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Showing papers by "University of Virginia published in 2000"


Journal ArticleDOI
TL;DR: In this article, the authors draw upon previous research conducted in the different social science disciplines and applied fields of business to create a conceptual framework for the field of entrepreneurship, and predict a set of outcomes not explained or predicted by conceptual frameworks already in existence in other fields.
Abstract: To date, the phenomenon of entrepreneurship has lacked a conceptual framework. In this note we draw upon previous research conducted in the different social science disciplines and applied fields of business to create a conceptual framework for the field. With this framework we explain a set of empirical phenomena and predict a set of outcomes not explained or predicted by conceptual frameworks already in existence in other fields.

11,161 citations


Journal ArticleDOI
06 Jan 2000-Nature
TL;DR: It is proposed that distinct histone modifications, on one or more tails, act sequentially or in combination to form a ‘histone code’ that is, read by other proteins to bring about distinct downstream events.
Abstract: Histone proteins and the nucleosomes they form with DNA are the fundamental building blocks of eukaryotic chromatin. A diverse array of post-translational modifications that often occur on tail domains of these proteins has been well documented. Although the function of these highly conserved modifications has remained elusive, converging biochemical and genetic evidence suggests functions in several chromatin-based processes. We propose that distinct histone modifications, on one or more tails, act sequentially or in combination to form a 'histone code' that is, read by other proteins to bring about distinct downstream events.

8,265 citations


Journal ArticleDOI
TL;DR: A new and related complexity measure is developed, sample entropy (SampEn), and a comparison of ApEn and SampEn is compared by using them to analyze sets of random numbers with known probabilistic character, finding SampEn agreed with theory much more closely than ApEn over a broad range of conditions.
Abstract: Entropy, as it relates to dynamical systems, is the rate of information production. Methods for estimation of the entropy of a system represented by a time series are not, however, well suited to analysis of the short and noisy data sets encountered in cardiovascular and other biological studies. Pincus introduced approximate entropy (ApEn), a set of measures of system complexity closely related to entropy, which is easily applied to clinical cardiovascular and other time series. ApEn statistics, however, lead to inconsistent results. We have developed a new and related complexity measure, sample entropy (SampEn), and have compared ApEn and SampEn by using them to analyze sets of random numbers with known probabilistic character. We have also evaluated cross-ApEn and cross-SampEn, which use cardiovascular data sets to measure the similarity of two distinct time series. SampEn agreed with theory much more closely than ApEn over a broad range of conditions. The improved accuracy of SampEn statistics should make them useful in the study of experimental clinical cardiovascular and other biological time series.

6,088 citations


Journal ArticleDOI
10 Aug 2000-Nature
TL;DR: A functional interdependence of site-specific H3 tail modifications is revealed and a dynamic mechanism for the regulation of higher-order chromatin is suggested.
Abstract: The organization of chromatin into higher-order structures influences chromosome function and epigenetic gene regulation. Higher-order chromatin has been proposed to be nucleated by the covalent modification of histone tails and the subsequent establishment of chromosomal subdomains by non-histone modifier factors. Here we show that human SUV39H1 and murine Suv39h1—mammalian homologues of Drosophila Su(var)3-9 and of Schizosaccharomyces pombe clr4—encode histone H3-specific methyltransferases that selectively methylate lysine 9 of the amino terminus of histone H3 in vitro. We mapped the catalytic motif to the evolutionarily conserved SET domain, which requires adjacent cysteine-rich regions to confer histone methyltransferase activity. Methylation of lysine 9 interferes with phosphorylation of serine 10, but is also influenced by pre-existing modifications in the amino terminus of H3. In vivo, deregulated SUV39H1 or disrupted Suv39h activity modulate H3 serine 10 phosphorylation in native chromatin and induce aberrant mitotic divisions. Our data reveal a functional interdependence of site-specific H3 tail modifications and suggest a dynamic mechanism for the regulation of higher-order chromatin.

