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PubMed1996

A vaccinia virus core protein, p39, is membrane associated.

We describe herein the characterization of p39, the product of the A4L gene of vaccinia virus. By immunolabelling of thawed cryosections from infected HeLa cells, we show that this protein is initially located in the central region, or viroplasm, of the viral factories, as well as in the immature virions, with very small amounts of labelling observed on the surrounding membranes. The localization of p39 changes dramatically during the transition of the immature virion to the intracellular mature virus (IMV), coincident with the appearance of the core structure in the center of the IMV, with p39 located between this core and the surrounding membranes. Complementary biochemical data, such as partitioning into the Triton X-114 detergent phase and stripping of the viral membranes with Nonidet P-40 and dithiothreitol, suggest that p39 is associated with the innermost of the two membranes surrounding the core. Sodium carbonate treatment also indicates that p39 is associated with membranes, even at the early stages of viral assembly. However, following in vitro translation of p39 in the presence of microsomal membranes, we failed to detect any association of the independently expressed protein with membranes. We also failed to detect any posttranslational acylation of p39 with myristate or palmitate, suggesting that p39 does not achieve its membrane association through lipid anchors. Therefore, p39 is most likely membrane associated through an interaction with an integral membrane protein(s) present in the innermost of the two membranes surrounding the IMV. These data, together with our recent data showing that p39 colocalizes with the spike-like protrusions on the IMV core (N. Roos, M. Cyrklaff, S. Cudmore, R. Blasco, J. Krijnse-Locker, and G. Griffiths, EMBO J. 15:2343-2355, 1996), suggest that p39 may form part of this spike and that it possibly functions as a matrix-like linker protein between the core and the innermost of the two membranes surrounding the IMV.

Cell Membrane↗

PubMed1989

High-level recombination specific to polyomavirus genomes targeted to the integration-transformation pathway.

An unusually high incidence of interviral recombination was found in the process of integration of the polyomavirus genome concomitant with neoplastic transformation of nonpermissive cells. Transformants were isolated after mixed infections of Fischer rat cells with two mutants lacking restriction endonuclease sites and were analyzed for the presence of unselected integrated recombinant restriction fragments. A large fraction of the transformants isolated (38% of the 64 transformed cell lines studied) contained recombinant viral genomes that had undergone recombination in a 1.3-, 1.7-, or 3.6-kilobase-pair interval. More than 90% of these recombinant transformants showed evidence of crossovers in multiple intervals. To our knowledge, the recombination frequencies observed in these experiments represent the highest frequencies of homologous recombination reported for a mitotic mammalian system that does not involve transfection. In contrast to the elevated level of recombination in the integrated viral genomes, no evidence of recombination was obtained among the replicated unintegrated pool of viral genomes isolated from the same population of infected cells from which the recombinant transformants were derived. Either of two hypotheses can provide an explanation for the segregated recombination: either recombination occurs at elevated levels in a small, recombination-prone fraction of the population destined to become transformed, or recombination occurs only among those viral genomes which are engaged in the process of integration and thus interact with a recombinogenic host machinery (for example, the host scaffold). We favor the latter hypothesis.

Animals↗

PubMed1995

Barrier function of the gastric mucus gel.

The gastric epithelium is covered by a continuous layer of secreted mucus and bicarbonate. The function of this mucobicarbonate layer in terms of protecting the epithelial cells from luminal acid is controversial. Several studies conducted in vitro have shown that gastric mucus can slow proton diffusion and can enable the formation of a pH gradient across the mucobicarbonate layer. In our laboratory, simultaneous measurements of intracellular pH and the thickness of the mucus gel overlying gastric surface cells in vivo indicated that surface cell acidification rates and mucus gel thickness were inversely related. This suggests that the gastric mucobicarbonate layer delays proton permeation into gastric surface cells, enabling secreted bicarbonate to neutralize luminal acid. Several theoretical models, including the effects of mucus and bicarbonate secretion, convection, stirring, and lipids are offered as a possible explanation for the experimental observations. Lipid content and additional unstirred layers outside of the mucus gel are offered as possible explanations for the experimental observations. On the basis of the available data and theoretical considerations, we can conclude that all of these factors probably interact in an integrated manner to protect the gastric epithelial cells from damage due to luminal acid.

Animals↗

PubMed1993

Gastric loads and cholecystokinin synergistically stimulate rat gastric vagal afferents.

