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PubMed2000

Integration of proviral sequences, but not at the common integration sites of the FGF8 locus, in an androgen-dependent mouse mammary Shionogi carcinoma.

A retroviral insertional mutation, especially by mouse mammary tumor virus (MMTV), is a major cause of murine mammary tumorigenesis. Prompted by our previous finding that FGF8, an insertionally activated cellular oncogene, is highly expressed in androgen-dependent mouse mammary Shionogi carcinoma cells, we here investigated retroviral integration adjacent to the fgf8 locus in Shionogi carcinoma. In the genomic Southern blots for fgf8 and its 5'-upstream gene npm3, the hybridized fragments were identical to the host DD/Sio mice, the original Shionogi carcinoma 115 tumor, and a pair of cultured Shionogi carcinoma cell lines of SC-3 and SC-4, suggesting that no retroviral integration occurred around either loci. The genomic cloning for the fgf8 locus from SC-3 cells also confirmed no MMTV integration. In addition, npm3, which is usually coactivated with fgf8 by MMTV insertion,was not up-regulated by androgens in SC-3 cells. All these findings led us to conclude that no retroviral insertion was present at the common integration sites adjacent to the fgf8 locus in Shionogi carcinoma although we demonstrated in this study that multiple proviral sequences of MMTV, Moloney murine sarcoma virus and FBJ-murine sarcoma virus are integrated into SC-3 cells in association with their distinct promoter activity in SC-3 cells.

Animals↗
PubMed2001

Integrated care: a position paper of the WHO European Office for Integrated Health Care Services.

The WHO European Office for Integrated Health Care Services in Barcelona is an integral part of the World Health Organizations' Regional Office for Europe. The main purpose of the Barcelona office is within the integration of services to encourage and facilitate changes in health care services in order to promote health and improve management and patient satisfaction by working for quality, accessibility, cost-effectiveness and participation. This position paper outlines the need for Integrated Care from a European perspective, provides a theoretical framework for the meaning of Integrated Care and its strategies and summarizes the programmes of the office that will support countries in the WHO European Region to improve health services.

Journal Article↗
PubMed2005

An integrative approach to CTL epitope prediction: a combined algorithm integrating MHC class I binding, TAP transport efficiency, and proteasomal cleavage predictions.

Reverse immunogenetic approaches attempt to optimize the selection of candidate epitopes, and thus minimize the experimental effort needed to identify new epitopes. When predicting cytotoxic T cell epitopes, the main focus has been on the highly specific MHC class I binding event. Methods have also been developed for predicting the antigen-processing steps preceding MHC class I binding, including proteasomal cleavage and transporter associated with antigen processing (TAP) transport efficiency. Here, we use a dataset obtained from the SYFPEITHI database to show that a method integrating predictions of MHC class I binding affinity, TAP transport efficiency, and C-terminal proteasomal cleavage outperforms any of the individual methods. Using an independent evaluation dataset of HIV epitopes from the Los Alamos database, the validity of the integrated method is confirmed. The performance of the integrated method is found to be significantly higher than that of the two publicly available prediction methods BIMAS and SYFPEITHI. To identify 85% of the epitopes in the HIV dataset, 9% and 10% of all possible nonamers in the HIV proteins must be tested when using the BIMAS and SYFPEITHI methods, respectively, for the selection of candidate epitopes. This number is reduced to 7% when using the integrated method. In practical terms, this means that the experimental effort needed to identify an epitope in a hypothetical protein with 85% probability is reduced by 20-30% when using the integrated method. The method is available at http://www.cbs.dtu.dk/services/NetCTL. Supplementary material is available at http://www.cbs.dtu.dk/suppl/immunology/CTL.php.

ATP-Binding Cassette Transporters↗
PubMed2002

Integral algorithm and density matrix integration scheme for ab initio band structure calculations on polymeric systems.

