Showing papers by "University of North Carolina at Chapel Hill published in 1996"

THE NF-κB AND IκB PROTEINS: New Discoveries and Insights

Abstract: ▪ Abstract The transcription factor NF-κB has attracted widespread attention among researchers in many fields based on the following: its unusual and rapid regulation, the wide range of genes that it controls, its central role in immunological processes, the complexity of its subunits, and its apparent involvement in several diseases. A primary level of control for NF-κB is through interactions with an inhibitor protein called IκB. Recent evidence confirms the existence of multiple forms of IκB that appear to regulate NF-κB by distinct mechanisms. NF-κB can be activated by exposure of cells to LPS or inflammatory cytokines such as TNF or IL-1, viral infection or expression of certain viral gene products, UV irradiation, B or T cell activation, and by other physiological and nonphysiological stimuli. Activation of NF-κB to move into the nucleus is controlled by the targeted phosphorylation and subsequent degradation of IκB. Exciting new research has elaborated several important and unexpected findings that...

Generalized gradient approximation for the exchange-correlation hole of a many-electron system

Abstract: We construct a generalized gradient approximation (GGA) for the density ${\mathit{n}}_{\mathrm{xc}}$(r,r+u) at position r+u of the exchange-correlation hole surrounding an electron at r, or more precisely for its system and spherical average 〈${\mathit{n}}_{\mathrm{xc}}$(u)〉=(4\ensuremath{\pi}${)}^{\mathrm{\ensuremath{-}}1}$\ensuremath{\int}d${\mathrm{\ensuremath{\Omega}}}_{\mathit{u}}$ ${\mathit{N}}^{\mathrm{\ensuremath{-}}1}$\ensuremath{\int}${\mathit{d}}^{3}$r n(r)${\mathit{n}}_{\mathrm{xc}}$(r,r+u). Starting from the second-order density gradient expansion, which involves the local spin densities ${\mathit{n}}_{\mathrm{\ensuremath{\uparrow}}}$(r),${\mathit{n}}_{\mathrm{\ensuremath{\downarrow}}}$(r) and their gradients \ensuremath{ abla}${\mathit{n}}_{\mathrm{\ensuremath{\uparrow}}}$(r),\ensuremath{ abla}${\mathit{n}}_{\mathrm{\ensuremath{\downarrow}}}$(r), we cut off the spurious large-u contributions to restore those exact conditions on the hole that the local spin density (LSD) approximation respects. Our GGA hole recovers the Perdew-Wang 1991 and Perdew-Burke-Ernzerhof GGA's for the exchange-correlation energy, which therefore respect the same powerful hole constraints as LSD. When applied to real systems, our hole model provides a more detailed test of these energy functionals, and also predicts the observable electron-electron structure factor. \textcopyright{} 1996 The American Physical Society.

R&D Spillovers and the Geography of Innovation and Production

Abstract: Previous research has indicated that investment in R&D by private firms and universities can lead to knowledge spillover, which can lead to exploitation from other third-party firms. If the ability of these third-party firms to acquire knowledge spillovers is influenced by their proximity to the knowledge source, then geographic clustering should be observable, especially in industries where access to knowledge spillovers is vital. The spatial distribution of innovation activity and the geographic concentration of production are examined, using three sources of economic knowledge: industry R&D, skilled labor, and the size of the pool of basic science for a specific industry. Results show that the propensity for innovative activity to cluster spatially is more attributable to the influence of knowledge spillovers and not merely the geographic concentration of production. (SFL)

Services Marketing: Integrating Customer Focus Across the Firm

Abstract: The Second European Edition of Services Marketing: Integrating Customer Focus Across the Firm by Wilson, Zeithaml, Bitner and Gremler uniquely focuses on the development of customer relationships through quality service. Reflecting the increasing importance of the service economy, Services Marketing is the only text that put the customer's experience of services at the centre of its approach. The core theories, concepts and frameworks are retained, and specifically the gaps model, a popular feature of the book. The text moves from the foundations of services marketing before introducing the gaps model and demonstrating its application to services marketing. In the second edition, the book takes on more European and International contexts to reflect the needs of courses, lecturers and students. The second edition builds on the wealth of European and International examples, cases, and research in the first edition, offering more integration of European content. It has also be fully updated with the latest research to ensure that it continues to be seen as the text covering the very latest services marketing thinking. In addition, the cases section has been thoroughly examined and revised to offer a range of new case studies with a European and global focus. The online resources have also been fully revised and updated providing an excellent package of support for lecturers and students.

