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PubMed1996

The HeLa 200 kDa U5 snRNP-specific protein and its homologue in Saccharomyces cerevisiae are members of the DEXH-box protein family of putative RNA helicases.

The primary structure of the 200 kDa protein of purified HeLa U5 snRNPs (U5-200kD) was characterized by cloning and sequencing of its cDNA. In order to confirm that U5-200kD is distinct from U5-220kD we demonstrate by protein sequencing that the human U5-specific 220 kDa protein is homologous to the yeast U5-specific protein Prp8p. A 246 kDa protein (Snu246p) homologous to U5-200kD was identified in Saccharomyces cerevisiae. Both proteins contain two conserved domains characteristic of the DEXH-box protein family of putative RNA helicases and RNA-stimulated ATPases. Antibodies raised against fusion proteins produced from fragments of the cloned mammalian cDNA interact specifically with the HeLa U5-200kD protein on Western blots and co-immunoprecipitate U5 snRNA and to a lesser extent U4 and U6 snRNAs from HeLa snRNPs. Similarly, U4, U5 and U6 snRNAs can be co-immunoprecipitated from yeast splicing extracts containing an HA-tagged derivative of Snu246p with HA-tag specific antibodies. U5-200kD and Snu246p are thus the first putative RNA helicases shown to be intrinsic components of snRNPs. Disruption of the SNU246 gene in yeast is lethal and leads to a splicing defect in vivo, indicating that the protein is essential for splicing. Anti-U5-200kD antibodies specifically block the second step of mammalian splicing in vitro, demonstrating for the first time that a DEXH-box protein is involved in mammalian splicing. We propose that U5-200kD and Snu246p promote one or more conformational changes in the dynamic network of RNA-RNA interactions in the spliceosome.

Amino Acid Sequence↗

PubMedDate not supplied

The students for peace project: a comprehensive violence-prevention program for middle school students.

Students for Peace is a three-year project (October 1993- September 1996) designed to evaluate a comprehensive, school-based intervention that seeks to prevent violence among sixth-, seventh-, and eighth-grade students in a large urban school district in Texas. This study examines the hypothesis that students exposed to a two-year multiple-component intervention will reduce aggressive behavior compared to students who receive the district's "usual care" of violence prevention activities. Students for Peace is based largely on Social Learning. Theory (SLT), which addresses both the psychosocial dynamics underlying health behavior and the methods of promoting behavior change, while emphasizing cognitive processes and their effect on behavior. SLT explains human behavior in terms of a model in which three factors-behavior, social-environmental influences, and personal factors (such as personality, perceptions and expectations, and affect)-all interact. Theoretically, an individual's behavior is uniquely determined by a combination of these factors; thus, these factors become the elements for intervention strategies. The intervention program includes four main components: (1) modification of the school environment, (2) a violence-prevention curriculum, (3) peer leadership, and (4) parent education. Students for Peace is using a nested cross-sectional and cohort design in which school is the unit of design, allocation, and analysis. Eight schools, four intervention and four control, are participating. In May 1994, a questionnaire was administered to all students in school the day of the survey. A posttest evaluation was taken in the spring of 1995 and will be followed by a final posttest in spring 1996. A total of 8,865 students responded to the baseline survey. Nearly all variables indicated comparability between treatment and control conditions. As a population, Students for Peace participants are largely Hispanic (65%) or African American (19%). Violence-related variables indicated 30-day fighting prevalence, 23%; 12-month prevalence of injuries due to fighting, 14%; 30-day hand-gun carrying prevalence, 11%; 30-day prevalence of taunts and threats at school, 27%, and threats going to and from school, 26%. Overall, the data from Year 1 activities indicate a population in need of violence-prevention intervention. The challenge is to mold existing district resources into a theoretically sound program of interventions. If that program is found effective, the district will already have the necessary documentation, personnel, and skills for broader dissemination.

Adolescent↗

PubMedDate not supplied

The impact of the Postponing Sexual Involvement curriculum among youths in California.

Postponing Sexual Involvement (PSI) is a widely implemented middle school curriculum designed to delay the onset of sexual intercourse. In an evaluation of its effectiveness among seventh and eighth graders in California, 10,600 youths from schools and community-based organizations statewide were recruited and participated in randomly assigned intervention or control groups; the curriculum was implemented by either adult or youth leaders. Survey data were collected before the program was implemented, and at three months and 17 months afterward. At three months, small but statistically significant changes were found in fewer than half of the measured attitudes, behaviors and intentions related to sexual activity; at 17 months, none of these significant positive effects of the PSI program had been sustained. At neither follow-up were there significant positive changes in sexual behavior; Youths in treatment and control groups were equally likely to have become sexually active, and youths in treatment groups were not less likely than youths in control groups to report a pregnancy or a sexually transmitted infection. The evaluation suggests that PSI may be too modest in length and scope to have an impact on youths' sexual behavior.