2,796 citations


Book
01 Jan 2000
TL;DR: In this paper, the authors present a model for making metal foams characterisation methods and properties of metal foam, and a constitutive model for metal foam design for Creep with Metal Foams Sandwich Structures Energy Management: Packaging and Blast Protection Sound Absorption and Vibration Suppression Thermal Management and Heat Transfer Electrical Properties of metal Foams Cutting, Finishing and Joining Cost Estimation and Viability Case Studies Suppliers of Metal Foam Web Sites Index
Abstract: Introduction Making Metal Foams Characterization Methods Properties of Metal Foams Design Analysis for Material Selection Design Formulae for Simple Structures A Constitutive Model for Metal Foams Design for Creep with Metal Foams Sandwich Structures Energy Management: Packaging and Blast Protection Sound Absorption and Vibration Suppression Thermal Management and Heat Transfer Electrical Properties of Metal Foams Cutting, Finishing and Joining Cost Estimation and Viability Case Studies Suppliers of Metal Foams Web Sites Index .

2,527 citations


Journal ArticleDOI
TL;DR: TGF‐β family members are multifunctional hormones, the nature of their effects depending on what has been called ‘the cellular context’ warrants mention at the outset.
Abstract: The deployment of a cell's genetic program in a multicellular organism must be tightly controlled for the sake of the organism as a whole. Over the past 20 years the transforming growth factor‐β (TGF‐β) family of secretory polypeptides has emerged as a major source of signals exerting this type of control. This family includes various forms of TGF‐β, the bone morphogenetic proteins (BMPs), the Nodals, the Activins, the anti‐Mullerian hormone, and many other structurally related factors in vertebrates, insects and nematodes (Massague, 1998). Produced by diverse cell types, these factors regulate cell migration, adhesion, multiplication, differentiation and death throughout the life span of the organism. Many of these responses result from changes in the expression of key target genes. Hence, transcriptional control by the TGF‐β family has become a subject of intense investigation in recent years. The present knowledge of these mechanisms is reviewed here. One basic concept concerning the role of the TGF‐β family as hormonally active agents warrants mention at the outset. Unlike classical hormones, whose actions are few and concrete, the members of the TGF‐β family have many different effects depending on the type and state of the cell. For example, in the same healing wound TGF‐β may stimulate or inhibit cell proliferation depending on whether the target is a fibroblast or a keratinocyte (Ashcroft et al ., 1999); in mammary epithelial cells TGF‐β will cause growth arrest or metastatic behavior depending on the level of oncogenic Ras activity present in the cell (Oft et al ., 1996); and human BMP4 and its Drosophila ortholog, DPP, can signal dorsalization in the fly (Padgett et al ., 1993) yet bone formation in a vertebrate (Sampath et al ., 1993). TGF‐β family members are multifunctional hormones, the nature of their effects depending on what has been called ‘the cellular context’. It was plausible …

2,011 citations


Journal ArticleDOI
TL;DR: In this paper, the authors analyzed whether complementary assets are required to gain cost advantage from implementing best practices, and found that capabilities for process innovation and implementation are complementary assets that moderate the relationship between best practices and cost advantage, a significant factor in determining firm performance.
Abstract: Research on the effects on firm performance of “best practices” of environmental management, which are supposed to enable firms to simultaneously protect the environment and reduce costs, has so far ignored the roles of existing firm resources and capabilities. Drawing on the resource-based view of the firm, this study analyzes whether complementary assets are required to gain cost advantage from implementing best practices. Results based on survey data from 88 chemical companies indicate that capabilities for process innovation and implementation are complementary assets that moderate the relationship between best practices and cost advantage, a significant factor in determining firm performance.

1,851 citations


Journal ArticleDOI
28 Apr 2000-Science
TL;DR: It is hypothesize that a self-sustained circadian pacemaker in the SCN entrains circadian oscillators in the periphery to maintain adaptive phase control, which is temporarily lost following large, abrupt shifts in the environmental light cycle.
Abstract: In multicellular organisms, circadian oscillators are organized into multitissue systems which function as biological clocks that regulate the activities of the organism in relation to environmental cycles and provide an internal temporal framework. To investigate the organization of a mammalian circadian system, we constructed a transgenic rat line in which luciferase is rhythmically expressed under the control of the mouse Per1 promoter. Light emission from cultured suprachiasmatic nuclei (SCN) of these rats was invariably and robustly rhythmic and persisted for up to 32 days in vitro. Liver, lung, and skeletal muscle also expressed circadian rhythms, which damped after two to seven cycles in vitro. In response to advances and delays of the environmental light cycle, the circadian rhythm of light emission from the SCN shifted more rapidly than did the rhythm of locomotor behavior or the rhythms in peripheral tissues. We hypothesize that a self-sustained circadian pacemaker in the SCN entrains circadian oscillators in the periphery to maintain adaptive phase control, which is temporarily lost following large, abrupt shifts in the environmental light cycle.