TNF- and Cancer Therapy-Induced Apoptosis: Potentiation by Inhibition of NF-κB

Abstract: Many cells are resistant to stimuli that can induce apoptosis, but the mechanisms involved are not fully understood. The activation of the transcription factor nuclear factor-kappa B (NF-kappaB) by tumor necrosis factor (TNF), ionizing radiation, or daunorubicin (a cancer chemotherapeutic compound), was found to protect from cell killing. Inhibition of NF-kappaB nuclear translocation enhanced apoptotic killing by these reagents but not by apoptotic stimuli that do not activate NF-kappaB. These results provide a mechanism of cellular resistance to killing by some apoptotic reagents, offer insight into a new role for NF-kappaB, and have potential for improvement of the efficacy of cancer therapies.

A Comparison of Continuous Intravenous Epoprostenol (Prostacyclin) with Conventional Therapy for Primary Pulmonary Hypertension

Abstract: Background Primary pulmonary hypertension is a progressive disease for which no treatment has been shown in a prospective, randomized trial to improve survival. Methods We conducted a 12-week prospective, randomized, multicenter open trial comparing the effects of the continuous intravenous infusion of epoprostenol (formerly called prostacyclin) plus conventional therapy with those of conventional therapy alone in 81 patients with severe primary pulmonary hypertension (New York Heart Association functional class III or IV). Results Exercise capacity was improved in the 41 patients treated with epoprostenol (median distance walked in six minutes, 362 m at 12 weeks vs. 315 m at base line), but it decreased in the 40 patients treated with conventional therapy alone (204 m at 12 weeks vs. 270 m at base line; P<0.002 for the comparison of the treatment groups). Indexes of the quality of life were improved only in the epoprostenol group (P<0.01). Hemodynamics improved at 12 weeks in the epoprostenol-treated pat...

The impact of environmental management on firm performance

Abstract: Environmental management has the potential to play a pivotal role in the financial performance of the firm. Many individuals suggest that profitability is hurt by the higher production costs of environmental management initiatives, while others cite anecdotal evidence of increased profitability. A theoretical model is proposed that links strong environmental management to improved perceived future financial performance, as measured by stock market performance. The linkage to firm performance is tested empirically using financial event methodology and archival data of firm-level environmental and financial performance. Significant positive returns were measured for strong environmental management as indicated by environmental performance awards, and significant negative returns were measured for weak environmental management as indicated by environmental crises. The implicit financial market valuation of these events also was estimated. Cross-sectional analysis of the environmental award events revealed differences for first-time awards and between industries. First-time award announcements were associated with greater increases in market valuation, although smaller increases were observed for firms in environmentally dirty industries, possibly indicative of market skepticism. This linkage between environmental management and financial performance can be used by both researchers and practitioners as one measure of the benefits experienced by industry leaders, and as one criterion against which to measure investment alternatives.

Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter

Abstract: Disruption of the mouse dopamine transporter gene results in spontaneous hyperlocomotion despite major adaptive changes, such as decreases in neurotransmitter and receptor levels. In homozygote mice, dopamine persists at least 100 times longer in the extracellular space, explaining the biochemical basis of the hyperdopaminergic phenotype and demonstrating the critical role of the transporter in regulating neurotransmission. The dopamine transporter is an obligatory target of cocaine and amphetamine, as these psychostimulants have no effect on locomotor activity or dopamine release and uptake in mice lacking the transporter.

An Integrative Model for the Study of Developmental Competencies in Minority Children

Abstract: In this article a conceptual model for the study of child development in minority populations in the United States is proposed. In support of the proposed model, this article includes (a) a delineation and critical analysis of mainstream theoretical frameworks in relation to their attention and applicability to the understanding of developmental processes in children of color and of issues at the intersection of social class, culture, ethnicity, and race, and (b) a description and evaluation of the conceptual frameworks that have guided the extant literature on minority children and families. Based on the above considerations, an integrative conceptual model of child development is presented, anchored within social stratification theory, emphasizing the importance of racism, prejudice, discrimination, oppression, and segregation on the development of minority children and families.

