asymmetric integration method was developed that can deal with data heterogeneity and exclude unhelpful datasets from the analysis. We adapted and applied this method to integrate genotype datasets with matched case and control individuals from the Michigan Genomics Initiative, using each cancer as the primary dataset of interest and the other cancers as auxiliary datasets, respectively. Conditional logistic regression models were coupled with the asymmetric integrated framework to handle the matched case-control study design and permutation tests were performed to control for false discovery rates (FDRs). At the same FDR level, the integrated analysis found more potential genetic variants and genes that are associated with the risks of various cancers, showcasing the promise of the proposed approach for integrated analysis of cancer datasets. AVAILABILITY AND IMPLEMENTATION: Our method is available as source code at https://github.com/rxxwang/integrate_cancer.

Journal Article↗