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PubMed2001

Stathmin/Op18 phosphorylation is regulated by microtubule assembly.

Stathmin/Op 18 is a microtubule (MT) dynamics-regulating protein that has been shown to have both catastrophe-promoting and tubulin-sequestering activities. The level of stathmin/Op18 phosphorylation was proved both in vitro and in vivo to be important in modulating its MT-destabilizing activity. To understand the in vivo regulation of stathmin/Op18 activity, we investigated whether MT assembly itself could control phosphorylation of stathmin/Op18 and thus its MT-destabilizing activity. We found that MT nucleation by centrosomes from Xenopus sperm or somatic cells and MT assembly promoted by dimethyl sulfoxide or paclitaxel induced stathmin/Op18 hyperphosphorylation in Xenopus egg extracts, leading to new stathmin/Op18 isoforms phosphorylated on Ser 16. The MT-dependent phosphorylation of stathmin/Op18 took place in interphase extracts as well, and was also observed in somatic cells. We show that the MT-dependent phosphorylation of stathmin/Op18 on Ser 16 is mediated by an activity associated to the MTs, and that it is responsible for the stathmin/Op18 hyperphosphorylation reported to be induced by the addition of "mitotic chromatin." Our results suggest the existence of a positive feedback loop, which could represent a novel mechanism contributing to MT network control.

Animals↗

PubMed2006

Expanding our conceptualization of program implementation: lessons from the genealogy of a school-based nutrition program.

This work presents a theoretical framework in which health promotion and health education program implementation can be conceived as an open dynamic system. By tracing the evolution of an elementary school-based nutrition program from its conception to its recent form, we construct a program genealogy. Data were derived from two interviews and three historical documents from which historical events were identified and reconstructed in the form of a tree analogy. Data analysis ensued using concepts from the actor-network theory about social innovation. These concepts identified social and technical program attributes and situated them within a process which evolved over time, thus permitting the program's genealogy to appear. The genealogy was found to be influenced by the ways in which the involved actors interpreted the issue of food security, namely, as a professional issue, with a nutrition education response and as a social issue, with a community-building response. The interaction between the interests of the actors and the technical components of the program resulted in three temporal program iterations. The results highlight the important role played by the involved actors during program implementation and suggest the need to take these interests into consideration during all phases of program planning.

Community Networks↗

PubMed1996

Conformational flexibility in RNA: the role of dihydrouridine.

In order to further understand the structural role of the modified nucleoside dihydrouridine in RNA the solution conformations of Dp and ApDpA were analyzed by one- and two-dimensional proton NRM spectroscopy and compared with those of the related uridine-containing compounds. The analyses indicate that dihydrouridine significantly destabilizes the C3'-endo sugar conformation associated with base stacked, ordered, A-type helical RNA. Equilibrium constants (Keq = [C2'-endo]/[C3'-endo]) for C2'-endo-C3'-endo interconversion at 25 degrees C for Dp, the 5'-terminal A of ApDpA and D in ApDpA are 2.08, 1.35 and 10.8 respectively. Stabilization of the C2'-endo form was shown to be enhanced at low temperature, indicating that C2'-endo is the thermodynamically favored conformation for dihydrouridine. DeltaH values show that for Dp the C2'-endo sugar conformation is stabilized by 1.5 kcal/mol compared with Up. This effect is amplified for D in the oligonucleotide ApDpA and propagated to the 5'-neighboring A, with stabilization of the C2'-endo form by 5.3 kcal/mol for D and 3.6 kcal/mol for the 5'-terminal A. Post-transcriptional formation of dihydrouridine therefore represents a biological strategy opposite in effect to ribose methylation, 2-thiolation or pseudouridylation, all of which enhance regional stability through stabilization of the C3'-endo conformer. Dihydrouridine effectively promotes the C2'-endo sugar conformation, allowing for greater conformational flexibility and dynamic motion in regions of RNA where tertiary interactions and loop formation must be simultaneously accommodated.

Drug Stability↗

PubMed1988

Skeletal tissue and transforming growth factor beta.