Both gastric preloads and exogenous cholecystokinin (CCK) administration inhibit food intake, and combinations of preloads and CCK suppress feeding to a greater degree than either stimulus delivered alone. A role for the vagus nerve in mediating CCK's inhibition of food intake has been proposed, and gastric vagal afferent fibers respond to both gastric loads and local CCK infusions. To examine whether combined load and CCK stimuli may synergistically augment gastric neural afferent activity at the level of the peripheral vagus, we have examined the gastric vagal afferent responses (n = 8) to a range of gastric saline loads (1, 2, and 3 ml) and exogenous close celiac arterial CCK (10 and 100 pmol) when administered alone or in combination. Gastric loads ineffective in eliciting a significant increase in vagal afferent activity when administered alone became effective when combined with doses of CCK that were subthreshold for the production of a vagal afferent response. Gastric loads that alone were effective in producing a significant vagal afferent response yielded an even greater response when administered in combination with both subthreshold and suprathreshold doses of CCK. These data demonstrate that, in rats, signals produced by combined gastric load and exogenous CCK administration are integrated peripherally and interact synergistically. These results suggest that signals arising from the vagus may provide sufficient information for the synergistic inhibition of food intake produced by combinations of gastric loads and exogenous CCK.

Afferent Pathways↗

PubMed1999

Evaluation of LH secretory dynamics during the rat proestrous LH surge.

The preovulatory luteinizing hormone (LH) surge results from the integration of complex interactions among gonadal steroids and hypothalamic and pituitary hormones. To evaluate changes in LH secretory dynamics that occur during the rat LH surge, we have 1) obtained frequently sampled serum LH concentration time series, 2) used both waveform-dependent and waveform-independent convolution analyses, and 3) independently assessed proestrous LH half-life and basal non-gonadotropin-releasing hormone (GnRH)-dependent LH secretion during the LH surge. Waveform-independent pulse analysis revealed a 24-fold increase in the maximal pulsatile LH secretory rate attained during late proestrus compared with early proestrus. A 15-fold increase was quantified for the mean LH secretory rate. In complementary analyses, we applied a measured LH half-life of 17 +/- 2.7 min and a median basal LH secretion rate of 0.0046 microgram. l-1. min-1 for convolution analysis, revealing a 16-fold increase in the mass of LH released/burst and more than sixfold rise in the amplitude of the secretory peaks. Evaluation of the approximate entropy of the LH surge profiles was performed, showing an increase in the orderliness of the LH release process during the surge. We conclude that both quantitative (mass/burst) and qualitative (approximate entropy) features of LH release are regulated during the proestrous LH surge.

Animals↗

PubMed2025

An Annotated Biobank of Triple-Negative Breast Cancer Patient-Derived Xenografts Features Treatment-Naïve and Longitudinal Samples during Neoadjuvant Chemotherapy.

UNLABELLED: Triple-negative breast cancer (TNBC) that fails to respond to neoadjuvant chemotherapy (NACT) can be lethal. Developing effective strategies to eradicate chemoresistant disease requires experimental models that recapitulate the heterogeneity characteristic of TNBC. To that end, we established a biobank of 92 orthotopic patient-derived xenograft (PDX) models of TNBC from the tumors of 75 patients enrolled in A Robust TNBC Evaluation fraMework to Improve Survival clinical trial (ARTEMIS, NCT02276443), including 12 longitudinal sets generated from serial patient biopsies collected throughout NACT treatment and from metastatic disease. Models were established from both chemosensitive and chemoresistant tumors, and nearly 30% of the PDX models were capable of metastasizing to the lungs. Comprehensive molecular profiling demonstrated conservation of genomes and transcriptomes between patient and corresponding PDX tumors, with representation of all major transcriptional subtypes. Transcriptional changes observed in the longitudinal PDX models highlighted dysregulation in pathways associated with DNA integrity, extracellular matrix interactions, the ubiquitin-proteasome system, epigenetics, and inflammatory signaling. These alterations revealed a complex network of adaptations associated with chemoresistance. Overall, this PDX biobank provides a valuable tool for tackling the most pressing issues facing the clinical management of TNBC. SIGNIFICANCE: The development of a patient-derived xenograft biobank that comprehensively captures the genomic and transcriptional diversity of triple-negative breast cancer promises to be a robust resource to investigate and overcome chemoresistance and metastasis.

Animals↗

PubMed1987

Single-scan stereotactic tumor biopsy and brachytherapy.