OBBTree: a hierarchical structure for rapid interference detection

Abstract: We present a data structure and an algorithm for efficient and exact interference detection amongst complex models undergoing rigid motion. The algorithm is applicable to all general polygonal models. It pre-computes a hierarchical representation of models using tight-fitting oriented bounding box trees (OBBTrees). At runtime, the algorithm traverses two such trees and tests for overlaps between oriented bounding boxes based on a separating axis theorem, which takes less than 200 operations in practice. It has been implemented and we compare its performance with other hierarchical data structures. In particular, it can robustly and accurately detect all the contacts between large complex geometries composed of hundreds of thousands of polygons at interactive rates. CR

Focal adhesions, contractility, and signaling

Abstract: Focal adhesions are sites of tight adhesion to the underlying extracellular matrix developed by cells in culture. They provided a structural link between the actin cytoskeleton and the extracellular matrix and are regions of signal transduction that relate to growth control. The assembly of focal adhesions is regulated by the GTP-binding protein Rho. Rho stimulates contractility which, in cells that are tightly adherent to the substrate, generates isometric tension. In turn, this leads to the bundling of actin filaments and the aggregation of integrins (extracellular matrix receptors) in the plane of the membrane. The aggregation of integrins activates the focal adhesion kinase and leads to the assembly of a multicomponent signaling complex.

Rho-stimulated contractility drives the formation of stress fibers and focal adhesions.

Abstract: Activated rhoA, a ras-related GTP-binding protein, stimulates the appearance of stress fibers, focal adhesions, and tyrosine phosphorylation in quiescent cells (Ridley, A.J., and A. Hall, 1992. Cell. 70:389-399). The pathway by which rho triggers these events has not been elucidated. Many of the agents that activate rho (e.g., vasopressin, endothelin, lysophosphatidic acid) stimulate the contractility of smooth muscle and other cells. We have investigated whether rho's induction of stress fibers, focal adhesions, and tyrosine phosphorylation is the result of its stimulation of contractility. We demonstrate that stimulation of fibroblasts with lysophosphatidic acid, which activates rho, induces myosin light chain phosphorylation. This precedes the formation of stress fibers and focal adhesions and is accompanied by increased contractility. Inhibition of contractility by several different mechanisms leads to inhibition of rho-induced stress fibers, focal adhesions, and tyrosine phosphorylation. In addition, when contractility is inhibited, integrins disperse from focal adhesions as stress fibers and focal adhesions disassemble. Conversely, upon stimulation of contractility, diffusely distributed integrins are aggregated into focal adhesions. These results suggest that activated rho stimulates contractility, driving the formation of stress fibers and focal adhesions and elevating tyrosine phosphorylation. A model is proposed to account for how contractility could promote these events.

Periodontal Disease and Cardiovascular Disease

Abstract: It is our central hypothesis that periodontal diseases, which are chronic Gramnegative infections, represent a previously unrecognized risk factor for atherosclerosis and thromboembolic events. Previous studies have demonstrated an association between periodontal disease severity and risk of coronary heart disease and stroke. We hypothesize that this association may be due to an underlying inflammatory response trait, which places an individual at high risk for developing both periodontal disease and atherosclerosis. We further suggest that periodontal disease, once established, provides a biological burden of endotoxin (lipopolysaccharide) and inflammatory cytokines (especially TxA2 , IL-1β, PGE2 , and TNF-α) which serve to initiate and exacerbate atherogenesis' and thromboembolic events. A cohort study was conducted using combined data from the Normative Aging Study and the Dental Longitudinal Study sponsored by the United States Department of Veterans Affairs. Mean bone loss scores and worst probing pocket depth scores per tooth were measured on 1,147 men during 1968 to 1971. Information gathered during follow-up examinations showed that 207 men developed coronary heart disease (CHD), 59 died of CHD, and 40 had strokes. Incidence odds ratios adjusted for established cardiovascular risk factors were 1.5, 1.9, and 2.8 for bone loss and total CHD, fatal CHD, and stroke, respectively. Levels of bone loss and cumulative incidence of total CHD and fatal CHD indicated a biologic gradient between severity of exposure and occurrence of disease. J Periodontol 1996;67:1123-1137.