A new program for band structure calculations of periodic one-dimensional systems has been constructed. It is distinguishable from other codes by the efficient two-electron integral evaluation and the integration schemes of the density matrix in the first Brillouin zone. The computation of polymeric two-electron integrals is based on the McMurchie Davidson algorithm and builds batches of the different cell indices included in the polymeric system. Consequently it presents efficient scaling with respect to the number of unit cells taken into account. Our algorithm takes into account fully the polymeric symmetry rather than the molecular symmetry. A semidirect procedure where only exchange integrals are computed at each SCF cycle is proposed in order to maintain balance between computation time and disk space. In addition, the integration of the density matrix over a large number of cell indices can be performed by different methods, such as Gauss-Legendre, Clenshaw-Curtis, Filon, and Alaylioglu-Evans-Hyslop. This last scheme is able to obtain an accuracy of 10(-13) a.u. on each individual density matrix element for all cell indices with only 48 k-points.

Journal Article↗
PubMed1995

Interpreting complex binding kinetics from optical biosensors: a comparison of analysis by linearization, the integrated rate equation, and numerical integration.

The binding kinetics recorded for many interactions using BIAcore and IAsys optical biosensors do not fit a simple bimolecular interaction model (A + B<-->AB). Three methods of analysis have been used to derive estimates for kinetic constants from such data:linearization, curve fitting using the integrated rate equation, and curve fitting using numerical integration. To test how well these methods could interpret complex binding kinetics, we generated and analyzed simulated data for two systems, one involving a two-state conformational change (A + B<-->AB<-->(AB)*) and a second involving surface heterogeneity (A + B<-->AB and A + B*<-->AB*). The linearization method assumed a simple bimolecular interaction and was inadequate at interpreting these systems as both produced complex kinetics in the association and dissociation phases. The sum of two integrated rate equations correctly modeled surface heterogeneity; but, when applied nonglobally, it fit the data from the conformational change system equally well and thus provided misleading results. Numerical integration allowed a choice of model for analysis and was therefore the only method capable of returning accurate estimates of rate constants for both complex systems. Global analysis, in combination with numerical integration, provided a stringent test of the assumed model. However, this stringency suggests that its application to experimental systems will require high-quality biosensor data.

Biosensing Techniques↗
PubMed2001

Convergence of the Integration Dynamics of the Construction-Integration Model.

The connectionist network corresponding to the nonlinear integration dynamical system associated with Kintsch's construction-integration (CI) model is analysed with linear algebra tools. This addresses some theoretical questions raised and left unanswered by Rodenhausen (1992, Psychological Review 99, 547-549). A mathematical characterization for equilibrium points, which allows an a priori enumeration of all possible asymptotic states for the integration dynamical system, given a connectivity matrix, is given. The dynamics of convergence of the integration dynamical system is characterized in some detail as well. This provides a tool for understanding CI simulations and helps in particular to let us know to what extent the outcome will depend on the initial conditions. The criteria also provide a new mathematical analysis which allows for the explicit calculation of asymptotic states of the integration process without requiring computer simulation experiments. The new mathematical analysis should facilitate comparisons of the model's predictions with behavioural data. Copyright 2001 Academic Press.

Journal Article↗
PubMedDate not supplied

Integrative study in physiology and medicine: obstacles on the road to integration.

A recent report of the Long-Range Planning Committee of the American Physiological Society identifies physiology with "integrative biology" and urges that physiologists make their field "a unique branch of biology that deals with synthesis and integration." However, certain institutional, procedural, and psychological obstacles lie in the way of those who would embark upon this task. The hurdles to be overcome include the following: the erroneous belief that biomedical scientists are already integrative; the inapplicability of the powerful methods of areas of specialization to integrative study; the fear of failure; the identification of integrative biology with the study of function; the disregard of hierarchy; the undervaluation of the abstract; and the loss of a sense of mystery. These obstacles, though insidious, pervasive, and powerful, can be surmounted.

Animals↗
PubMed1988

Non-homologous integration of transforming vectors in the fungus Podospora anserina: sequences of junctions at the integration sites.

Transformation of the ura5-6 mutant strain of Podospora anserina with a recombinant vector carrying the ura5+ gene often results in the integration of the transforming plasmid by non-homologous recombination outside of the genomic ura5 locus. To investigate the mechanism of such integration, we rescued the integrated plasmid from three transformants. In two cases, the rescued plasmid was highly altered compared with the original transforming vector. We cloned the junctions between plasmidic DNA and genomic DNA of the transformants and determined their nucleotide sequences. It was found that there was little homology between plasmidic and genomic DNA sequences. Moreover, in all cases deletions of plasmid sequences at the integration site had occurred. These rearrangements can be explained by the formation of multimeric plasmids prior to integration.

