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PubMed2002

The structure and dynamics of the U4/U6 snRNP: implications for pre-mRNA splicing and use as a model system to investigate the RNA-mediated effects of (5F)Ura.

Pre-mRNA splicing is one of the most complex and intricate processes in eukaryotic cell biology. Over the past decade, my laboratory has been interested in determining the structures of RNA components of the spliceosome, and in investigating how the structure, stability and dynamics of these RNA components are perturbed by nucleoside analog substitution. In particular, we have investigated the U4/U6 snRNA complex as a model system for understanding the biophysical basis for the RNA-mediated effects of the widely-used anticancer drug 5-fluorouracil ((5F)Ura). In this review, our studies that have provided novel information concerning the structure of U4 snRNA and its interactions with U6 snRNA and the Sm (or common) snRNA binding proteins are summarized. These studies have also quantified the structural and thermodynamic consequences of (5F)Ura in this model system. Our work to date provides the foundation on which future studies investigating the biophysical basis for spliceosomal assembly and for clarifying the mechanisms of anticancer drugs targeted at nucleic acid-mediated processes will be developed.

Base Sequence↗

PubMed2002

Rat vasopressin mRNA: a model system to characterize cis-acting elements and trans-acting factors involved in dendritic mRNA sorting.

The genes encoding the vasopressin (VP) and oxytocin (OT) precursors are expressed in magnocellular neurons of the hypothalamo-neurohypophyseal system. The neuropeptides have a dual function: (1) they are secreted from the nerve terminals into the systemic circulation to act as hormones on various peripheral target organs; and (2) VP and OT are also released from the dendrites into the central nervous system where they presumably play a role as either neurotransmitters or as modulators of the classical transmitters. Substantial amounts of VP and OT mRNAs are sorted to both axons and dendrites. Since the latter are equipped with components of the translation machinery, the peptide hormone precursors are likely to be locally synthesized in dendrites of magnocellular neurons. Evidence for axonal precursor synthesis, on the other hand, has not been obtained. Subcellular mRNA localization is a complex pathway. It is determined by sequences (cis-acting elements) within the RNA and proteins (trans-acting factors) which interact with these elements in order to guide the molecules to their ultimate destination. We have investigated the mechanisms involved in mRNA targeting in neurons by using VP mRNA as a model system. Recombinant eukaryotic expression vectors harboring the VP cDNA have been microinjected into the cell nuclei of cultured superior cervical ganglion (SCG) neurons. The subcellular distribution of the vector-expressed mRNAs was determined by non-radioactive in situ hybridization techniques. This revealed transport of VP mRNA to the dendrites, but not to the axonal compartment of SCG neurons. A complex dendritic localizer sequence (DLS) that spans part of the coding region as well as the 3'-untranslated region was identified by microinjecting constructs encoding partial sequences of the VP mRNA. In order to characterize trans-acting factors interacting with this element, protein/RNA binding experiments with radiolabeled in vitro synthesized VP RNA probes and proteins extracted from rat brain have been carried out. A protein specifically interacts with the DLS of the VP mRNA but not with sequences that obviously lack a role in subcellular RNA transport. Biochemical purification revealed that this protein is the multifunctional poly(A)-binding protein (PABP). It is well known for its ability to bind with high affinity to poly(A) tails of mRNAs, prerequisite for mRNA stabilization and stimulation of translational initiation, respectively. With lower affinities, PABP can also associate with non-poly(A) sequences. The physiological consequences of these PABP/RNA interactions include functions such as translational silencing. The translational state of mRNAs subject to dendritic sorting is most likely influenced by external stimuli. Consequently, PABP could represent one of several components necessary to regulate local synthesis of the VP precursor and possibly of other proteins.

Animals↗

PubMed2003

Bdelloid rotifers as model system to study developmental biology in space.