Stereotactic tumor biopsy and brachytherapy catheter implantation can be accomplished with targets derived from computed axial tomography and magnetic resonance scans. Computer manipulation of image data allows both diagnostic and therapeutic procedures to be carried out from a single set of scan slices. This eliminates the need for repeat scanning as part of the surgical procedure. Microcomputer technology is sufficiently advanced to handle the images and graphics necessary for stereotactic neurosurgery. A system based on the IBM PC/AT designed for this purpose uses readily available graphics software and custom-designed imaging programs. Direct loading of computed axial or magnetic resonance scan images from magnetic tape can be accomplished. Determination of points, contours and volumes in three-dimensional space allows intraoperative alignment of image data and patient landmarks within the stereotactic head frame using pattern recognition overlays. Three-axis scaling for magnification correction along with rotational and linear data transformations provide the basis for single-scan stereotaxis. Interactive computer graphics integrate image, patient and frame coordinates for target determination. This method eliminates the need to design and fabricate nonmagnetic or radiolucent scanner-compatible devices.

Biopsy↗

PubMed1990

Neural pathway for aggressive display in Betta splendens: midbrain and hindbrain control of gill-cover erection behavior.

Horseradish peroxidase (HRP) was used to identify parts of the presumptive neural pathway for gill cover erection, a behavioral display pattern performed by Siamese fighting fish (Betta splendens) during aggressive interactions. Motor, motor integration and sensory areas were identified in the medulla and mesencephalon. Motor neurons of the dilator operculi muscle, the effector muscle for gill cover erection, are located in the lateral and medial parts of the caudal trigeminal motor nucleus. Iontophoretic injections of HRP into the lateral trigeminal motor nucleus resulted in labeled cell bodies in two motor areas (medial part of the trigeminal motor nucleus, anterior part of the motor nucleus of cranial nerve IX-X), two parts of the reticular formation (medial and inferior reticular areas), and two nuclei of the octavolateralis system (nucleus medialis, magnocellular octaval nucleus). The HRP injections in the medial part of the caudal trigeminal motor nucleus resulted in labeled cells in the lateral part of the nucleus and in the medial reticular nucleus. Discrete injections of HRP into nucleus medialis revealed a strong axonal projection that terminated in the torus semicircularis. The medial reticular area and both of the octavolateralis nuclei received projections from their contralateral counterparts. Connections between motor areas, and between parts of the reticular formation, may coordinate the performance of gill cover erection with other behavioral patterns used during aggressive display. Connections with the octavolateralis system may provide information on the strength of an opponent's tail beats via the lateral-line system, as well as vestibular information about the fish's own orientation during aggressive display. The organization of inputs to the trigeminal motor nucleus in Betta, a perciform fish, was found to differ from that reported in the common carp, a cypriniform fish. These differences may underlie the different behavioral capabilities of the two groups of fish.

Afferent Pathways↗

PubMed1991

A consensus approach to electrolytes and blood pressure. Could we all be right?

This commentary sets forth the hypothesis that the putative beneficial or detrimental effects of specific electrolytes on blood pressure regulation in fact reflect highly integrated responses to interactions among these cationic and anionic species. In this paradigm, the impact of any given intake of an electrolyte on arterial pressure will be influenced by the concurrent consumption of other electrolytes. Thus, the heterogeneous blood pressure response in humans to isolated manipulations of nutrients such as sodium, calcium, and potassium may be determined, in part, by the adequacy of the dietary intake of other mineral elements. If this hypothesis is validated by continued research in this area, we would have new strategies available to improve blood pressure control in humans. For example, treatment of "NaCl sensitivity" in some humans might be more effectively approached by correcting dietary deficiencies of either potassium or calcium than by restricting dietary NaCl.

Blood Pressure↗

PubMed2004

Neural mechanisms for the robust representation of junctions.

Junctions provide important cues in various perceptual tasks, such as the determination of occlusion relationships for figure-ground separation, transparency perception, and object recognition, among others. In computer vision, junctions are used in a number of tasks, like point matching for image tracking or correspondence analysis. We propose a biologically motivated approach to junction representation in which junctions are implicitly characterized by high activity for multiple orientations within a cortical hypercolumn. A local measure of circular variance is suggested to extract junction points from this distributed representation. Initial orientation measurements are often fragmented and noisy. A coherent contour representation can be generated by a model of V1 utilizing mechanisms of collinear long-range integration and recurrent interaction. In the model, local oriented contrast estimates that are consistent within a more global context are enhanced while inconsistent activities are suppressed. In a series of computational experiments, we compare junction detection based on the new recurrent model with a feedforward model of complex cells. We show that localization accuracy and positive correctness in the detection of generic junction configurations such as L- and T-junctions is improved by the recurrent long-range interaction. Further, receiver operating characteristics analysis is used to evaluate the detection performance on both synthetic and camera images, showing the superior performance of the new approach. Overall, we propose that nonlocal interactions implemented by known mechanisms within V1 play an important role in detecting higher-order features such as corners and junctions.