Ascomycota↗
PubMed1993

Multiple tandem integrations of transforming DNA sequences in yeast chromosomes suggest a mechanism for integrative transformation by homologous recombination.

In yeast, the fate of linear DNA molecules upon transformation is determined by the existence of sequence homology between chromosomes and the ends of the transforming molecule. To understand the mechanism of integration of transforming DNA, we have studied the influence of DNA concentration on the frequency and type of transformants obtained, using either non-replicative or replicative plasmids. In both cases, increasing DNA concentration results in multiple tandem repeats integrated into the chromosome containing the homologous target sequence. When a diploid strain is transformed, multiple tandem repeats occur in only one of the two homologous chromosomes at a time. The frequency distribution of the different types of integrants observed indicates non-independent integration events likely to result from plasmid-plasmid interaction prior to chromosome integration. In addition, our results define the proper conditions for optimized gene targetting or gene rescue experiments.

Base Sequence↗
PubMedDate not supplied

Molecular dynamics integration time step dependence of the split integration symplectic method on system density.

This paper shows that the maximal size of the integration time step of the Split Integration Symplectic Method (SISM) for molecular dynamics (MD) integration, a combination of the analytical solution of the high-frequency harmonic part of the Hamiltonian and the numerical solution of the low-frequency remaining part, depends on the system density. This approach was tested on a system of linear chain molecules. The numerical results indicate that the integration time step used by the SISM is limited by atoms' motion generated by the electrostatic and Lennard-Jones interactions in the system. As the density of the system increases, the size of the integration time step allowed by the SISM thus becomes smaller but remains significantly larger than possible by standard methods of the same order and complexity.

Journal Article↗
PubMed1988

The distinction between integral and separable dimensions: evidence for the integrality of pitch and loudness.

Six experiments are reported that investigated the reality and generality of dimensional integrality (Garner, 1974a) by evaluating whether the auditory dimensions of pitch and loudness are psychologically privileged and whether they combine in an integral fashion. In Experiment 1 we psychophysically scaled the dimensions to ensure that, within the stimulus range used, the perceived value on each dimension would remain constant in the face of variation on the other dimension. In Experiments 2 through 4 we assessed performance by using the converging operations by which Garner defined integrality and separability. Experiment 2 showed that in speeded classification, pitch and loudness lead to facilitation with redundant variation and interference with orthogonal variation. Experiment 3 showed that unspeeded classifications are guided predominantly by overall similarity. Experiment 4 established that the better-fitting metric by which multidimensional similarity is appreciated is Euclidean rather than city block. These results suggest that the dimensions of pitch and loudness combine in an integral fashion. In Experiments 5 and 6 we investigated whether the dimensions of pitch and loudness have a privileged status by assessing the impact of rotating the dimensional axes on performance in a speeded sorting task. Experiment 5 looked at six alternative dimensional orientations to pitch and loudness. If anything, rotating the dimensional axes increased the amount of interference in filtering. In Experiment 6 we assessed an alternative dimensional description of the stimuli based on the dimensions of volume and brightness. We found greater interference when the stimuli varied along the dimensions of volume and brightness than when they varied along the dimensions of pitch and loudness. The fact that the least interference is observed when the stimuli vary along the dimensions of pitch and loudness suggests that these dimensions are the more psychologically valid ones. These findings indicate that integrality is not a "myth," that is, merely a case of psychophysical mismatch. Instead, dimensions that are psychologically real are sometimes processed in a unitary fashion.

Acoustic Stimulation↗
PubMed1999

Quantitative modeling of visual attention processes in patients with Parkinson's disease: effects of stimulus integrality on selective attention and dimensional integration.

Parkinson's disease (PD) patients and normal controls (NCs) were administered a series of visual attention tasks. The dimensional integration task required integration of information from 2 stimulus dimensions. The selective attention task required selective attention to 1 stimulus dimension while ignoring the other stimulus dimension. Both integral- and separable-dimension stimuli were examined. A series of quantitative models of attentional processing was applied to each participant's data. The results suggest that (a) PD patients were not impaired in integrating information from 2 stimulus dimensions, (b) PD patients were impaired in selective attention, (c) selective attention deficits in PD patients were not due to perceptual interference, and (d) PD patients were affected by manipulations of stimulus integrality and separability in much the same way as were NCs.