Adolescent↗

PubMedDate not supplied

Using practice genograms to understand and describe practice configurations.

BACKGROUND: Demands for change in medical practices are coming from multiple sources. Since interventions to change clinical practice continue to have limited success, understanding the functional structure of primary care practices and the dynamics of providing care have become increasingly important. METHODS: To portray and understand the primary care office system, we developed "practice genograms" that describe practice participants and their relationships with each other. Formal organizational structure is evaluated using family systems theory and family of origin genogram techniques. RESULTS: Practice genograms provided a more dynamic, relational model than the organizational chart and promoted identification of relationship strengths and weaknesses within a practice the same way that family genograms identify these characteristics in a family system. CONCLUSIONS: Research implications for the use of the practice genogram include enhanced data gathering, increased understanding of the complexity of practices as adaptive systems, and increased understanding of current and potential approaches to changing practices.

Family Practice↗

PubMed2000

The effects of metapopulation structure on indirect interactions in host-parasitoid assemblages.

The interaction between two species that do not compete for resources but share a common natural enemy is known as apparent competition. In the absence of other limiting factors, such three-species interactions are impermanent, with one species being excluded from the assemblage by the natural enemy. Here, the effects of metapopulation structure are explored in a system of two hosts that experience apparent competition through a shared parasitoid. A coupled-map lattice model is developed and used to explore species coexistence and patterns of patch occupancy at the metapopulation scale. Linking local and regional dynamics favours coexistence by uncoupling the dynamics of the three species in space. Coexistence is promoted by the inferior species being either a fugitive or a sedentary species. The occurrence of these two mutually exclusive mechanisms of coexistence is influenced by the relative dispersal of the inferior apparent competitor.

Animals↗

PubMed2002

Impact of enzyme motion on activity.

Experimental and theoretical data imply that enzyme motion plays an important role in enzymatic reactions. Enzyme motion can influence both the activation free energy barrier and the degree of barrier recrossing. A hybrid theoretical approach has been developed for the investigation of the relation between enzyme motion and activity. This approach includes both electronic and nuclear quantum effects. It distinguishes between thermally averaged promoting motions that influence the activation free energy barrier and dynamical motions that influence the barrier recrossings. Applications to hydride transfer in liver alcohol dehydrogenase and dihydrofolate reductase resulted in the identification and characterization of important enzyme motions. These applications have also led to the proposal of a network of coupled promoting motions in enzymatic reactions. These concepts have important implications for protein engineering and drug design.

Alcohol Dehydrogenase↗

PubMed2006

Mechanical compressive loading stimulates the activity of proximal region of human COL2A1 gene promoter in transfected chondrocytes.

Previous studies have demonstrated that the mechanical compressive loading affects the biosynthesis of chondrocytes seeded in three dimensional scaffolds. In this study, the level of type II collagen mRNA expression was increased by a continuous dynamic compression at 10% compressive strain and 0.1 Hz in chondrocytes seeded in a biodegradable, elastomeric scaffold, poly(L-lactide-co-epsilon-caprolactone) (PLCL). To further examine this molecular mechanism, the promoter region of COL2A1 gene, which is encoding type II collagen, was analyzed using rabbit chondrocytes transfected with luciferase reporter vectors containing the 5'-flanking regions of human COL2A1 gene. A deletion mutant analysis revealed that the most active short promoter in response to continuous dynamic compression is in the region between -509 and -109 base pairs, where the transcription factor Sp1 is located. Additionally, an mRNA decay experiment using transcription inhibitor actinomycin D demonstrated that dynamic compression do not stabilize type II collagen mRNA. Our results indicate that mechanical compression increases the level of type II mRNA expression by transcriptional activation possibly through the Sp1 binding sites residing in the proximal region of the COL2A1 gene promoter.

Animals↗

PubMed2003

Chemoreflex drive and the dynamics of ventilation and gas exchange during exercise at hypoxia.

