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PubMed2002

A new role for BiP: closing the aqueous translocon pore during protein integration into the ER membrane.

In mammalian cells, most membrane proteins are inserted cotranslationally into the ER membrane at sites termed translocons. Although each translocon forms an aqueous pore, the permeability barrier of the membrane is maintained during integration, even when the otherwise tight ribosome-translocon seal is opened to allow the cytoplasmic domain of a nascent protein to enter the cytosol. To identify the mechanism by which membrane integrity is preserved, nascent chain exposure to each side of the membrane was determined at different stages of integration by collisional quenching of a fluorescent probe in the nascent chain. Comparing integration intermediates prepared with intact, empty, or BiP-loaded microsomes revealed that the lumenal end of the translocon pore is closed by BiP in an ATP-dependent process before the opening of the cytoplasmic ribosome-translocon seal during integration. This BiP function is distinct from its previously identified role in closing ribosome-free, empty translocons because of the presence of the ribosome at the translocon and the nascent membrane protein that extends through the translocon pore and into the lumen during integration. Therefore, BiP is a key component in a sophisticated mechanism that selectively closes the lumenal end of some, but not all, translocons occupied by a nascent chain. By using collisional quenchers of different sizes, the large internal diameter of the ribosome-bound aqueous translocon pore was found to contract when BiP was required to seal the pore during integration. Therefore, closure of the pore involves substantial conformational changes in the translocon that are coupled to a complex sequence of structural rearrangements on both sides of the ER membrane involving the ribosome and BiP.

Adenosine Triphosphate↗
PubMed2004

Social integration and mortality: a prospective study of French employees of Electricity of France-Gas of France: the GAZEL Cohort.

The authors investigated associations between social integration and all-cause and cause-specific mortality among French employees of Electricity of France-Gas of France. A total of 12,347 men aged 40-50 years in 1989 and 4,352 women aged 35-50 years in 1989 comprised the sample. In age-adjusted survival analyses for all causes of death, men who were least socially integrated were 4.42 times as likely to die during follow-up (1993-1999) as those with the highest level of integration (p < 0.0001). After adjustment for age, occupation, smoking, alcohol consumption, body mass index, self-reported health, depressive symptoms, and region of France, relative risks for men ranging from the least socially integrated to the most socially integrated were 2.70 (95% confidence interval (CI): 1.17, 6.23), 1.95 (95% CI: 1.25, 3.04), and 1.37 (95% CI: 0.92, 2.04) in comparison with the most integrated men. In multivariate cause-specific analyses, isolated men had elevated risks of dying from cancer (relative risk = 3.60) and from accidents and suicide (relative risk = 3.54). Among women, in multivariate analyses, the relative risk was 3.64 (95% CI: 0.72, 18.58). The small number of deaths among women (n = 29) limited statistical power and prohibited cause-specific analyses. These results suggest that in this employed cohort of middle-aged men and women, social integration is an important predictor of mortality.

Adult↗
PubMed2026

SIVA: diagonal integration of spatial multi-omics data via spatially informed variational autoencoders and anchor guidance.

MOTIVATION: Understanding cellular states and regulatory programs requires integrative analysis of multiple omics layers. Although recent spatial sequencing technologies allow molecular profiling of cells within their tissue context, paired spatial multi-omics assays are still limited by technical complexity and cost. This creates a pressing need for diagonal integration methods that enable joint analysis of unpaired spatial omics datasets. RESULTS: We propose SIVA, a deep generative framework based on Spatially-Informed Variational Autoencoders with Anchor Guidance, for diagonal integration of spatial multi-modal data. SIVA employs modality-specific variational autoencoders (VAEs) with a hybrid latent embedding that integrates Gaussian process and standard Gaussian priors, enabling joint modeling of spatially structured variation and dominant underlying data distributions across modalities. To facilitate cross-modal alignment in the absence of one-to-one cell correspondence, SIVA adopts a dual integration strategy combining global distribution alignment via Maximum Mean Discrepancy and local correspondence guidance using mutual nearest neighbor anchors. Extensive experiments across multiple cross-slice integration scenarios demonstrate that SIVA achieves robust and accurate integration of unpaired spatial omics datasets, consistently outperforming existing methods. AVAILABILITY AND IMPLEMENTATION: The source codes are available at https://github.com/PelenJiang/SIVA.