1,800 citations


Journal ArticleDOI
15 Dec 2000-Science
TL;DR: This study presents a comprehensive view of the temporal compartmentalization of physiological pathways by the circadian clock in a eukaryote.
Abstract: Like most organisms, plants have endogenous biological clocks that coordinate internal events with the external environment. We used high-density oligonucleotide microarrays to examine gene expression in Arabidopsis and found that 6% of the more than 8000 genes on the array exhibited circadian changes in steady-state messenger RNA levels. Clusters of circadian-regulated genes were found in pathways involved in plant responses to light and other key metabolic pathways. Computational analysis of cycling genes allowed the identification of a highly conserved promoter motif that we found to be required for circadian control of gene expression. Our study presents a comprehensive view of the temporal compartmentalization of physiological pathways by the circadian clock in a eukaryote.

1,600 citations


Journal ArticleDOI
TL;DR: Using complete phylogenies of contemporary carnivores and primates, the first comparative test is presented showing that high trophic level, low population density, slow life history and small geographical range size are all significantly and independently associated with a high extinction risk in declining species.
Abstract: What biological attributes predispose species to the risk of extinction? There are many hypotheses but so far there has been no systematic analysis for discriminating between them. Using complete phylogenies of contemporary carnivores and primates, we present, to our knowledge, the first comparative test showing that high trophic level, low population density slow life history and, in particular, small geographical range size are all significantly and independently associated with a high extinction risk in declining species. These traits together explain nearly 50% of the total between-species variation in extinction risk. Much of the remaining variation can be accounted for by external anthropogenic factors that affect species irrespective of their biology.

1,486 citations


Journal ArticleDOI
28 Sep 2000-Nature
TL;DR: It is shown that the ER isoform, ERα, binds in a ligand-dependent manner to the p85α regulatory subunit of phosphatidylinositol-3-OH kinase (PI(3)K).
Abstract: Oestrogen produces diverse biological effects through binding to the oestrogen receptor (ER). The ER is a steroid hormone nuclear receptor, which, when bound to oestrogen, modulates the transcriptional activity of target genes. Controversy exists, however, concerning whether ER has a role outside the nucleus, particularly in mediating the cardiovascular protective effects of oestrogen. Here we show that the ER isoform, ER alpha, binds in a ligand-dependent manner to the p85alpha regulatory subunit of phosphatidylinositol-3-OH kinase (PI(3)K). Stimulation with oestrogen increases ER alpha-associated PI(3)K activity, leading to the activation of protein kinase B/Akt and endothelial nitric oxide synthase (eNOS). Recruitment and activation of PI(3)K by ligand-bound ER alpha are independent of gene transcription, do not involve phosphotyrosine adapter molecules or src-homology domains of p85alpha, and extend to other steroid hormone receptors. Mice treated with oestrogen show increased eNOS activity and decreased vascular leukocyte accumulation after ischaemia and reperfusion injury. This vascular protective effect of oestrogen was abolished in the presence of PI(3)K or eNOS inhibitors. Our findings define a physiologically important non-nuclear oestrogen-signalling pathway involving the direct interaction of ER alpha with PI(3)K.

Journal ArticleDOI
TL;DR: In this paper, the authors compare the observed variability to that simulated in a coupled ocean-atmosphere model, making use of both existing instrumental analyses and newly available proxy-based multi-century surface temperature estimates.
Abstract: Analyses of proxy based reconstructions of surface temperatures during the past 330 years show the existence of a distinct oscillatory mode of variability with an approximate time scale of 70 years. This variability is also seen in instrumental records, although the oscillatory nature of the variability is difficult to assess due to the short length of the instrumental record. The spatial pattern of this variability is hemispheric or perhaps even global in scale, but with particular emphasis on the Atlantic region. Independent analyses of multicentury integrations of two versions of the GFDL coupled atmosphere-ocean model also show the existence of distinct multidecadal variability in the North Atlantic region which resembles the observed pattern. The model variability involves fluctuations in the intensity of the thermohaline circulation in the North Atlantic. It is our intent here to provide a direct comparison of the observed variability to that simulated in a coupled ocean-atmosphere model, making use of both existing instrumental analyses and newly available proxy based multi-century surface temperature estimates. The analyses demonstrate a substantial agreement between the simulated and observed patterns of multidecadal variability in sea surface temperature (SST) over the North Atlantic. There is much less agreement between the model and observations for sea level pressure. Seasonal analyses of the variability demonstrate that for both the model and observations SST appears to be the primary carrier of the multidecadal signal.