Bdelloid rotifers are suitable model systems for space experiments. Due to their developmental pattern they appear adequate to investigate the role of the cytoskeleton during oogenesis and during early developmental stages, and to reflect the effects of disturbances in the spatial arrangement of cytoskeletal components. The effect of weightlessness on the developmental pattern of a bdelloid rotifer will be studied in the International Space Station: in preparation for it we are performing ground-based experiments on the development of rotifer embryos under either increased or decreased gravity. The model studied is Macrotrachela quadricornifera, a species of rotifers belonging to the Bdelloidea class. Samples exposed to gravity disturbance were analyzed for morphology and fitness-related parameters. Rotifers were exposed over several days to altered gravity conditions and the morphology of eggs laid during this period were investigated using a confocal laser microscope. A subset of eggs was allowed to hatch to determine newborn developmental time and age at maturity. High (up to 20 g) gravity was obtained in a slow centrifuge suitable for animal cultivation over several days. To produce low (simulated 0.0001 g) gravity a Random Positioning Machine equipped with a 'rotifer bioreactor' was used. Under all conditions the rotifer retained normal life-history traits, and did not show permanent changes in embryo morphology, regardless to the stresses to which it was exposed. Only some modification of the shape of early embryos, experiencing 20 g, has been noted, but later developmental stages appeared unaffected, and normal juveniles hatched. Whether this result indicates any capacity to repair damage during embryogenesis of these Spiralia experiencing 20 g is an open question. The significance of the result as well as the use of instruments to simulate gravity perturbations are discussed.

Animals↗

PubMed1999

The use of in vitro expanded erythroid cells in a model system for the isolation of fetal cells from maternal blood.

The development of a non-invasive prenatal diagnostic test using fetal nucleated red blood cells (NRBCs) isolated from the maternal circulation is hampered by the low frequency of these cells in maternal blood, requiring extensive enrichment procedures before any analytical procedure can be performed. In order to improve and simplify these procedures, we have used in vitro expanded erythroid cells derived from male umbilical cord blood in a model system for the isolation of fetal NRBCs from maternal blood. Erythroblast cells were expanded in vitro to high cell numbers and were immunophenotypically identical to fetal NRBCs isolated from maternal blood. Magnetic activated cell sorting (MACS) isolation procedures were optimized using in vitro expanded male NRBCs diluted up to 1 in 400,000 with female peripheral blood mononucleated cells. The number of recovered male cells was determined using two-colour fluorescence in situ hybridization with X and Y chromosomal probes. Using this model system, an NRBC isolation technique is described. It is based on a one-step MACS enrichment protocol for CD71 positive cells, which showed a significant (Wilcoxon signed ranks test, p<0.05) two-fold higher yield of male NRBCs than previously described MACS methodologies, in which CD71 positive cells were enriched after depletion of other cell types. Application of these isolation strategies to maternal blood samples resulted in a similar improved enrichment of male fetal cells after the direct enrichment of CD71 positive cells.

Antigens, CD↗

PubMed2006

Investigation of age-related cognitive decline using mice as a model system: behavioral correlates.

OBJECTIVE: With recent advances in molecular genetics, mouse models have been generated for a number of disease states. Recently, the authors and others have begun to examine normal age-related cognitive decline using mice as a model system. In this article, and the companion article that follows, the authors present data intended to better parameterize the aging phenotype in mice and examine the possible underlying neuronal mechanisms with special emphasis on age-related changes in calcium homeostasis. METHODS: Young (4-6-month-old) and aged (22-24-month-old) C57BL/6 mice were analyzed in terms of their spatial learning abilities in the hidden platform version of the Morris water maze and the delay win-shift version of the Olton radial arm maze. RESULTS: Although aged mice exhibited cognitive impairments in both behavioral tasks used, the extent of impairment differed between the two tasks, which might prove to be advantageous under certain experimental settings. CONCLUSIONS: Like in other areas of biomedical research, mice have become an invaluable research tool in the investigation of learning and memory. It is expected that similar benefits can be realized by developing mouse models for age-related cognitive decline.

Aging↗

PubMed1998

A new muffle model system to study root canal morphology and instrumentation techniques.

A new muffle model system is presented using the principle of internal indexing. The system is composed of a metal stand, four pins, and a single Teflon mold that is used for the investment of all teeth. This system is very precise, reproducible, and versatile. The sectioned specimens can easily be stored assembled, as opposed to previous systems that rely on external indexing.