Autoencoder↗
PubMed2006

Functional specializations in lateral prefrontal cortex associated with the integration and segregation of information in working memory.

Control processes are thought to play an important role in working memory (WM), by enabling the coordination, transformation, and integration of stored information. Yet little is known about the neural mechanisms that subserve such control processes. This study examined whether integration operations within WM involve the activation of distinct neural mechanisms within lateral prefrontal cortex (PFC). Event-related functional magnetic resonance imaging was used to monitor brain activity while participants performed a mental arithmetic task. In the integration (IN) condition, a WM preload item had to be mentally inserted into the last step of the math problem. This contrasted with the segregation (SG) condition, which also required maintenance of the WM preload while performing mental arithmetic but had no integration requirement. Two additional control conditions involved either ignoring the preload (math only condition) or ignoring the math problem (recall only condition). Left anterior PFC (Brodmann's Area [BA] 46/10) was selectively engaged by integration demands, with activation increasing prior to, as well as during the integration period. A homologous right anterior PFC region showed selectively increased activity in the SG condition during the period in which the math problem and preload digit were reported. Left middorsolateral PFC regions (BA 9/46) showed increased, but equivalent, activity in both the SG and IN conditions relative to both control conditions. These results provide support for the selective role of lateral PFC in cognitive control over WM and suggest more specific hypotheses regarding dissociable PFC mechanisms involved during the integration and segregation of stored WM items.

Adolescent↗
PubMed1994

Integration of plasmids into the bacteriophage T4 genome.

We have analyzed the integration of plasmids into the bacteriophage T4 genome via homologous recombination. As judged by genetic selection for a plasmid-borne marker, a mutation in phage gene uvsX or uvsY essentially blocked the integration of a plasmid with homology to the T4 genome but no phage replication origin (non-origin plasmid). The strict requirement for these two proteins suggests that plasmid integration can proceed via a strand-invasion reaction similar to that catalyzed in vitro by the T4-encoded strand-exchange protein (UvsX) in concert with UvsY and gp32. In contrast to the results with the non-origin plasmid, a mutation in uvsX or uvsY reduced the integration of a T4 replication origin-containing plasmid by only 3-10-fold. These results suggest that the origin-containing plasmid integrates by both the UvsXY-dependent pathway used by the non-origin plasmid and by a UvsXY-independent pathway. The origin-containing plasmid integrated into the phage genome during a uvsX- or uvsY-mutant infection of a recA-mutant host, and therefore origin-dependent integration can occur in the absence of both phage- and host-encoded strand-exchange proteins (UvsX and RecA, respectively).

Adenosine Triphosphatases↗
PubMed1995

The size and continuity of DNA segments integrated in Bacillus transformation.

We investigated the size and continuity of DNA segments integrated in Bacillus subtilis transformation. We transformed B. subtilis strain 1A2 toward rifampicin resistance (coded by rpoB) with genomic DNA and with a PCR-amplified 3.4-kb segment of the rpoB gene from several donors. Restriction analysis showed that smaller lengths of donor DNA integrated into the chromosome with transformation by PCR-amplified DNA than by genomic DNA. Nevertheless, integration of very short segments (< 2 kb) from large, genomic donor molecules was not a rare event. With PCR-amplified segments as donor DNA, smaller fragments were integrated when there was greater sequence divergence between donor and recipient. There was a large stochastic component to the pattern of recombination. We detected discontinuity in the integration of donor segments within the rpoB gene, probably due to multiple integration events involving a single donor molecule. The transfer of adaptations across Bacillus species may be facilitated by the small sizes of DNA segments integrated in transformation.

Bacillus subtilis↗
PubMed1990

Effects of contextual integration on recall of pictures by older adults.

This study investigated age-related differences in the ability to utilize integrative relationships between target and context as a memory support by directly manipulating the relationship between a target picture and context. We hypothesized that as the active integration required between target and cue increased, age differences would increase. Old and young adults were instructed to remember target pictures, each presented with a pictorial cue. The cue/target relationship was one of three types: categorically related (high integration condition), visually interacting (high integration condition), or unrelated and noninteracting (low integration condition). Cued recall of the targets was tested. The results indicated that the poorly integrated target-context relationship produced the largest age difference, supporting the integration hypothesis.