Models, Neurological↗

PubMedDate not supplied

School evolution: scientist-practitioner educators creating optimal learning environments for all students.

Similarities and differences between discursive practitioners and scientist-practitioners are discussed in reference to a variety of issues. The scientist-practitioner's approach to generating and evaluating new knowledge is illustrated with two partnerships: (a) between the University of Washington Multidisciplinary Learning Disability Center and a school district (at-risk first graders in the Los Angeles Unified School District) and (b) between the University of Washington Literacy Trek Project and a local school (at-risk second graders in Seattle public schools). Both partnerships involved mostly children who were English language learners. These partnerships also illustrated how Vygotsky's approach to fostering cognitive development through social interaction can be integrated with that of his pupil Luria, who assessed the neuropsychological processes of the individual mind/brain. The most effective instruction for school-age children, who exhibit biological and cultural diversity, takes into account individual and social-cultural variables.

Biomedical Research↗

PubMed2001

Scanning electric conductivity gradients with ultrasonically-induced Lorentz force.

The ions in a fluid element oscillating under the effect of a sound wave in the presence of a magnetic field are submitted to Lorentz force. This gives rise to a bulk current density proportional to the medium's electric conductivity. In the present study, the integrality of this interaction current was collected using a pair of plane electrodes located on opposite sides of the sample. A focused transducer produced ultrasound bursts of 10 micros duration, 500 kHz frequency and 1.5 MPa peak pressure. The magnetic field was created by a purpose-built 0.35 T permanent magnet. Wiener inverse filtering was used to retrieve the system response from the recorded waveforms. The final signal was shown to be proportional to the gradient of sigma/rho along ultrasound propagation axis. Electric conductivity, sigma, predominantly controls this parameter since mass density, rho, does not vary in great proportions in biological media. Rectangular blocks of Agar gel and a layered bacon sample were used as models of biological media. The signals obtained in gel blocks had a longitudinal spatial resolution better than 1 mm. The successive layers of the bacon sample were clearly resolved. The advantages of this new modality for tissue characterization include the permeability of body tissue to magnetic field and ultrasound, the harmlessness of the applied fields and the improved spatial resolution in the measurement of a tissue's electric conductivity distribution.

Electric Conductivity↗

PubMed1986

Divorce and marital instability over the life course.

"This study uses a [U.S.] national sample of married persons under age 55, interviewed in 1980 and again in 1983, to estimate why divorce and marital instability vary by age and duration of marriage. Results indicate that the accumulation of assets substantially reduces the propensity to divorce. We also find that several important correlates of divorce and instability (age at marriage, health, social integration, and income) interact with age and duration. In general, these factors seem to operate almost exclusively among young people and young marriages."

Age Factors↗

PubMed2004

Implications for domain fusion protein-protein interactions based on structural information.

BACKGROUND: Several in silico methods exist that were developed to predict protein interactions from the copious amount of genomic and proteomic data. One of these methods is Domain Fusion, which has proven to be effective in predicting functional links between proteins. RESULTS: Analyzing the structures of multi-domain single-chain peptides, we found that domain pairs located less than 30 residues apart on a chain are almost certain to share a physical interface. The majority of these interactions are also conserved across separate chains. We make use of this observation to improve domain fusion based protein interaction predictions, and demonstrate this by implementing it on a set of Saccharomyces cerevisiae proteins. CONCLUSION: We show that existing structural data supports the domain fusion hypothesis. Empirical information from structural data also enables us to refine and assess domain fusion based protein interaction predictions. These interactions can then be integrated with downstream biochemical and genetic assays to generate more reliable protein interaction data sets.

Amino Acids↗

PubMed2006

PhosphoregDB: the tissue and sub-cellular distribution of mammalian protein kinases and phosphatases.

BACKGROUND: Protein kinases and protein phosphatases are the fundamental components of phosphorylation dependent protein regulatory systems. We have created a database for the protein kinase-like and phosphatase-like loci of mouse http://phosphoreg.imb.uq.edu.au that integrates protein sequence, interaction, classification and pathway information with the results of a systematic screen of their sub-cellular localization and tissue specific expression data mined from the GNF tissue atlas of mouse. RESULTS: The database lets users query where a specific kinase or phosphatase is expressed at both the tissue and sub-cellular levels. Similarly the interface allows the user to query by tissue, pathway or sub-cellular localization, to reveal which components are co-expressed or co-localized. A review of their expression reveals 30% of these components are detected in all tissues tested while 70% show some level of tissue restriction. Hierarchical clustering of the expression data reveals that expression of these genes can be used to separate the samples into tissues of related lineage, including 3 larger clusters of nervous tissue, developing embryo and cells of the immune system. By overlaying the expression, sub-cellular localization and classification data we examine correlations between class, specificity and tissue restriction and show that tyrosine kinases are more generally expressed in fewer tissues than serine/threonine kinases. CONCLUSION: Together these data demonstrate that cell type specific systems exist to regulate protein phosphorylation and that for accurate modelling and for determination of enzyme substrate relationships the co-location of components needs to be considered.