Journal ArticleDOI
TL;DR: The authors examined teachers' judgments of the prevalence and types of problems children present upon entering kindergarten and found that up to 46% of teachers reported that half their class or more had specific problems in any of a number of areas in kindergarten transition.

Journal ArticleDOI
TL;DR: This statement summarizes the consensus achieved in discussions to develop a consensus defining the criteria for cure of acromegaly.
Abstract: In February 1999, a workshop was held in Cortina, Italy to develop a consensus defining the criteria for cure of acromegaly. The workshop was sponsored by the University of Brescia and hosted by the Italian Society of Endocrinology. Invited international participants included endocrinologists, neurosurgeons, and radiotherapists skilled in the management of acromegaly. This statement summarizes the consensus achieved in these discussions.

Journal ArticleDOI
13 Oct 2000-Cell
TL;DR: This review concludes with a recommendation that further studies are needed into the determinants of immune-inflammatory bowel disease and the Kessler-Corsi verdict is in order.

Journal ArticleDOI
TL;DR: Par6 is a key adaptor that links Cdc42 and atypical PKCs to Par3, and is implicated in the formation of normal tight junctions at epithelial cell–cell contacts.
Abstract: PAR (partitioning-defective) proteins, which were first identified in the nematode Caenorhabditis elegans, are essential for asymmetric cell division and polarized growth, whereas Cdc42 mediates establishment of cell polarity. Here we describe an unexpected link between these two systems. We have identified a family of mammalian Par6 proteins that are similar to the C. elegans PDZ-domain protein PAR-6. Par6 forms a complex with Cdc42-GTP, with a human homologue of the multi-PDZ protein PAR-3 and with the regulatory domains of atypical protein kinase C (PKC) proteins. This assembly is implicated in the formation of normal tight junctions at epithelial cell-cell contacts. Thus, Par6 is a key adaptor that links Cdc42 and atypical PKCs to Par3.


Journal ArticleDOI
TL;DR: In this article, the authors present a dynamic, ecologically informed approach to conceptualizing and studying the transition to formal schooling, and suggest that future policy, practice, and research be based on the following three premises: 1) The transition to school must be conceptualized in terms of relationships between children and their surrounding contexts, such as schools, peers, families, and neighborhoods.

Journal ArticleDOI
21 Apr 2000-Science
TL;DR: The tau mutation is a semidominant autosomal allele that dramatically shortens period length of circadian rhythms in Syrian hamsters and the mechanism by which the mutation leads to the observed aberrant circadian phenotype in mutant animals is proposed.
Abstract: The tau mutation is a semidominant autosomal allele that dramatically shortens period length of circadian rhythms in Syrian hamsters. We report the molecular identification of the tau locus using genetically directed representational difference analysis to define a region of conserved synteny in hamsters with both the mouse and human genomes. The tau locus is encoded by casein kinase I epsilon (CKIɛ), a homolog of the Drosophila circadian gene double-time . In vitro expression and functional studies of wild-type and tau mutant CKIɛ enzyme reveal that the mutant enzyme has a markedly reduced maximal velocity and autophosphorylation state. In addition, in vitro CKIɛ can interact with mammalian PERIOD proteins, and the mutant enzyme is deficient in its ability to phosphorylate PERIOD. We conclude that tau is an allele of hamster CKIɛ and propose a mechanism by which the mutation leads to the observed aberrant circadian phenotype in mutant animals.