Adolescent↗
PubMed1987

Integration of a vector containing rodent repetitive elements in the rat genome.

We have previously shown that integration of a polyoma vector containing rodent repetitive elements into rat cellular DNA is non-random (Wallenburg et al. J. Virol. 50: 678-683). Junctions between the polyoma vector and the host DNA occur in the repetitive sequences of the vector about ten times more frequently than would be expected if sequences from the vector were used randomly for integration. In this paper we looked at the host sequences involved in these junctions. Our analysis did not reveal any repetitive or specific sequences and we presume therefore that the repetitive sequences of the vector acted as hot spots for illegitimate recombination. We also analysed the integration mechanism and found that: First, even though the polyoma vector was transfected in the presence of carrier DNA, integration did not involve the formation of a transgenome. Second, in at least one of the clones analysed, integration resulted in deletion of host DNA sequences. Third, the host DNA displaced at the integration site was considerably longer than the integrated segment.

Animals↗
PubMed2005

Analysis of flowering pathway integrators in Arabidopsis.

Flowering is regulated by an integrated network of several genetic pathways in Arabidopsis. The key genes integrating multiple flowering pathways are FT, SOC1 and LFY. To elucidate the interactions among these integrators, genetic analyses were performed. FT and SOC1 share the common upstream regulators CO, a key component in the long day pathway, and FLC, a flowering repressor integrating autonomous and vernalization pathways. However, the soc1 mutation further delayed the flowering time of long day pathway mutants including ft, demonstrating that SOC1 acts partially independently of FT. Although soc1 did not show an obvious defect in flower meristem determination on its own, it dramatically increased the number of coflorescences in a lfy mutant, which is indicative of a defect in floral initiation. Therefore, double mutant analysis shows that the three integrators have both overlapping and independent functions in the determination of flowering time and floral initiation. The expression analysis showed that FT regulates SOC1 expression, and SOC1 regulates LFY expression, but not vice versa, which is consistent with the fact that FT and LFY have the least overlapping functions among the three integrators. The triple mutation ft soc1 lfy did not block flowering completely under long days, indicating the presence of other integrators. Finally, vernalization accelerated flowering of flc ft soc1 and ft soc1 lfy triple mutants, which shows that the vernalization pathway also has targets other than FLC, FT, SOC1 and LFY. Our genetic analysis reveals the intricate nature of genetic networks for flowering.

Arabidopsis↗
PubMed1997

Effects of water- and lipid-soluble antioxidants on turkey sperm viability, membrane integrity, and motility during liquid storage.

Aerobic conditions are required to maintain the viability of turkey sperm in vitro. In mammalian sperm, excess oxygen during in vitro storage results in lipid peroxidation, causing membrane damage and reduced sperm motility and subsequent fertility. The effect of adding antioxidants to turkey sperm during liquid storage was studied. Semen was collected and pooled from 20 toms and antioxidants were tested at a minimum of six concentrations, n = 6 observations per concentration. Semen was diluted into Beltsville Poultry Semen Extender. Extended semen served as a control; treatments were extended semen supplemented with tocopherol (vitamin E, 1 to 80 micrograms/mL); butylated hydroxytoluene (BHT, 0.02 to 1.25 mM); Tempo (0.039 to 1.25 microM), or vitamin C (1 to 400 micrograms/mL) and stored at 5 C for 48 h. Sperm viability in extended semen was evaluated after 0, 24, or 48 h storage. Membrane integrity and motility were also measured. Flow cytometric analysis was done using the live/dead stain combination (SYBR-14/propidium iodide) for sperm viability, and membrane integrity was assessed using a hypo-osmotic stress test. Sperm motility was evaluated subjectively. Control sperm viability was reduced almost 50% between 0 and 48 h. However, supplementation with vitamin E, Tempo, and BHT maintained populations of viable sperm similar to the 0 h levels at 48 h. Hypo-osmotic membrane integrity in the control sperm was reduced to approximately 22% (at 24 h, P < or = 0.05) and 5% (at 48 h, P < or = 0.05) of the total sperm population. Similar to controls after 24 h in vitro storage, sperm treated with the antioxidants vitamin E, Tempo, and BHT had reduced hypo-osmotic membrane integrity compared to 0 h samples. However, many of these treated samples maintained hypo-osmotic membrane integrity observed from 24 through 48 h (range, 21.5 to 44.6%), whereas hypo-osmotic membrane integrity fell to 4.6% at 48 h for the control (P < or = 0.05). Vitamin C treatments were similar to controls at all time points. Addition of the antioxidants vitamin E, BHT, and Tempo to extended turkey semen improves sperm survival, membrane integrity, and reduces the loss of motility after 48 h storage.