We tested the hypothesis that the promotion of hypoxic ventilatory responsiveness (HVR) and/or hypercapnic ventilatory responsiveness (HCVR) mostly acting on the carotid body with a changing work rate can be attributed to faster hypoxic ventilatory dynamics at the onset of exercise. Eleven subjects performed a cycling exercise with two repetitions of 6 minutes while breathing at FIO(2) = 12%. The tests began with unloaded pedaling, followed by three constant work rates of 40%, 60%, and 80% of the subject's ventilatory threshold at hypoxia. Reference data were obtained at the 80% ventilatory threshold work rate during normoxia. Using three inhaled 100% O(2) breath tests, a comparison of hypoxia and normoxia revealed an augmentation of HVR in hypoxia, which then significantly increased proportionally with the increase in work rate. In contrast, HCVR using three inhaled 10% CO(2) breath tests was unaffected by the difference in work rate at hypoxia but did exceed its level at normoxia. The decrease in the half-time of hypoxic ventilation became significant with an increase in work rates and was significantly lower than at normoxia. Using a multiregression equation, HVR was found to account for 63% of the variance of hypoxic ventilatory dynamics at the onset of exercise and HCVR for 9%. O(2) uptake on-kinetics and off-kinetics under hypoxic conditions were significantly slower than under normoxic conditions, whereas they were not altered by the changing work rates at hypoxia. These results suggest that the faster hypoxic ventilatory dynamics at the onset of exercise can be mostly attributed to the augmentation of HVR with an increase in work rates rather than to HCVR. Otherwise, O(2) uptake dynamics are affected by the lower O(2), not by the changing work rates under hypoxic conditions.

Adult↗

PubMed2005

RelB/p52 NF-kappaB complexes rescue an early delay in mammary gland development in transgenic mice with targeted superrepressor IkappaB-alpha expression and promote carcinogenesis of the mammary gland.

Classical NF-kappaB (p65/p50) transcription factors display dynamic induction in the mammary gland during pregnancy. To further elucidate the role of NF-kappaB factors in breast development, we generated a transgenic mouse expressing the IkappaB-alpha S32/36A superrepressor (SR) protein under control of the mouse mammary tumor virus (MMTV) long terminal repeat promoter. A transient delay in mammary ductal branching was observed in MMTV-SR-IkappaB-alpha mice early during pregnancy at day 5.5 (d5.5) and d7.5; however, development recovered by mid- to late pregnancy (d14.5). Recovery correlated with induction of nuclear cyclin D1 and RelB/p52 NF-kappaB complexes. RelB/p52 complexes induced cyclin D1 and c-myc promoter activities and failed in electrophoretic mobility shift assay to interact with IkappaB-alpha-glutathione S-transferase, indicating that their weak interaction with IkappaB-alpha can account for the observed recovery of mammary gland development. Activation of IKKalpha and NF-kappaB-inducing kinase was detected by d5.5, implicating the alternative NF-kappaB signaling pathway in RelB/p52 induction. Constitutively active IKKalpha induced p52, RelB, and cyclin D1 in untransformed mammary epithelial cells. Moreover, mouse mammary tumors induced by 7,12-dimethylbenz(a)anthracene treatment displayed increased RelB/p52 activity. Inhibition of RelB in breast cancer cells repressed cyclin D1 and c-Myc levels and growth in soft agar. These results implicate RelB/p52 complexes in mammary gland development and carcinogenesis.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1987

[What is dynamic optimization and how can it be used in quality control?].

By means of an interdisciplinary approach concerning quality problems of tablets an access to the method of dynamic optimization is described. It could be shown that one needs only one equation to understand the basic principles of the application of this method in quality monitoring. This understanding is promoted by graphic methods effectively. Furthermore it is demonstrated that the dynamic optimization can be useful for the organization of quality control when the result of the quality monitoring process depends on the sequence of various tests.

Chemistry, Pharmaceutical↗

PubMed2004

Frequency domain chemical Langevin analysis of stochasticity in gene transcriptional regulation.

We present a frequency domain Langevin approach for stochastic analysis that remains valid for many important gene circuit elements even as molecular populations approach zero. We begin by considering the case of low-rate transcription and show that the previously reported shot noise representation is exact at all mRNA population levels for a constant transcription rate. Next, we consider transcriptional control through protein-DNA interactions at an operator site within the gene promoter region. This analysis results in expressions for the dynamics and noise behavior of this important gene sub-circuit, including the spectral density of the intrinsic operator noise and the processing of extrinsic noise by this transcriptional regulation system. This analysis shows that mRNA synthesis noise is composed of wideband shot noise and band-limited operator binding generated noise components. We find that the bandwidth of operator noise and its ultimate effect on total mRNA and protein noise is controlled by operator binding and unbinding dynamics. The most substantial impact of the operator noise is seen at transcription rates just above basal expression. This analysis captures the full behavior of this transcriptional regulation system, and points to potentially serious flaws in simplified mathematical relationships often used to model transcriptional regulation.