Dental Pulp Cavity↗

PubMed1990

Bovine retinal explants cultured in collagen gels. A model system for the study of proliferative retinopathy.

We have developed a model system for studying proliferative retinopathy in vitro using bovine retinal explants cultured in collagen gels. Cellular outgrowth from retinal explants occurred after 7 days as single cells from peripapillary explants or as cell sheets and tubular outgrowths from peripheral retinal explants. Single cell outgrowths were shown immunohistochemically to be endothelial cells or macrophages; sheetlike and tubular outgrowths also constituted cords of endothelial cells with stromal macrophages, but in addition glial cells were closely associated with the endothelial cells. Cellular outgrowths were preceded by extensive macrophage activation within the ischemic retinal explant, suggesting that macrophage-derived angiogenic factors may be important in inducing retinal endothelial cell proliferation. In addition, glial cell-derived factors may have a role in the development of vessellike tubular structures from endothelial cell outgrowths.

Animals↗

PubMed2003

Differential roles of ERK and JNK in early and late stages of neuritogenesis: a study in a novel PC12 model system.

The rat pheochromocytoma PC12 cell line has been an invaluable model system for studying neuritogenesis. Nerve growth factor (NGF) elicits multiple aspects of neurite outgrowth in PC12 cells. It is therefore difficult to dissect and assign an individual signaling pathway to each stage of neuritogenesis. We have recently reported the isolation of a variant PC12 cell line, PC12-N1 (N1), which spontaneously extends neuritic processes and exhibits an increased sensitivity to NGF. Here, we show that, under different culture conditions, the cells display three distinct phases of neuritogenesis consisting of neurite initiation, rapid neurite elongation, and a maturation process characterized by the thickening of neurites and increase in cell soma sizes. We demonstrate that signaling through ERK, but not p38 or JNK, is required for the spontaneous neurite initiation and extension. Treatment with low concentrations of NGF induces rapid neurite elongation without affecting neurite branching and cell soma sizes. Such a rapid neurite outgrowth can be blocked by the inhibition of ERK, but not JNK, activities. In the presence of higher concentrations of NGF, the N1 cells undergo further differentiation with many characteristics of mature neurons in culture, e.g. larger cell soma and numerous branches/connections. This process can be completely blocked by inhibiting ERK or JNK activities using specific inhibitors. These results suggest that ERK and JNK signals play different roles in neuritogenesis, and that JNK activity is essential in the late stages of neuritogenesis. Furthermore, our results demonstrate that signaling dosage is important in the activation of a specific pathway, leading to distinctive biological outcomes.

Animals↗

PubMed1999

Reconstitution of killer cell inhibitory receptor-mediated signal transduction machinery in a cell-free model system.

Recognition of class I MHC molecules on target cells by killer cell inhibitory receptors (KIRs) blocks natural cytotoxicity and antibody-dependent cell cytotoxicity of NK cells and CD3/TCR dependent cytotoxicity of T cells. The inhibitory effect of KIR ligation requires phosphorylation of the cytoplasmic tail of KIR and subsequent recruitment of an SH2-containing protein tyrosine phosphatase, SHP-1. To better understand the molecular mechanism of the KIR-mediated inhibitory signal transduction, we developed an in vitro assay system using a purified His-tag fusion protein of KIR cytoplasmic tail (His-CytKIR) and Jurkat T cell lysates. We identified a target molecule of SHP-1 by comparing the phosphorylation of major cellular substrates following in vitro phosphorylation of Jurkat cell lysates in the presence and absence of the His-CytKIR in this cell-free model system. The His-CytKIR was tyrosine phosphorylated by Lck in vitro, and the phosphorylated His-CytKIR recruited SHP-1. Interestingly, we observed that among major substrates phosphorylated in vitro, PLC-gamma exhibited a dramatic decrease in phosphorylation when the His-CytKIR was mixed with Jurkat T cell lysates. However, PLC-gamma exhibited no decrease in phosphorylation when SHP-1 or Lck was depleted or deficient in this reaction mixture, suggesting that the SHP-1 recruited by the phosphorylated His-CytKIR directly mediate the dephosphorylation of PLC-gamma. The cell-free model system could be used to reveal the detailed molecular interactions in the KIR-mediated signal transduction.