Amino Acid Sequence↗

PubMed2006

Targeted disruption of cubilin reveals essential developmental roles in the structure and function of endoderm and in somite formation.

BACKGROUND: Cubilin is a peripheral membrane protein that interacts with the integral membrane proteins megalin and amnionless to mediate ligand endocytosis by absorptive epithelia such as the extraembryonic visceral endoderm (VE). RESULTS: Here we report the effects of the genetic deletion of cubilin on mouse embryonic development. Cubilin gene deletion is homozygous embryonic lethal with death occurring between 7.5-13.5 days post coitum (dpc). Cubilin-deficient embryos display developmental retardation and do not advance morphologically beyond the gross appearance of wild-type 8-8.5 dpc embryos. While mesodermal structures such as the allantois and the heart are formed in cubilin mutants, other mesoderm-derived tissues are anomalous or absent. Yolk sac blood islands are formed in cubilin mutants but are unusually large, and the yolk sac blood vessels fail to undergo remodeling. Furthermore, somite formation does not occur in cubilin mutants. Morphological abnormalities of endoderm occur in cubilin mutants and include a stratified epithelium in place of the normally simple columnar VE epithelium and a stratified cuboidal epithelium in place of the normally simple squamous epithelium of the definitive endoderm. Cubilin-deficient VE is also functionally defective, unable to mediate uptake of maternally derived high-density lipoprotein (HDL). CONCLUSION: In summary, cubilin is required for embryonic development and is essential for the formation of somites, definitive endoderm and VE and for the absorptive function of VE including the process of maternal-embryo transport of HDL.

Animals↗

PubMed2006

A rational model for assessing and evaluating complex interventions in health care.

BACKGROUND: Understanding how new clinical techniques, technologies and other complex interventions become normalized in practice is important to researchers, clinicians, health service managers and policy-makers. This paper presents a model of the normalization of complex interventions. METHODS: Between 1995 and 2005 multiple qualitative studies were undertaken. These examined: professional-patient relationships; changing patterns of care; the development, evaluation and implementation of telemedicine and related informatics systems; and the production and utilization of evidence for practice. Data from these studies were subjected to (i) formative re-analysis, leading to sets of analytic propositions; and to (ii) a summative analysis that aimed to build a robust conceptual model of the normalization of complex interventions in health care. RESULTS: A normalization process model that enables analysis of the conditions necessary to support the introduction of complex interventions is presented. The model is defined by four constructs: interactional workability; relational integration; skill set workability and contextual integration. This model can be used to understand the normalization potential of new techniques and technologies in healthcare settings CONCLUSION: The normalization process model has face validity in (i) assessing the potential for complex interventions to become routinely embedded in everyday clinical work, and (ii) evaluating the factors that promote or inhibit their success and failure in practice.

Chronic Disease↗

PubMed2006

Trauma: the role of the innate immune system.

Immune dysfunction can provoke (multiple) organ failure in severely injured patients. This dysfunction manifests in two forms, which follow a biphasic pattern. During the first phase, in addition to the injury by trauma, organ damage is caused by the immune system during a systemic inflammatory response. During the second phase the patient is more susceptible for sepsis due to host defence failure (immune paralysis). The pathophysiological model outlined in this review encompasses etiological factors and the contribution of the innate immune system in the end organ damage. The etiological factors can be divided into intrinsic (genetic predisposition and physiological status) and extrinsic components (type of injury or "traumaload" and surgery or "intervention load"). Of all the factors, the intervention load is the only one which, can be altered by the attending emergency physician. Adjustment of the therapeutic approach and choice of the most appropriate treatment strategy can minimize the damage caused by the immune response and prevent the development of immunological paralysis. This review provides a pathophysiological basis for the damage control concept, in which a staged approach of surgery and post-traumatic immunomonitoring have become important aspects of the treatment protocol. The innate immune system is the main objective of immunomonitoring as it has the most prominent role in organ failure after trauma. Polymorphonuclear phagocytes and monocytes are the main effector-cells of the innate immune system in the processes that lead to organ failure. These cells are controlled by cytokines, chemokines, complement factors and specific tissue signals. The contribution of tissue barrier integrity and its interaction with the innate immune system is further evaluated.

Journal Article↗