Gene Expression Regulation↗

PubMed2006

Spatiotemporal dynamics of RhoA activity in migrating cells.

Rho family GTPases regulate the actin and adhesion dynamics that control cell migration. Current models postulate that Rac promotes membrane protrusion at the leading edge and that RhoA regulates contractility in the cell body. However, there is evidence that RhoA also regulates membrane protrusion. Here we use a fluorescent biosensor, based on a novel design preserving reversible membrane interactions, to visualize the spatiotemporal dynamics of RhoA activity during cell migration. In randomly migrating cells, RhoA activity is concentrated in a sharp band directly at the edge of protrusions. It is observed sporadically in retracting tails, and is low in the cell body. RhoA activity is also associated with peripheral ruffles and pinocytic vesicles, but not with dorsal ruffles induced by platelet-derived growth factor (PDGF). In contrast to randomly migrating cells, PDGF-induced membrane protrusions have low RhoA activity, potentially because PDGF strongly activates Rac, which has previously been shown to antagonize RhoA activity. Our data therefore show that different extracellular cues induce distinct patterns of RhoA signalling during membrane protrusion.

3T3 Cells↗

PubMed2000

[Fibromyalgia (generalized tendomyopathy): defect of a program of movements and their realization].

It was established that fulfillment of any motor action implies a design of the program of action in CNS and its realization by peripheral elements of locomotor system. A program includes an acceptor of the result of action and efferent synthesis on a central level (parietal-premotor area, pallidostriatal system, lymbico-reticular complex, ex cetera). A very motor act is realized by the activity of a segmental apparatus of the spinal cord and skeletal muscles. Acceptor of the result of action provides a control of the coincidence between afferent parameters of the result of an action and its real characteristics by means of the reverse feed-back (P.K. Anokhin, 1975). Incoordination of its parameters is a condition for the existence of a physiologic functional system for the construction of the necessary movement, while a coincidence of their indices resulted in the disintegration of this system. Appearance of myofascicular hypertonus in this system distorts a real parameters of the movement because of a deficit and imbalance of the proprioception in a segmental apparatus and central formations. A proprioceptive desafferentation promotes disinhibition of the neurons and formation of the generators of pathologically increased irritation with positive feed-back on rubro-segmental (A), pallido-thalamic (B), strio-piramidal (C) and parietal-premotor (D) levels of the construction of the movement according to N.A. Bernshtein (1966). Its appearance on the B and C levels prevents destruction of the physiologic system of organization after realization of its activity and promotes its reformation into the pathologic one. It manifested clinically in appearance of a pathologic dynamic stereotype. Additional integration of lymbico-reticular complex, and high centers of autonomic supplement into this system promotes a formation of the stable neurotic, depressive reactions and autonomic disorders. Such reactions are transitory and have adaptive character at normal program of construction and fulfillment of the motion, while at pathologic one they have desadaptive character. Clinically they are known as multiple psychoautonomic syndromes combined with muscular, fascial and ligamental pains of different location.

Electromyography↗

PubMed2006

Dynamical determinants of drug-inducible gene expression in a single bacterium.

A primitive example of adaptation in gene expression is the balance between the rate of synthesis and degradation of cellular RNA, which allows rapid responses to environmental signals. Here, we investigate how multidrug efflux pump systems mediate the dynamics of a simple drug-inducible system in response to a steady level of inducer. Using fluorescence correlation spectroscopy, we measured in real time within a single bacterium the transcription activity at the RNA level of the acrAB-TolC multidrug efflux pump system. When cells are exposed to constant level of anhydrotetracycline inducer and are adsorbed onto a poly-L-lysine-coated surface, we found that the acrAB-TolC promoter is steadily active. We also monitored the activity of the tet promoter to characterize the effect of this efflux system on the dynamics of drug-inducible transcription. We found that the transcriptional response of the tet promoter to a steady level of aTc rises and then falls back to its preinduction level. The rate of RNA degradation was constant throughout the transcriptional pulse, indicating that the modulation of intracellular inducer concentration alone can produce this pulsating response. Single-cell experiments together with numerical simulations suggest that such pulsating response in drug-inducible genetic systems is a property emerging from the dependence of drug-inducible transcription on multidrug efflux systems.

Anti-Bacterial Agents↗

PubMed1996

A comparison of performance in added-purpose occupations and rote exercise for dynamic standing balance in persons with hemiplegia.