Normal skeletal growth results from a balance between the processes of bone matrix synthesis and resorption. These activities are regulated by both systemic and local factors. Bone turnover is dynamic, and skeletal growth must be maintained throughout life. Although many growth promoters are associated with bone matrix, it is enriched particularly with transforming growth factor beta (TGF-beta) activity. Experimental evidence indicates that TGF-beta regulates replication and differentiation of mesenchymal precursor cells, chondrocytes, osteoblasts, and osteoclasts. Recent studies further suggest that TGF-beta activity in skeletal tissue may be controlled at multiple levels by other local and systemic agents. Consequently, the intricate mechanisms by which TGF-beta regulates bone formation are likely to be fundamental to understanding the processes of skeletal growth during development, maintenance of bone mass in adult life, and healing subsequent to bone fracture.

Alkaline Phosphatase↗

PubMed1995

Professional competencies in the changing health care system: physicians' views on the importance and adequacy of formal training in medical school.

PURPOSE: To examine physicians' attitudes toward 16 competencies deemed essential to the effective practice of medicine in the changing health care system. METHOD: In early 1991 a telephone survey was conducted of 300 physicians from random samples selected as representative of the physician population in the continental United States. The physicians were categorized as general practitioners, surgery specialists, and other specialists, and as belonging to the graduation cohorts of 1960-1969, 1970-1979, and 1980-1989. The physicians were asked to rate (1) the importance of formal undergraduate training in each of 16 competencies and (2) the adequacy of their own undergraduate training in the competencies (these ratings are reported only for the 87 physicians in the 1980-1989 cohort). The competencies were derived from the skills, attitudes, and behaviors defined by the Pew Health Professions Commission as necessary for the nation's health care practitioners to meet society's evolving health care needs. RESULTS: Fifty percent or more of the physicians thought that 12 of the 16 competencies were "very important" to include in undergraduate training. Over 75% thought that it was "very important" to include the five competencies involving skills traditionally valued in medical practice: diagnosis and treatment, effective communication with patients, problem solving, lifelong learning, and counseling on medical ethics. More than 50% thought that undergraduate training was "very important" in some competencies that reflect the changing dynamics of medicine and care delivery over the past ten years: health promotion and preventive medicine, involvement of patient and family in care, management of large volumes of information, appropriate use of technology, working on a team with other professionals, and consideration of cost in clinical decision making. In rating their own training, over 50% felt well prepared (ratings of "excellent" or "good") in the five traditional competencies and, in addition, in their abilities to promote health, to manage large volumes of information, to work in teams, to understand and respond to diverse cultures, and to expand access to care. However, a majority felt that their training was only "fair" or "poor" regarding the involvement of patients and their families, evaluation of the appropriateness of costly technology, consideration of cost implications in their decision making, and understanding and supporting the community's role in health care. Forty percent or more felt poorly prepared to work in managed care settings or to accommodate increasing external scrutiny. CONCLUSION: The physicians validated the traditional strengths of medical schools, but revealed curricular weaknesses in the teaching of competencies proposed as important for the emerging health care system, especially in the managed care environment.

Attitude of Health Personnel↗

PubMed2000

Endotoxin promotes adhesion of human erythrocytes to human vascular endothelial cells under conditions of flow.