Analysis of Variance↗
PubMed2006

Chimeric Mos1 and piggyBac transposases result in site-directed integration.

Genetic transformation systems based on Mos1 and piggyBac transposable elements are used to achieve stable chromosomal integration. However, integration sites are randomly distributed in the genome and transgene expression can be influenced by position effects. We developed a novel technology that utilizes chimeric transposases to direct integration into specific sites on a target DNA molecule. The Gal4 DNA binding domain was fused to the NH(2) terminus of the Mos1 and piggyBac transposases and a target plasmid was created that contained upstream activating sequences (UAS), to which the Gal4 DBD binds with high affinity. The transpositional activity of the Gal4-Mos1 transposase was 12.7-fold higher compared to controls where the Gal4-UAS interaction was absent and 96% of the recovered transposition products were identical, with integration occurring at the same TA site. In a parallel experiment, a Gal4-piggyBac transposase resulted in an 11.6-fold increase in transpositional activity compared to controls, with 67% of the integrations occurring at a single TTAA site. This technology has the potential to minimize nonspecific integration events that may result in insertional mutagenesis and reduced fitness. Site-directed integration will be advantageous to the manipulation of genomes, study of gene function, and for the development of gene therapy techniques.

Aedes↗
PubMed2002

Integrated fellowship in vascular surgery and intervention radiology: a new paradigm in vascular training.

OBJECTIVE: To evaluate an integrated fellowship in vascular surgery and interventional radiology initiated to train vascular surgeons in endovascular techniques and to train radiology fellows in clinical aspects of vascular diseases. SUMMARY BACKGROUND DATA: The rapid evolution of endovascular techniques for the treatment of vascular diseases requires that vascular surgeons develop proficiency in these techniques and that interventional radiologists develop proficiency in the clinical evaluation and management of patients who are best treated with endovascular techniques. In response to this need the authors initiated an integrated fellowship in vascular surgery and interventional radiology and now report their interim results. METHODS: Since 1999 vascular fellows and radiology fellows performed an identical year-long fellowship in interventional radiology. During the fellowship, vascular surgery and radiology fellows perform both vascular and nonvascular interventional procedures. Both vascular surgery and radiology-based fellows spend one quarter of the year on the vascular service performing endovascular aortic aneurysm repairs and acquiring clinical experience in the vascular surgery inpatient and outpatient services. Vascular surgery fellows then complete an additional year-long fellowship in vascular surgery. To evaluate the type and number of interventional radiology procedures, the authors analyzed records of cases performed by all interventional radiology and vascular surgery fellows from a prospectively maintained database. The attitudes of vascular surgery and interventional radiology faculty and fellows toward the integrated fellowship were surveyed using a formal questionnaire. RESULTS: During the fellowship each fellow performed an average of 1,201 procedures, including 808 vascular procedures (236 diagnostic angiograms, 70 arterial interventions, 59 diagnostic venograms, 475 venous interventions, and 43 hemodialysis graft interventions) and 393 nonvascular procedures. On average fellows performed 20 endovascular aortic aneurysm repairs per year. There was no significant difference between the vascular surgery and radiology fellows in either the spectrum or number of cases performed. Eighty-eight percent (23/26) of the questionnaires were completed and returned. Both interventional radiologists and vascular surgeons strongly supported the integrated fellowship model and favored continuation of the integrated program. Vascular surgery and interventional radiology faculty members wanted additional training in clinical vascular surgery for the radiology-based fellows. With the exception of the radiology fellows there was uniform agreement that vascular surgery fellows benefit from training in nonvascular aspects of interventional radiology. CONCLUSIONS: Integration of vascular surgery and interventional radiology fellowships is feasible and is mutually beneficial to both disciplines. Furthermore, the integrated fellowship provides exceptional training for vascular surgery and interventional radiology fellows in all catheter-based techniques that far exceeds the minimum requirements for credentialing suggested by various professional societies. There is a clear need for cooperation and active involvement on the parts of the American Board of Radiology and the American Board of Surgery and its Vascular Board to create hybrid training programs that meet mutually agreed-on criteria that document sufficient acquisition of both the cognitive and technical skills required to manage patients undergoing endovascular procedures safely and effectively.