OBJECTIVES: Adding purpose to daily occupations to promote performance is a basic premise of occupational therapy. This study investigated the hypothesis that in persons with hemiplegia, two added-purpose occupations would elicit more exercise repetitions than a rote exercise. METHOD: In a counterbalanced order, 21 subjects with hemiplegia, aged 51 to 78 years, experienced all three conditions of a dynamic standing balance exercise that involved bending down, reaching, standing up, and extending the arm. One condition of added purpose involved the use of materials (small balls and target); a second added-purpose condition involved the subjects' imagination of the small balls. The third condition was the rote exercise without added purpose. RESULTS: A one-way analysis of variance for related measures indicated that the subjects performed significantly differently in each of the three conditions (p < .001). A Tukey multiple comparison test revealed that the subjects did significantly more exercise repetitions in the added-materials condition and in the imagery-based condition than in the rote exercise condition (p < .05). CONCLUSION: This study demonstrates how added purpose can enhance motor performance in persons with hemiplegia. Purpose may be effectively added to an exercise through the use of materials or imagery.

Aged↗

PubMed2005

Transcription of the murine gammaherpesvirus 68 ORF73 from promoters in the viral terminal repeats.

Gammaherpesviruses persist as latent episomes in a dynamic lymphocyte pool. The regulated production of an episome maintenance protein is therefore crucial to their survival. The transcription initiation site of the murine gammaherpesvirus 68 episome maintenance protein, ORF73, was mapped to the viral terminal repeats, more than 10 kb distant from the open reading frame (ORF) itself. A 5' non-coding exon in the terminal repeats was spliced to the right end of the viral unique sequence, and then across ORFs 75a, 75b, 75c and 74 to ORF73. The right-hand portion of a single repeat unit was sufficient for constitutive promoter activity. The unique left end of the viral genome further enhanced ORF73 transcription. This, together with the large size of the predominant ORF73 mRNA, suggested that transcription initiates in distal repeat units and then splices between repeats to generate an extensive 5' untranslated region. A second promoter in the left-hand portion of the proximal terminal repeat unit generated a transcript which overlapped that of ORF73, but failed to splice to the ORF73 coding exon and so transcribed ORF75a. In distal repeat copies, however, transcription from this promoter would enter the next repeat unit to become an ORF73 mRNA. There was a third promoter just upstream of ORF73 itself. These data indicate that ORF73 transcription is highly complex, and support the idea that the terminal repeats of gamma-2-herpesviruses constitute a vital component of episomal persistence.

Animals↗

PubMed1995

Role of saliva in caries models.

The crucial role played by the actions of saliva in controlling the equilibrium between de- and remineralization in a cariogenic environment is demonstrated by the effects on caries incidence of salivary dysfunction and by the distribution of sites of caries predilection to those were salivary effects are restricted. However, of the several properties of saliva which may confer protective effects, it is not certain which are most important. A distinction can be made between static protective effects, which act continuously, and dynamic effects, which act during the time-course of the Stephan curve. Evidence implicates salivary buffering and sugar clearance as important dynamic effects of saliva to prevent demineralization; of these, the buffering of plaque acids may predominate. Enhanced remineralization of white spot lesions may also be regarded as dynamic protective effects of saliva. Fluoride in saliva (from dentifrices, ingesta, etc.) may promote remineralization and (especially fluoride in plaque) inhibit demineralization. The design of experiments using caries models must take into account the static and dynamic effects of saliva. Some models admit a full expression of these effects, while others may exclude them, restricting the range of investigations possible. The possibility is raised that protective effects of saliva and therapeutic agents may act cooperatively.

Animals↗

PubMed2005

Molecular mechanisms of kinetochore capture by spindle microtubules.

For high-fidelity chromosome segregation, kinetochores must be properly captured by spindle microtubules, but the mechanisms underlying initial kinetochore capture have remained elusive. Here we visualized individual kinetochore-microtubule interactions in Saccharomyces cerevisiae by regulating the activity of a centromere. Kinetochores are captured by the side of microtubules extending from spindle poles, and are subsequently transported poleward along them. The microtubule extension from spindle poles requires microtubule plus-end-tracking proteins and the Ran GDP/GTP exchange factor. Distinct kinetochore components are used for kinetochore capture by microtubules and for ensuring subsequent sister kinetochore bi-orientation on the spindle. Kar3, a kinesin-14 family member, is one of the regulators that promote transport of captured kinetochores along microtubules. During such transport, kinetochores ensure that they do not slide off their associated microtubules by facilitating the conversion of microtubule dynamics from shrinkage to growth at the plus ends. This conversion is promoted by the transport of Stu2 from the captured kinetochores to the plus ends of microtubules.

Biological Transport↗