Amino Acid Sequence↗

PubMed1997

Spice constituents scavenging free radicals and inhibiting pentosidine formation in a model system.

Many antioxidants have been found in spices and herbs, and some of them are well known as strong scavengers of active oxygen radicals. We have isolated active products, which markedly inhibited the formation of malondialdehyde (MDA from 2-deoxyribose and the hydroxylation of benzoate with the hydroxyl radical, from methanol extracts of allspice and clove. Pimentol from allspice, and biflorin and its isomer, abbreviated as clove3, from clove were identified as the active principles. These revealed strong activity as hydroxyl radical scavengers at a concentration of 2.0 microM. The antioxidative activities in an in vitro model system involving the rabbit erythrocyte membrane ghost were as strong as those of alpha-tocopherol at 200 microM. Such advanced glycation end products (AGE) as pentosidine are biomarkers of diabetes mellitus, and active oxygens have been suggested to be involved in the formation of AGE. The above-mentioned free radical scavengers effectively inhibited the formation of pentosidine in a model system of N alpha-t-butoxycarbonyl-fructoselysine and N alpha-t-butoxycarbonyl-arginine.

Animals↗

PubMed2026

Nurse-led attribution remodeling training based on the Neuman systems model to enhance resilience, adaptive coping, and attributional style in women newly diagnosed with breast cancer: A randomized controlled trial.

BACKGROUND: Psychological interventions for patients with breast cancer often overlook the critical role of maladaptive attributional style in shaping their adjustment. Therefore, the need for theory-driven, scalable interventions that target cognitive restructuring, particularly during the vulnerable post-diagnosis period, is clear. OBJECTIVE: To evaluate the effectiveness of a nurse-led attribution remodeling training intervention grounded in the Neuman systems model for improving resilience, adaptive coping, and attributional style among women newly diagnosed with breast cancer. DESIGN: A randomized controlled trial. SETTING: A tertiary general hospital. PARTICIPANTS: A total of 130 eligible women newly diagnosed with breast cancer were recruited between March and November 2024. METHODS: A two-arm parallel-group randomized controlled trial was conducted. Participants were randomly assigned to receive either attribution remodeling training plus routine nursing (n = 65) or routine nursing only (n = 65). The nurse-led attribution remodeling training intervention, delivered via a blended model of in-person sessions and continued support through the WeChat mobile platform, was designed to systematically reshape maladaptive attributions into more adaptive ones. Resilience (primary indicator), coping strategy (i.e., confrontation, avoidance, resignation), and attributional style (secondary indicators) were assessed at baseline and at 1, 3, and 6 months post-baseline. A linear mixed model was used to analyze the effects of group, time, and group-by-time interactions. Effect sizes (Cohen's D) were calculated based on the means and standard deviations. RESULTS: At the 6-month follow-up, the intervention group had better outcomes than the control group in terms of resilience (mean difference: 1.49, 95% confidence interval: 0.37, 2.61), confrontation coping (3.35 [2.33, 4.37]), and adaptive attributional style (4.16 [3.87, 4.45]). Avoidance coping showed a small increase (0.82 [0.22, 1.42]), whereas resignation coping decreased (-1.66 [-2.49, -0.83]). Group effects and group-by-time interactions were statistically significant for all outcomes. Effect sizes at 6 months ranged from small for resilience (D = 0.28) and avoidance coping (D = 0.26) to moderate for confrontation coping (D = 0.60) and resignation coping reduction (D = -0.51), and large for attributional style (D = 0.94). CONCLUSIONS: Attribution remodeling training is a promising and effective theory-based intervention that can enhance psychological adaptation in women newly diagnosed with breast cancer. By strengthening key defense mechanisms, as conceptualized by the Neuman systems model, the program is effective, scalable, and nurse-deliverable for psycho-oncology care, bridging a critical gap in supportive cancer care and empowering nurses as primary psychological support providers. REGISTRATION: ChiCTR2000031827, registered prospectively on April 11, 2020, www.Chictr.or.cn.