Contemporary Issues in Electron Transfer Research

Abstract: This is an overview of some of the important, challenging, and problematic issues in contemporary electron transfer research. After a qualitative discussion of electron transfer, its time and distance scales, energy curves, and basic parabolic energy models are introduced to define the electron transfer process. Application of transition state theory leads to the standard Marcus formulation of electron transfer rate constants. Electron transfer in solution is coupled to solvent polarization effects, and relaxation processes can contribute to and even control electron transfer. The inverted region, in which electron transfer rate constants decrease with increasing exoergicity, is one of the most striking phenomena in electron transfer chemistry. It is predicted by both semiclassical and quantum mechanical models, with the latter appropriate if there are coupled high- or medium-frequency vibrations. The intramolecular reorganizational energy has different contributions from different vibrational modes, whic...

A Brief Survey of Bandwidth Selection for Density Estimation

Abstract: There has been major progress in recent years in data-based bandwidth selection for kernel density estimation. Some “second generation” methods, including plug-in and smoothed bootstrap techniques, have been developed that are far superior to well-known “first generation” methods, such as rules of thumb, least squares cross-validation, and biased cross-validation. We recommend a “solve-the-equation” plug-in bandwidth selector as being most reliable in terms of overall performance. This article is intended to provide easy accessibility to the main ideas for nonexperts.

Periodontal Infection as a Possible Risk Factor for Preterm Low Birth Weight

Abstract: Periodontal diseases are Gram-negative anaerobic infections that can occur in women of childbearing age (18 to 34 years). In the present investigation we sought to determine whether the prevalence of maternal periodontal infection could be associated with preterm low birth weight (PLBW), controlling for known risk factors and potential covariates. A case-control study of 124 pregnant or postpartum mothers was performed. PLBW cases were defined as a mother with a birth of less than 2,500 g and one or more of the following: gestational age <37 weeks, preterm labor (PTL), or premature rupture of membranes (PROM). Controls were normal birth weight infants (NBW). Assessments included a broad range of known obstetric risk factors, such as tobacco use, drug use, alcohol consumption, level of prenatal care, parity, genitourinary infections, and nutrition. Each subject received a periodontal examination to determine clinical attachment level. PLBW cases and primiparous PLBW cases (n = 93) had significantly worse periodontal disease than the respective NBW controls. Multivariate logistic regression models, controlling for other risk factors and covariates, demonstrated that periodontal disease is a statistically significant risk factor for PLBW with adjusted odds ratios of 7.9 and 7.5 for all PLBW cases and primiparous PLBW cases, respectively. These data indicate that periodontal diseases represent a previously unrecognized and clinically significant risk factor for preterm low birth weight as a consequence of either PTL or preterm PROM. J Periodontol 1996;67:1103-1113.

European integration from the 1980s: State-centric v. multi-level governance

Abstract: This article takes initial steps in evaluating contending models of EU governance. We argue that the sovereignty of individual states is diluted in the European arena by collective decision-making and by supranational institutions. In addition, European states are losing their grip on the mediation of domestic interest representation in international relations. We make this argument along two tracks. First, we analyse the conditions under which central state executives may lose their grip on power. Next, we divide up the policy process into stages and specify which institutional rules may induce various actors to deepen EU policy-making.

Carvedilol Produces Dose-Related Improvements in Left Ventricular Function and Survival in Subjects With Chronic Heart Failure

Abstract: Background We conducted a multicenter, placebo-controlled trial designed to establish the efficacy and safety of carvedilol, a “third-generation” β-blocking agent with vasodilator properties, in chronic heart failure. Methods and Results Three hundred forty-five subjects with mild to moderate, stable chronic heart failure were randomized to receive treatment with placebo, 6.25 mg BID carvedilol (low-dose group), 12.5 mg BID carvedilol (medium-dose group), or 25 mg BID carvedilol (high-dose group). After a 2- to 4-week up-titration period, subjects remained on study medication for a period of 6 months. The primary efficacy parameter was submaximal exercise measured by two different techniques, the 6-minute corridor walk test and the 9-minute self-powered treadmill test. Carvedilol had no detectable effect on submaximal exercise as measured by either technique. However, carvedilol was associated with dose-related improvements in LV function (by 5, 6, and 8 ejection fraction [EF] units in the low-, medium-, ...

Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter

Abstract: Maintenance of fluid and electrolyte homeostasis is critical for normal neuromuscular function Bartter's syndrome is an autosomal recessive disease characterized by diverse abnormalities in electrolyte homeostasis including hypokalaemic metabolic alkalosis; Gitelman's syndrome represents the predominant subset of Bartter's patients having hypomagnesemia and hypocalciuria We now demonstrate complete linkage of Gitelman's syndrome to the locus encoding the renal thiazide-sensitive Na–Cl cotransporter, and identify a wide variety of non-conservative mutations, consistent with loss of function alleles, in affected subjects These findings demonstrate the molecular basis of Gitelman's syndrome We speculate that these mutant alleles lead to reduced sodium chloride reabsorption in the more common heterozygotes, potentially protecting against development of hypertension

DNA excision repair

Abstract: In nucleotide excision repair DNA damage is removed through incision of the damaged strand on both sides of the lesion, followed by repair synthesis, which fills the gap using the intact strand as a template, and finally ligation. In prokaryotes the damaged base is removed in a 12-13 nucleotide (nt)-long oligomer; in eukaryotes including humans the damage is excised in a 24-32 nt-long fragment. Excision in Escherichia coli is accomplished by three proteins designated UvrA, UvrB, and UvrC. In humans, by contrast, 16 polypeptides including seven xeroderma pigmentosum (XP) proteins, the trimeric replication protein A [RPA, human single-stranded DNA binding protein (HSSB)], and the multisubunit (7-10) general transcription factor TFIIH are required for the dual incisions. Transcribed strands are specifically targeted for excision repair by a transcription-repair coupling factor both in E. coli and in humans. In humans, excision repair is an important defense mechanism against the two major carcinogens, sunlight and cigarette smoke. Individuals defective in excision repair exhibit a high incidence of cancer while individuals with a defect in coupling transcription to repair suffer from neurological and skeletal abnormalities.

The Soft Gamma Repeaters as Very Strongly Magnetized Neutron Stars. II. Quiescent Neutrino, X-Ray, and Alfvén Wave Emission

Abstract: We calculate the quiescent X-ray, neutrino, and Alfven wave emission from a neutron star with a very strong magnetic field, Bdipole ~ 1014 − 1015 G and Binterior ~ (5–10) × 1015 G. These results are compared with observations of quiescent emission from the soft gamma repeaters and from a small class of anomalous X-ray pulsars that we have previously identified with such objects. The magnetic field, rather than rotation, provides the main source of free energy, and the decaying field is capable of powering the quiescent X-ray emission and particle emission observed from these sources. New features that are not present in the decay of the weaker fields associated with ordinary radio pulsars include fracturing of the neutron star crust, strong heating of its core, and effective suppression of thermal conduction perpendicular to the magnetic field. As the magnetic field is forced through the crust by diffusive motions in the core, multiple small-scale fractures are excited, as well as a few large fractures that can power soft gamma repeater bursts. The decay rate of the core field is a very strong function of temperature and therefore of the magnetic flux density. The strongest prediction of the model is that these sources will show no optical emissions associated with X-ray heating of an accretion disk.

Periodontal diseases: pathogenesis.

Abstract: Question Set 1. What are the important destructive mechanisms in periodontal diseases? 2. What are the important protective mechanisms in periodontal diseases? 3. What are the important genetic factors and what is the state-of-the art relative to assessing these genetic factors in periodontal diseases? 4. What do we know about the mechanism of action of possible risk factors, such as smoking and diabetes on the host? 5. What is the evidence that host modulating agents will be effective in prevention or treatment ofperiodontal diseases?