OBJECTIVE: To investigate the effects of endotoxin on adhesion of human red blood cells to human vascular endothelial cells under conditions of flow. DESIGN: Prospective, randomized, controlled in vitro study. SETTINGS: University-affiliated cell biology laboratory. SUBJECTS: Human erythrocytes and human vascular endothelial cells. INTERVENTIONS: Fresh human erythrocytes and human vascular endothelial cells grown as monolayers were incubated with either saline or endotoxin. After incubation, endothelial monolayers were superfused with erythrocytes, and the number of erythrocytes adhering to the endothelial monolayer was quantified. MEASUREMENTS AND MAIN RESULTS: Adhesion of erythrocytes to vascular endothelium was measured under conditions of continuous flow in different settings: a) exposure of both endothelial cells and erythrocytes to saline; b) incubation of both erythrocytes and endothelial cells with endotoxin; c) exposure of erythrocytes only to endotoxin; d) incubation of endothelial cells only to endotoxin; and e) both the endothelial cells and erythrocytes incubated with different concentrations of endotoxin. Erythrocyte adhesion in the saline control group was 71 +/- 8 cells/mm2. Incubation of both components with endotoxin increased the number of adhesive erythrocytes to 172 +/- 9 cells/mm2 (p < .05). When only the endothelial cells were treated with endotoxin, 142 +/- 8 cells/mm2 adhered to the endothelial monolayer, whereas the incubation of the erythrocytes only to endotoxin resulted in adhesion of 102 +/- 3 cells/mm2. Decreasing concentrations of endotoxin reduced adhesion from 172 +/- 9 cells/mm2 (endotoxin, 75 microg/mL) to 165 +/- 9 cells/mm2 (endotoxin, 25 microg/mL), 153 +/- 4 cells/mm2 (endotoxin, 1 microg/mL), and 146 +/- 6.1 cells/mm2 (endotoxin, 5 ng/mL). CONCLUSIONS: Exposure of human erythrocytes and human venous vascular endothelial cells to an inflammatory stimulus such as endotoxin promotes a dose-dependent adhesion of erythrocytes to endothelium in a dynamic environment. These adhesive erythrocyte-endothelium interactions can be produced by exposure of either red blood cells or endothelial cells to endotoxin, with a higher degree of adhesion after activation of the endothelial cell component.

Cell Adhesion↗

PubMed1989

Mechanisms of myocardial ischemia.

Myocardial ischemia occurs as a result of an imbalance between tissue oxygen supply and demand. The clinical correlates of the syndrome include classic unstable and Prinzmetal variant angina. Although controversial, it has been postulated that the pathogenesis of unstable angina involves a combination of (1) fixed atherosclerotic coronary artery stenosis, (2) dynamic coronary artery obstruction mediated by coronary vasospasm, and (3) platelet aggregation promoting intracoronary thrombotic occlusion. The authors review evidence to support the conclusion that the interaction of these processes may be mediated by an imbalance in the levels of two eicosanoids, thromboxane A2 (TxA2) and prostacyclin (PGI2), which are responsible for platelet-vascular wall homeostasis. TxA2 is a powerful endogenous vasoconstrictor and promoter of platelet aggregation, whereas PGI2 has diametrically opposed, protective actions. Management and preventive strategies for unstable angina have, therefore, concentrated on the pharmacologic and dietary prohibition of TxA2 activity by agents targeted at inhibiting its synthesis and antagonizing its actions. These agents are discussed and differentiated.

Angina Pectoris↗

PubMed2006

Nucleosome displacement in transcription.

Recent reports reinforce the notion that nucleosomes are highly dynamic in response to the process of transcription. Nucleosomes are displaced at promoters during gene activation in a process that involves histone modification, ATP-dependent nucleosome remodeling complexes, histone chaperones and perhaps histone variants. During transcription elongation nucleosomes are acetylated and transferred behind RNA polymerase II where they are required to suppress spurious transcription initiation within the body of the gene. It is becoming increasingly clear that the eukaryotic transcriptional machinery is adapted to exploit the presence of nucleosomes in very sophisticated ways.

Animals↗

PubMed2006

Chameau HAT and DRpd3 HDAC function as antagonistic cofactors of JNK/AP-1-dependent transcription during Drosophila metamorphosis.

Gene regulation by AP-1 transcription factors in response to Jun N-terminal kinase (JNK) signaling controls essential cellular processes during development and in pathological situations. Here, we report genetic and molecular evidence that the histone acetyltransferase (HAT) Chameau and the histone deacetylase DRpd3 act as antagonistic cofactors of DJun and DFos to modulate JNK-dependent transcription during thorax metamorphosis and JNK-induced apoptosis in Drosophila. We demonstrate in cultured cells that DFos phosphorylation mediated by JNK signaling plays a central role in coordinating the dynamics of Chameau and DRpd3 recruitment and function at AP-1-responsive promoters. Activating the pathway stimulates the HAT function of Chameau, promoting histone H4 acetylation and target gene transcription. Conversely, in response to JNK signaling inactivation, DRpd3 is recruited and suppresses histone acetylation and transcription. This study establishes a direct link among JNK signaling, DFos phosphorylation, chromatin modification, and AP-1-dependent transcription and its importance in a developing organism.