Humans↗

PubMed1994

Clover development during spaceflight: a model system.

The development of legume root nodules was studied as a model system for the examination of gravitational effects on plant root development. In order to examine whether rhizobial association with clover roots can be achieved in microgravity, experiments were performed aboard the KC-135 parabolic aircraft and aboard the sounding rocket mission Consort 3. Binding of rhizobia to roots and the initial stages of root nodule development successfully occurred in microgravity. Seedling germination experiments were performed in the sliding block device, the Materials Dispersion Apparatus, aboard STS-37. When significant hydration of the seeds was achieved, normal rates of germination and seedling development were observed.

Cell Differentiation↗

PubMed2006

Myoglobin oxidation in a model system as affected by nonheme iron and iron chelating agents.

A model system was used to study the effect of nonheme iron on myoglobin oxidation at pH 5.6 and pH 7.2 at 23 degrees C. The addition of ferrous iron significantly (p < 0.05) increased the rate of myoglobin oxidation in the absence of lipid, demonstrating that iron promoted myoglobin oxidation independent of the effect of lipid oxidation. The addition of the type II, iron chelating antioxidants sodium tripolyphosphate (at pH 7.2) or milk mineral (at pH 5.6) negated the effect of added iron, slowing oxidation of myoglobin. A clear concentration dependence was seen for iron-stimulated myoglobin oxidation, based on both spectral and visual evidence. Further investigation is needed to determine the possible role for nonheme ferrous iron on myoglobin oxidation in vivo or in meat.

Ferrous Compounds↗

PubMed1997

Biomimetic metabolism of artelinic acid by chemical cytochrome P-450 model systems.

PURPOSE: To study the reaction of artelinic acid with chemical model systems of cytochrome P-450 as a means of obtaining authentic samples of the putative metabolites necessary for identification of the mammalian metabolites of artelinic acid. METHODS: Artelinic acid was reacted with different organic complexes of iron(II). The reaction products were isolated and characterized by NMR and thermospray mass spectroscopy. RESULTS: Five compounds which are putative metabolites of artelinic acid were isolated from these reactions and unambiguously identified, while the identity of two other compounds await final confirmation. CONCLUSIONS: Standards of possible metabolites of artelinic acid can be produced by the reaction of the compound with ferrous complexes that may simulate cytochrome P-450 catalyzed metabolism of xenobiotics. This approach may provide a simple and versatile method for the formation of metabolites of artemisinin compounds which is more advantageous than previous approaches with fungal-based systems.

Antimalarials↗

PubMed1985

Stability of tryptophan during food processing and storage. 1. Comparative losses of tryptophan, lysine and methionine in different model systems.

The stability of tryptophan was evaluated in several different food model systems using a chemical method (high pressure liquid chromatography after alkaline-hydrolysis) and rat assays. Losses of tryptophan were compared with the losses of lysine and methionine. Whey proteins stored in the presence of oxidizing lipids showed large losses of lysine and extensive methionine oxidation but only minor losses of tryptophan as measured chemically. The observed decrease in bioavailable tryptophan was explained by a lower protein digestibility. Casein treated with hydrogen peroxide to oxidize all methionine to methionine sulphoxide showed a 9% loss in bioavailable tryptophan. When casein was reacted with caffeic acid at pH 7 in the presence of monophenol monooxygenase (tyrosinase; EC 1.14.18.1), no chemical loss of tryptophan occurred, although fluorodinitrobenzene-reactive lysine fell by 23%. Tryptophan bioavailability fell 15%, partly due to an 8% reduction in protein digestibility. Alkali-treated casein (0.15 M-sodium hydroxide, 80 degrees, 4 h) did not support rat growth. Chemically-determined tryptophan, available tryptophan and true nitrogen digestibility fell 10, 46 and 23% respectively. Racemization of tryptophan was found to be 10% (D/(D+L)). In whole-milk powder, which had undergone "early' or "advanced' Maillard reactions, tryptophan, determined chemically or in rat assays, was virtually unchanged. Extensive lysine losses occurred. It was concluded that losses of tryptophan during food processing and storage are small and of only minor nutritional importance, especially when compared with much larger losses of lysine and the more extensive oxidation of methionine.