Aged↗
PubMed2005

Molecular dynamics integration and molecular vibrational theory. I. New symplectic integrators.

New symplectic integrators have been developed by combining molecular dynamics integration with the standard theory of molecular vibrations to solve the Hamiltonian equations of motion. The presented integrators analytically resolve the internal high-frequency molecular vibrations by introducing a translating and rotating internal coordinate system of a molecule and calculating normal modes of an isolated molecule only. The translation and rotation of a molecule are treated as vibrational motions with the vibrational frequency zero. All types of motion are thus described in terms of the normal coordinates. The method's time reversibility requirement was used to determine the equations of motion for internal coordinate system of a molecule. The calculation of long-range forces is performed numerically within the generalized second-order leap-frog scheme, in the same way as in standard second-order symplectic methods. The new methods for integrating classical equations of motion using normal mode analysis allow us to use a long integration step and are applicable to any system of molecules with one equilibrium configuration.

Journal Article↗
PubMed2000

Phenotypic Integration and the Plasticity of Integration in an Amphicarpic Annual.

In annual plants, including amphicarpic annuals, variation in light availability can evoke phenotypic plasticity in multiple traits. We examined plasticity to light availability of vegetative and reproductive performance traits in Amphicarpaea bracteata (Fabaceae) by developing and evaluating three path-analysis models using data from a greenhouse study. To assess whether light availability altered the phenotypic integration of these performance traits, we examined the models' fit to data collected within a high- or a low-light treatment. We also examined whether a single model or alternate models were required to fit data from the two contrasting light treatments. Using our path-analysis approach, we also made comparisons among three population types: shade- and sun-native populations of the widespread variety A. bracteata var. bracteata and sun-native populations of the variety A. bracteata var. comosa. Although each type of population was somewhat distinctive in patterns of integration and in the plasticity of integration, patterns did not correspond to contrasting ecological affinity, i.e., shade- and sun-native population types or to genetic relatedness of the two varieties. Counter to the prediction that selection regimes involving variation in one or more environmental factor favor intermediate levels of integration, phenotypic integration in A. bracteata was very flexible, with plasticity occurring in a trait-by-trait manner. In particular, there was an inverse relationship between aerial and subterranean reproductive modes in low but not high light. Previous studies of amphicarpic annuals have not observed this type of environment-specific life history trade-off.

Journal Article↗
PubMed2025

IGCN: integrative graph convolution networks for patient level insights and biomarker discovery in multi-omics integration.

MOTIVATION: Developing computational tools for integrative analysis across multiple types of omics data has been of immense importance in cancer molecular biology and precision medicine research. While recent advancements have yielded integrative prediction solutions for multi-omics data, these methods lack a comprehensive and cohesive understanding of the rationale behind their specific predictions. To shed light on personalized medicine and unravel previously unknown characteristics within integrative analysis of multi-omics data, we introduce a novel integrative neural network approach for cancer molecular subtype and biomedical classification applications, named Integrative Graph Convolutional Networks (IGCN). RESULTS: To demonstrate the superiority of IGCN, we compare its performance with other state-of-the-art approaches across different cancer subtype and biomedical classification tasks. Our experimental results show that our proposed model outperforms the state-of-the-art and baseline methods. IGCN identifies which types of omics data receive more emphasis for each patient when predicting a specific class. Additionally, IGCN has the capability to pinpoint significant biomarkers from a range of omics data types. AVAILABILITY AND IMPLEMENTATION: The source code is available at https://github.com/bozdaglab/IGCN.

Humans↗
PubMed2006

Selective attention and audiovisual integration: is attending to both modalities a prerequisite for early integration?

Interactions between multisensory integration and attention were studied using a combined audiovisual streaming design and a rapid serial visual presentation paradigm. Event-related potentials (ERPs) following audiovisual objects (AV) were compared with the sum of the ERPs following auditory (A) and visual objects (V). Integration processes were expressed as the difference between these AV and (A + V) responses and were studied while attention was directed to one or both modalities or directed elsewhere. Results show that multisensory integration effects depend on the multisensory objects being fully attended--that is, when both the visual and auditory senses were attended. In this condition, a superadditive audiovisual integration effect was observed on the P50 component. When unattended, this effect was reversed; the P50 components of multisensory ERPs were smaller than the unisensory sum. Additionally, we found an enhanced late frontal negativity when subjects attended the visual component of a multisensory object. This effect, bearing a strong resemblance to the auditory processing negativity, appeared to reflect late attention-related processing that had spread to encompass the auditory component of the multisensory object. In conclusion, our results shed new light on how the brain processes multisensory auditory and visual information, including how attention modulates multisensory integration processes.