Involvement of the cyclin-dependent kinase inhibitor p16 (INK4a) in replicative senescence of normal human fibroblasts

Abstract: Human diploid fibroblasts (HDFs) can be grown in culture for a finite number of population doublings before they cease proliferation and enter a growth-arrest state termed replicative senescence. The retinoblastoma gene product, Rb, expressed in these cells is hypophosphorylated. To determine a possible mechanism by which senescent human fibroblasts maintain a hypophosphorylated Rb, we examined the expression levels and interaction of the Rb kinases, CDK4 and CDK6, and the cyclin-dependent kinase inhibitors p21 and p16 in senescent HDFs. Cellular p21 protein expression increased dramatically during the final two to three passages when the majority of cells lost their growth potential and neared senescence but p21 levels declined in senescent HDFs. During this period, p16 mRNA and cellular protein levels gradually rose with the protein levels in senescent HDFs reaching nearly 40-fold higher than early passage cells. In senescent HDFs, p16 was shown to be complexed to both CDK4 and CDK6. Immunodepletion analysis of p21 and p16 from the senescent cell extracts revealed that p16 is the major CDK inhibitor for both CDK4 and CDK6 kinases. Immunoprecipitation of CDK4 and CDK6 and their associated proteins from radiolabeled extracts from senescent HDFs showed no other CDK inhibitors. Based upon these results, we propose that senescence is a multistep process requiring the expression of both p21 and p16. p16 up-regulation is a key event in the terminal stages of growth arrest in senescence, which may explain why p16 but not p21 is commonly mutated in immortal cells and human tumors.

Efficient long-term gene transfer into muscle tissue of immunocompetent mice by adeno-associated virus vector.

Abstract: Muscle-directed gene transfer is being considered for the treatment of several metabolic diseases, including hemophilia and Duchene's muscular dystrophy. Previous efforts to target this tissue for somatic delivery with various vector systems have resulted in transient expression due to silencing of the transgene or to an immune response against the vector-transduced cells. We introduced recombinant adeno-associated virus vector (rAAV) carrying a lacZ reporter into muscle tissue of immunocompetent mice. The lacZ reporter gene was efficiently transduced and expressed with no evidence of a cellular immune response. Moreover, gene expression persisted for more than 1.5 years. Molecular characterization of rAAV vector DNA suggests a mechanism for persistence, since vector episomes convert to high-molecular-weight genomic DNA. These data provide the first report for establishing long-term gene transduction into mammalian muscle cells in vivo without the need for immune modulation of the organism.

Death Don't Have No Mercy: Cell Death Programs in Plant-Microbe Interactions.

Abstract: A nearly ubiquitous feature of plant-pathogen interactions is host cell death. In its most recognizable form, host cell death is manifested as the rapid collapse of tissue, termed the hypersensitive response (HR). This response accompanies "incompatible interactions" and leads to disease resistance. As detailed below, the HR is programmed genetically in the plant and is a consequence of new host transcription and trans? lation (Dixon et al., 1994; Godiard et al., 1994). The HR is a correlative feature of many but not all incompatible interac? tions controlled by classic disease resistance (R) genes (Dangl, 1995; Staskawicz et al., 1995; see also Bent, 1996, in this is? sue). A local HR is often associated with the onset of systemic acquired resistance (SAR; Chester, 1933; Enyedi et al., 1992; Ryals et al., 1994, 1996, in this issue) in distal plant tissues. In addition, sites of the HR are invariably focal points for tran? scriptional induction of plant defense genes in neighboring cells (Somssich et al., 1988; Schmelzer et al., 1989). Subse? quent biosynthesis of protective secondary metabolites and cell wall buttressing around the HR site are also thought to contribute to overall pathogen containment. Signals derived from cells undergoing the HR apparently contribute signifi? cantly to the induction of defense gene transcription in adjacent cells. However, certain bacterial mutants unable to elicit an HR are still competent to trigger the transcription of defense genes that are normally induced during both incompatible and compatible interactions (Jakobek and Lindgren, 1993). Whether the cell death that constitutes the HR actually causes disease resistance by depriving the incoming patho? gen of nutrients or by releasing microbiocidal compounds from dying cells is unclear. Alternatively, the HR could be the con? sequence of a mechanism that is actually killing both host and microbe cells. In fact, recent evidence discussed below sug? gests that HR cell death is not required to stop pathogen growth in at least some cases (Century et al., 1995; Hammond-Kosack et al., 1996). If this separation of resistance per se and cell death is generalizable, can we glean insight from the mecha? nism by which host cells die that is relevant to the mechanism that kills or stops an invading pathogen?