Attitude of Health Personnel↗
PubMedDate not supplied

Factors that lead to successful community integration following severe traumatic brain injury.

OBJECTIVE: To assess and identify predictive factors of community integration of people 3 to 15 years after severe traumatic brain injury (TBI). PARTICIPANTS: Forty participants with severe TBI (an average of 8.8 years postinjury). MAIN OUTCOME MEASURES: The Community Integration Questionnaire, the Community Integration Measure, and the Sydney Psychosocial Reintegration Scale. Data related to factors that may predict community integration were also collected. RESULTS: There was considerable variation in the level of community integration. Discriminant function analyses identified the following factors as predictive of the level of community integration: severity of injury, age at the time of injury, level of disability, and challenging behavior. CONCLUSION: Interventions that minimize challenging behavior and disability may make a significant difference to the level of community integration experienced by people with severe TBI.

Activities of Daily Living↗
PubMed2005

Viewpoint: what is the best and most ethical model for the relationship between mainstream and alternative medicine: opposition, integration, or pluralism?

Despite radical improvements in medicine over the past 60 years, patients maintain multiple health care pathways that include high utilization of unconventional treatments. The authors examine three possible relationships between mainstream and alternative medicine: opposition, integration, and pluralism. Opposition, the traditional ethical position that the medical profession must eradicate unconventional medicine for the good of the patient, has withered away. Integration of mainstream and alternative medicine is increasingly advocated in tandem with hospital-based programs that amalgamate the use of conventional and alternative therapies. While advocates of integrative medicine often speak of "evidence-based" complementary and alternative medicine (CAM), integration fosters double standards for validating conventional and unconventional treatments. Integration also ignores unbridgeable epistemological beliefs and practices between mainstream and alternative medicine. Pluralism, which has been relatively ignored, calls for cooperation between the different medical systems rather than their integration. By recognizing the value of freedom of choice in medical options, pluralism is compatible with the principle of patient autonomy. Nonetheless, the pluralistic model does not amount to a relativistic stance according in which there would be no objective standards for comparing the therapeutic merit of conventional and CAM treatments. As an ethical model, pluralism realizes that physicians must be prepared to disagree with patient choices to pursue alternative therapies, and urge patients not to forgo medically indicated treatment. Pluralism encourages cooperation, research, and open communication and respect between practitioners despite the possible existence of honest disagreement, and preserves the integrity of each of the treatment systems involved.

Clinical Medicine↗
PubMedDate not supplied

Community integration after burn injuries.

Evaluation of community integration is a meaningful outcome criterion after major burn injury. The Community Integration Questionnaire (CIQ) was administered to 463 individuals with major burn injuries. The CIQ results in Total, Home Integration, Social Integration, and Productivity scores. The purposes of this study were to determine change in CIQ scores over time and what burn injury and demographic factors predict CIQ scores. The CIQ scores did not change significantly from 6 to 12 to 24 months postburn injury. Home integration scores were best predicted by sex and living situation; Social Integration scores by marital status; and Productivity scores by functional outcome, burn severity, age, and preburn work factors. The data demonstrate that individuals with burn injuries have significant difficulties with community integration due to burn and nonburn related factors. CIQ scores did not improve over time but improvement may have occurred before the initial 6-month postburn injury follow-up in this study.

Adult↗
PubMedDate not supplied

Effects of entorhinal cortex lesions on sensory integration and spatial learning.