Acoustic Stimulation↗
PubMed2004

Nitric oxide signaling: systems integration of oxygen balance in defense of cell integrity.

PURPOSE OF REVIEW: Nitric oxide has emerged as a ubiquitous signaling molecule subserving diverse pathophysiologic processes, including cardiovascular homeostasis and its decompensation in atherogenesis. Recent insights into molecular mechanisms regulating nitric oxide generation and the rich diversity of mechanisms by which it propagates signals reveal the role of this simple gas as a principle mediator of systems integration of oxygen balance. RECENT FINDINGS: The molecular lexicon by which nitric oxide propagates signals encompasses the elements of posttranslational modification of proteins by redox-based nitrosylation of transition metal centers and free thiols. Spatial and temporal precision and specificity of signal initiation, amplification, and propagation are orchestrated by dynamic assembly of supramolecular complexes coupling nitric oxide production to upstream and downstream components in specific subcellular compartments. The concept of local paracrine signaling by nitric oxide over subcellular distances for short durations has expanded to include endocrine-like effects over anatomic spatial and temporal scales. From these insights emerges a role for nitric oxide in integrating system responses controlling oxygen supply and demand to defend cell integrity in the face of ischemic challenge. In this context, nitric oxide coordinates the respiratory cycle to acquire and deliver oxygen to target tissues by regulating hemoglobin function and vascular smooth muscle contractility and matches energy supply and demand by down-regulating energy-requiring functions while shifting metabolism to optimize energy production. SUMMARY: Insights into mechanisms regulating nitric oxide production and signaling and their integration into responses mediating homeostasis place into specific relief the role of those processes in pathophysiology. Indeed, endothelial dysfunction associated with altered production of nitric oxide regulating tissue integrity contributes to the pathogenesis underlying atherogenesis. Moreover, this central role in pathophysiology identifies nitric oxide signaling as a key target for novel therapeutic interventions to minimize irreversible tissue damage associated with ischemic cardiovascular disease.

Animals↗
PubMed1996

New integrated sensor pacemaker: comparison of rate responses between an integrated minute ventilation and activity sensor and single sensor modes during exercise and daily activities and nonphysiological interference.

A dual sensor DDDR pacemaker (DX2 Model 7970, Medtronic Inc.) has integrated the rate response of minute ventilation (MV) and activity (ACT) sensors. False rate acceleration by the ACT (constrained upper rate) and MV (cross-checked by ACT) is reduced. We examined the rate response profile and rate kinetics of the automatically optimized integrated sensor by comparing with the projected rate response of ACT and MV sensors alone in nine patients. After 1 month of sensor optimization using rate profile optimization (RPO), patients underwent maximal and submaximal treadmill exercises and performed activities of daily living (ADL). The integrated sensor mode gave a faster speed of rate response with a shorter delay time, time to 50% rate response and time to 90% of rate response compared to the MV sensor during hall walk (0.37 +/- 0.08, 0.7 +/- 0.09, 1.43 +/- 0.19 vs 1.11 +/- 0.1, 1.75 +/- 0.14, 2.91 +/- 0.17 min; P < 0.05). The average maximal sensor rates were significantly more proportional for the integrated sensor mode compared with either the ACT or MV mode. There was no significant difference in both the maximal pacing rate among the three sensor modes during maximal exercise and the rate decay during recovery. During interference studies by arm swinging (30-40 swings/min) and external tapping of the pacemakers (2 taps/s), there was only a moderate increase in pacing rate by 13 +/- 9, 16 +/- 5 beats/min. Hence, the new integrated sensor with the automatic rate profile optimization algorithm resulted in improved rate response profiles during submaximal exercise and ADL compared to the individual sensor response, and the sensor blending and cross-checking algorithm made the pacemaker relatively immune to false triggering of both the ACT and MV sensors.

Activities of Daily Living↗