Acetylation↗

PubMed2004

The Arabidopsis microtubule-associated protein AtMAP65-1: molecular analysis of its microtubule bundling activity.

The 65-kD microtubule-associated protein (MAP65) family is a family of plant microtubule-bundling proteins. Functional analysis is complicated by the heterogeneity within this family: there are nine MAP65 genes in Arabidopsis thaliana, AtMAP65-1 to AtMAP65-9. To begin the functional dissection of the Arabidopsis MAP65 proteins, we have concentrated on a single isoform, AtMAP65-1, and examined its effect on the dynamics of mammalian microtubules. We show that recombinant AtMAP65-1 does not promote polymerization and does not stabilize microtubules against cold-induced microtubule depolymerization. However, we show that it does induce microtubule bundling in vitro and that this protein forms 25-nm cross-bridges between microtubules. We further demonstrate that the microtubule binding region resides in the C-terminal half of the protein and that Ala409 and Ala420 are essential for the interaction with microtubules. Ala420 is a conserved amino acid in the AtMAP65 family and is mutated to Val in the cytokinesis-defective mutant pleiade-4 of the AtMAP65-3/PLEIADE gene. We show that AtMAP65-1 can form dimers and that a region in the N terminus is responsible for this activity. Neither the microtubule binding region nor the dimerization region alone could induce microtubule bundling, strongly suggesting that dimerization is necessary to produce the microtubule cross-bridges. In vivo, AtMAP65-1 is ubiquitously expressed both during the cell cycle and in all plant organs and tissues with the exception of anthers and petals. Moreover, using an antiserum raised to AtMAP65-1, we show that AtMAP65-1 binds microtubules at specific stages of the cell cycle.

Amino Acid Sequence↗

PubMed2003

Testing an intervention for preventing osteoporosis in postmenopausal breast cancer survivors.

PURPOSE: To test a 12-month multicomponent intervention for preventing or treating osteoporosis in 21 postmenopausal women who had completed treatment (except Tamoxifen) for breast cancer, and for whom hormone replacement therapy (HRT) was contraindicated. DESIGN: Pilot intervention study. METHODS: The intervention consisted of home-based strength and weight training exercises, 5 or 10 mg alendronate per day, 1500 mg calcium per day, 400 IU vitamin D per day, education on osteoporosis, and facilitative strategies to promote adherence to the intervention. Outcome measures were: adherence to the intervention, dynamic balance, muscle strength, and bone mineral density (BMD) of the hip, spine, and forearm. FINDINGS AND CONCLUSIONS: Adherence to calcium, vitamin D, and alendronate therapy was above 95%, and adherence to strength training exercises was above 85%. Over the 12 months, the 21 participants had significant improvements in dynamic balance, muscle strength for hip flexion, hip extension, and knee flexion, and BMD of the spine and hip. Participants had a significant decrease in BMD of the forearm. Three of the 21 women who had measurable bone loss at baseline had normal BMD after 12 months of the intervention.

Adult↗

PubMed2002

Visualization of a Ran-GTP gradient in interphase and mitotic Xenopus egg extracts.

The small guanosine triphosphatase Ran is loaded with guanosine triphosphate (GTP) by the chromatin-bound guanine nucleotide exchange factor RCC1 and releases import cargoes in the nucleus during interphase. In mitosis, Ran-GTP promotes spindle assembly around chromosomes by locally discharging cargoes that regulate microtubule dynamics and organization. We used fluorescence resonance energy transfer-based biosensors to visualize gradients of Ran-GTP and liberated cargoes around chromosomes in mitotic Xenopus egg extracts. Both gradients were required to assemble and maintain spindle structure. During interphase, Ran-GTP was highly enriched in the nucleoplasm, and a steep concentration difference between nuclear and cytoplasmic Ran-GTP was established, providing evidence for a Ran-GTP gradient surrounding chromosomes throughout the cell cycle.