BACKGROUND: The entorhinal cortex provides sensory information to the hippocampus for memory and learning. Damage to the entorhinal cortex is common in patients who experience traumatic brain injury, stroke, and Alzheimer's disease. Entorhinal damage is assumed to interfere with sensory integration; however, substantive knowledge of behavioral patterns is lacking. OBJECTIVES: To describe specific behavioral deficits associated with entorhinal cortex injury related to special senses identification, sensory integration, and spatial learning. METHOD: Adult male rats received bilateral entorhinal cortex damage (n = 19) or sham surgery (n = 11) with a subset randomized to participate in special senses identification, exploration, and sensory integration testing. Spatial learning was examined using a water maze. RESULTS: Lesion and control animals were similar in special senses identification testing. Sensory integration was markedly impaired in lesion animals over 3 days for all integration tasks; however, travel deficit persisted for 4 days. By day 5 sensory integration ability was equal. Lesion animals were significantly impaired across all days of spatial learning for swim time (p = .0001) and directional heading error (p = .03). Control animals exposed to sensory testing demonstrated significantly more efficient learning (p = .005) on swim days 2 and 3 versus control animals not exposed to sensory testing. CONCLUSIONS: Early and prolonged behavioral changes are evident following entorhinal cortex damage including sensory integration deficits and persistent spatial learning impairment.

Alzheimer Disease↗
PubMedDate not supplied

Maintaining data integrity in randomized clinical trials.

BACKGROUND: The process of attaining and maintaining data integrity is critical to ensure a successful randomized clinical trial. Methodologic strategies to achieve data integrity when repeated measures are used has not been discussed in detail in the literature. The National Institutes of Health requires that data integrity and safety monitoring boards or plans be established for randomized clinical trials. OBJECTIVES: The objectives of this paper are to (a) examine important data collection issues nurse scientists often encounter in randomized clinical trials and (b) present a process that researchers can apply to achieve data integrity. METHODS: The process to achieve data integrity is based on strategies that were developed by an interdisciplinary hospice research team involved in an ongoing National Institutes of Health-funded clinical trial. The process and key issues are illustrated with methodologic examples from the randomized clinical trial and supporting literature. RESULTS: The process of achieving data integrity involves developing protocols in three key areas: data collection, training of data collectors, and data monitoring. The use of these protocols will increase the rigor of the clinical trial and assist in maintaining study validity. CONCLUSIONS: Investigators conducting clinical trials need to consider all issues involved in achieving data integrity and have tested protocols in place throughout the study. These approaches will not only help maintain study validity but also help ensure data of sufficient quantity and quality to achieve the desired statistical power.

Bias↗
PubMed1997

Early detection of progression in adolescent idiopathic scoliosis by measurement of changes in back shape with the Integrated Shape Imaging System scanner.

STUDY DESIGN: A retrospective study of 78 patients with right thoracic idiopathic scoliosis was done. OBJECTIVES: To evaluate the reliability of the integrated Shape Imaging System scan (Oxford Metrics Ltd, Oxford, UK) in detecting progression of scoliosis and the use of back shape data in predicting scoliosis progression. SUMMARY OF BACKGROUND DATA: At first presentation and every 3-6 months during the follow-up period, all patients underwent integrated Shape Imaging System scans and radiographic examinations, from which the Cobb angle was measured. The follow-up period was 18-49 months (mean = 31.4 months). METHODS: Patients were divided into three groups according to the severity and progression of the Cobb angle. The spinal fusion, brace, and observation groups were compared using analysis of variance and the student's t test to detect significant differences among groups in the progression of deformity as measured by the integrated Shape Imaging System parameters and the Cobb angle. RESULTS: Three of the Integrated Shape Imaging System parameters detected significant progression in the spinal fusion group 1 year earlier than the Cobb angle. Only one of the Integrated Shape Imaging System parameters detected a significant difference in progression between the brace and observation groups. CONCLUSIONS: The Integrated Shape Imaging System technique demonstrated significant changes in this group of patients with progressive scoliosis. Serial measurements of back surface shape, particularly the size of the rib hump, may be predictive of progression. Serial Integrated Shape Imaging System scanning has advantages over serial radiography in the management of idiopathic scoliosis in addition to the avoidance of exposure to ionizing radiation.

Adolescent↗