Animals↗

PubMed1998

[The uptake characteristics of 5-fluorouracil in the Caco-2 model system].

The uptake characteristics of 5-fluorouracil in the Caco-2 model system were studied. The uptake of 5-fluorouracil was determined at different pH and concentrations, and in the presence of various inhibitors. The results indicated that the uptake of 5-fluorouracil was the best at pH 6.0. The rate of uptake was saturable with a Km of 24 mmol.L-1, and a Vmax of 20.9 nmol.min-1.mg-1 protein. The uptake was inhibited by noncompetitive inhibitors such as NaCN, ouabain, and dipyridamole. The uptake was also inhibited competitively by analogous compounds such as uracil, thymine, and uridine (but not by hypoxanthine). In conclusion, the evidence suggests that 5-fluorouracil was transported by uracil carrier in Caco-2 cells.

Antimetabolites, Antineoplastic↗

PubMed1983

Mechanisms of epileptogenesis in brain-slice model systems.

Studies of the mechanisms of epileptogenesis in brain-slice model systems have indicated that there are three underlying processes which interact with one another and lead to the development of interictal discharge. These include (a) intrinsic burst activity, (b) disinhibition, and (c) excitatory synaptic coupling. Intrinsic membrane excitability may be altered by neuromodulators, injury, genetic, and other factors. Disinhibition in effect releases intrinsic burst generating capacities in populations of neurons, and may become an important factor following cortical injury or repetitive activation of inhibitory circuits. Excitatory synaptic coupling is required for evoking intrinsic burst discharges, and also to synchronize populations of neurons. EPSPs also serve as one of the generators for slow depolarization shifts. The contribution of each of these factors to epileptogenesis presumably varies with a type of pathological process and the properties of the involved neuronal population.

Action Potentials↗

PubMed2005

Systems model guided balance rehabilitation in an individual with declarative memory deficits and a total knee arthroplasty: a case report.

BACKGROUND AND PURPOSE: The clinical management of functional mobility problems of individuals with primary musculoskeletal impairments is complicated by the concurrent presence of neurologic diagnoses. There are few case descriptions present in the literature of clinical decision making in the context of combined musculoskeletal and neurologic impairments. The purpose of this case report is to describe the application and use of a systems model of motor control for defining the appropriate rehabilitation program for an individual with both orthopedic and neurologic impairments leading to complaints of frequent losses of balance and falls during community mobility. DESCRIPTION: RG was a 67-year-old male referred to physical therapy because of balance problems. Review of his previous medical history revealed that he had suffered an anoxic brain injury 5 years earlier but had recovered full independence in activities of daily living (ADLs) with shortterm memory deficits being the primary residual effect of the brain injury. His balance problems developed only after having undergone a unilateral total knee arthroplasty 4 months prior to his initial physical therapy examination. Through examination and evaluation, RG's problems were determined to be consistent with postsurgery induced deconditioning coupled with anoxic brain injury related motor and cognitive deficits. INTERVENTION AND OUTCOMES: Physical therapy intervention focused on increasing RG's strength, decreasing the range of motion limitations in his lower extremities, balance exercises specific to his dynamic balance deficits, as well as increased amounts of practice to maximize procedural learning. Upon completion of his initial episode of care, RG's musculoskeletal impairments had improved; his scores on balance tests had increased, and his frequency of falls had decreased. Following his discharge, RG continued with a physical therapist designed secondary prevention program. DISCUSSION: This case report describes the successful rehabilitation of an individual with concurrent orthopedic and neurologic diagnoses. Important components of this rehabilitation course include: (1) the application of a systems model of motor control to guide clinical interventions, (2) the consideration of the effects of memory deficits on rehabilitation outcomes, and (3) the utilization of a secondary prevention program to prevent reoccurrence of balance problems.

Aged↗