Active Transport, Cell Nucleus↗

PubMed2000

The bacterial flagellar cap as the rotary promoter of flagellin self-assembly.

The growth of the bacterial flagellar filament occurs at its distal end by self-assembly of flagellin transported from the cytoplasm through the narrow central channel. The cap at the growing end is essential for its growth, remaining stably attached while permitting the flagellin insertion. In order to understand the assembly mechanism, we used electron microscopy to study the structures of the cap-filament complex and isolated cap dimer. Five leg-like anchor domains of the pentameric cap flexibly adjusted their conformations to keep just one flagellin binding site open, indicating a cap rotation mechanism to promote the flagellin self-assembly. This represents one of the most dynamic movements in protein structures.

Bacteria↗

PubMed2004

Spatial comparison between wall shear stress measures and porcine arterial endothelial permeability.

A better understanding of how hemodynamic factors affect the integrity and function of the vascular endothelium is necessary to appreciate more fully how atherosclerosis is initiated and promoted. A novel technique is presented to assess the relation between fluid dynamic variables and the permeability of the endothelium to macromolecules. Fully anesthetized, domestic swine were intravenously injected with the albumin marker Evans blue dye, which was allowed to circulate for 90 min. After the animals were euthanized, silicone casts were made of the abdominal aorta and its iliac branches. Pulsatile flow calculations were subsequently made in computational regions derived from the casts. The distribution of the calculated time-dependent wall shear stress in the external iliac branches was directly compared on a point-by-point basis with the spatially varying in vivo uptake of Evans blue dye in the same arteries. The results indicate that in vivo endothelial permeability to albumin decreases with increasing time-average shear stress over the normal range. Additionally, endothelial permeability increases slightly with oscillatory shear index.

Albumins↗

PubMed1997

Fibroblast growth factor-2 potentiates vascular smooth muscle cell migration to platelet-derived growth factor: upregulation of alpha2beta1 integrin and disassembly of actin filaments.

Fibroblast growth factor-2 (FGF-2) has been implicated in vascular smooth muscle cell (SMC) migration, a key process in vascular disease. We demonstrate here that FGF-2 promotes SMC motility by altering beta1 integrin-mediated interactions with the extracellular matrix (ECM). FGF-2 significantly increased surface expression of alpha2beta1, alpha3beta1, and alpha5beta1 integrins on human SMCs, as assessed by flow cytometry. The greatest increase was for the collagen-binding alpha2beta1 integrin. Despite this, FGF-2 did not increase SMC adhesion to type I collagen but instead promoted SMC elongation and SMC motility. The latter was evaluated by using a microchemotaxis chamber and by digital time-lapse video microscopy. Although FGF-2 was not chemotactic for human SMCs, cells preincubated with FGF-2 displayed a 3.1-fold increase in migration to the undersurface of porous type I collagen-coated membranes and a 2.1-fold increase in migration speed on collagen. Furthermore, chemotaxis to platelet-derived growth factor-BB on collagen was significantly greater in SMCs exposed to FGF-2. FGF-2-induced elongation and migration on collagen were inhibited by a blocking anti-alpha2beta1 antibody; however, SMC adhesion to collagen was unaffected. SMC migration on fibronectin was also enhanced by FGF-2, although less prominently: migration through porous membranes increased 1.8-fold, and migration speed increased 1.3-fold. Also, FGF-2 completely disassembled the smooth muscle alpha-actin-containing stress fiber network contemporaneously with the change in integrin expression and cell shape. We conclude that (1) exogenous FGF-2 promotes SMC migration and potentiates chemotaxis to PDGF-BB; (2) the promigratory effect of FGF-2 is especially prominent on type I collagen and is mediated by upregulation of alpha2beta1 integrin; and (3) FGF-2 disassembles actin stress fibers, which may promote differential utilization of alpha2beta1 integrin for motility but not adhesion. This dynamic SMC-ECM interplay may be an important mechanism by which FGF-2 facilitates SMC motility in vivo.

Actin Cytoskeleton↗

PubMedDate not supplied

What we know about using research findings: implications for improving special education practice.

This article discusses the alternative roles and responsibilities that researchers might assume to bridge the gap between special education research and classroom practice. Literature is reviewed that addresses why some research-based practices fail, and the factors likely to lead to sustained use of research-based practices. The roles of researchers as collaborators, facilitators and coaches, interpreters of the culture and dynamics of the school, and critics are described in an attempt to promote researchers as leaders in efforts to improve practices in the field of special education.

Child↗

PubMed1999

Obesity among Kuwait University students: an explorative study.

University students' dietary habits have been criticised for their nutritional inadequacy and faddism. Kuwait University students may face the risk of obesity because of affluence and modernization and the dynamic changes in their level of physical activity and caloric intake. This promoted a study of a random sample of 842 Kuwait University students for dietary and socioeconomic factors associated with obesity. Weight and height were measured to calculate the body mass index (BMI), which is the weight in kilograms divided by the height in meters squared (kg/m2). Obesity was classified into grade 1 and 2 (BMI > 25 and > 30 kg/m2). The associated factors studied and obtained through questionnaires included gender, age, marital status, parental obesity, education and occupation, dieting, last dental and health check-up, year of study, number of siblings (total, brothers and sisters), eating in between meals, high school and college GPA and major, exercising, number of regular meals eaten, obese relatives, those living at home, and servants, highest desired degree, birth order, having a chronic disease, countries prefer visiting, family income, governorate, and socioeconomic status (SES). Grade 1 and 2 obesity were found to be 32.0 and 8.9%, respectively. Factors that were found to be significantly associated with obesity included gender, age, marital status, obesity among parents, dieting, last physical check-up, year of study, number of brothers, sisters and regular meals eaten and high school GPA. Logistic regression analysis revealed that the same factors significantly contributed to the development of obesity except the last four. The level of obesity among Kuwait University students is high. Obesity is a risk factor for a variety of chronic diseases. There is a need to address the challenge of instituting measures that would reduce the future ill-effects of obesity on young adults. It is widely believed that during the young adult years many important health habits are formed and set. It is at this stage (or earlier) that wellness and self-care programming for college students is essential and worthy of being explored and its efficacy assessed.

Adolescent↗

PubMed2005

Epigenetic mechanisms in the dopamine D2 receptor-dependent inhibition of the prolactin gene.

Transcription of the prolactin gene is dynamically controlled by positive and negative hormone signals that target the regulatory promoter region. Based on the inducibility of prolactin gene expression by inhibitors of histone deacetylases (HDACs), we examined the role of histone acetylation at the genomic prolactin promoter as a late step in transcriptional regulation. Chromatin immunoprecipitation analysis of GH4 cells revealed elevated levels of acetylated histones in the promoter and enhancer regions of the gene, compared with downstream intron sequences. 17beta-Estradiol stimulated histone H4 acetylation in the promoter region by 2- to 3-fold within 30 min. Dopamine inhibited histone H4 acetylation by 2-fold in 30 min, an effect mimicked by the MAPK kinase (MEK1) inhibitor U0126. In contrast, the synthetic glucocorticoid dexamethasone, which inhibits prolactin transcription, failed to alter histone acetylation over the same time frame. Association of transcription activator Pit-1 with the prolactin promoter was unchanged by hormone treatment. However, in response to dopamine, histone deacetylase HDAC2 and corepressor mSin3A were rapidly recruited to the prolactin promoter, and association was sustained above basal levels over a 1-h period. Consistent with this corepressor function, depletion of endogenous mSin3A by small interfering RNA was sufficient to enhance prolactin gene expression by 70%, comparable to the induction by the HDAC inhibitor, trichostatin A. These studies demonstrate that dopamine D2 receptor activation and inhibition of MAPK (ERK1/2) signaling lead to rapid deacetylation of histones at the genomic prolactin promoter. Recruitment of specific HDAC/ corepressor complexes may be an important mechanism for repression of target gene transcription by Gi/o-coupled receptors.

Acetylation↗