Journal ArticleDOI
TL;DR: In this paper, the authors propose a structural model that explains how service firms can disseminate their customer-oriented strategy by aligning the strategy with specific management and employee-initiated control mechanisms that lead to increased commitment and shared values on the part of customer contact employees.
Abstract: It is widely held that a customer-oriented firm is more likely to deliver exceptional service quality and create satisfied customers. However, little research has addressed the question of how the orientation can be disseminated among employees throughout the firm. This dissemination is especially important in service firms in which frontline, customer contact employees are responsible for translating a customer-oriented strategy into quality service. The authors propose a structural model that explains how service firms can disseminate their customer-oriented strategy by aligning the strategy with specific management- and employee-initiated control mechanisms (i.e., formalization, empowerment, behavior-based employee evaluation, and work group socialization) that lead to increased commitment and shared values on the part of customer contact employees. The findings indicate that there are three “corridors of influence” between customer-oriented strategy and shared employee values. The dominant co...

Journal ArticleDOI

Journal ArticleDOI
TL;DR: It is reported that histone acetylation and phosphorylation are synergistic, and this results illustrate how the addition of multiple histone modifications may be coupled during the process of gene expression.

Journal ArticleDOI
TL;DR: The NCI CTC v. 2.0 represents an improvement in the evaluation and grading of acute toxicity for all modalities and the opportunity to grade acute radiation effects not adequately captured under the previous RTOG system.
Abstract: In 1997, the National Cancer Institute (NCI) led an effort to revise and expand the Common Toxicity Criteria (CTC) with the goal of integrating systemic agent, radiation, and surgical criteria into a comprehensive and standardized system. Representatives from the Radiation Therapy Oncology Group (RTOG) participated in this process in an effort to improve acute radiation related criteria and to achieve better clarity and consistency among modalities. CTC v. 2.0 replaces the previous NCI CTC and the RTOG Acute Radiation Morbidity Scoring Criteria and includes more than 260 individual adverse events with more than 100 of these applicable to acute radiation effects. One of the advantages of the revised criteria for radiation oncology is the opportunity to grade acute radiation effects not adequately captured under the previous RTOG system. A pilot study conducted by the RTOG indicated the new criteria are indeed more comprehensive and were preferred by research associates. CTC v. 2.0 represents an improvement in the evaluation and grading of acute toxicity for all modalities.

Journal ArticleDOI
TL;DR: This paper presents a meta-modelling system that automates the very labor-intensive and therefore time-heavy and therefore expensive and expensive process of manually cataloging and cataloging medical equipment for use in the health care system.
Abstract: John A. Swets, Robyn M. Dawes, and John Monahan BBN Technologies (emeritus), Cambridge, Massachusetts; Radiology Department, Brigham and Women’s Hospital, and Department of Health Care Policy, Harvard Medical School, Boston, Massachusetts, Department of Social and Decision Sciences, Carnegie Mellon University, Pittsburgh, Pennsylvania, and School of Law, University of Virginia, Charlottesville, Virginia

Journal ArticleDOI
TL;DR: This review provides examples that illustrate strategies for interpreting the data in terms of specific rearrangements in secondary and tertiary structure in site-direct spin labeling combined with electron paramagnetic resonance (EPR) spectroscopy.
Abstract: Site-direct spin labeling combined with electron paramagnetic resonance (EPR) spectroscopy is a powerful tool for detecting structural changes in proteins. This review provides examples that illustrate strategies for interpreting the data in terms of specific rearrangements in secondary and tertiary structure. The changes in the mobility and solvent accessibility of the spin label side chains, and in the distances between spin labels, report (i) rigid body motions of alpha-helices and beta-strands (ii) relative movements of domains and (iii) changes in secondary structure. Such events can be monitored in the millisecond time-scale, making it possible to follow structural changes during function. There is no upper limit to the size of proteins that can be investigated, and only 50-100 picomoles of protein are required. These features make site-directed spin labeling an attractive approach for the study of structure and dynamics in a wide range of systems.

Journal ArticleDOI
TL;DR: Beta-blockers are associated with a significant reduction in cardiac events in LQTS patients, particularly in those who were symptomatic before starting this therapy, and these events continue to occur while patients are on prescribed beta-blocker therapy.
Abstract: Background—β-blockers are routinely prescribed in congenital long-QT syndrome (LQTS), but the effectiveness and limitations of β-blockers in this disorder have not been evaluated. Methods and Results—The study population comprised 869 LQTS patients treated with β-blockers. Effectiveness of β-blockers was analyzed during matched periods before and after starting β-blocker therapy, and by survivorship methods to determine factors associated with cardiac events while on prescribed β-blockers. After initiation of β-blockers, there was a significant (P<0.001) reduction in the rate of cardiac events in probands (0.97±1.42 to 0.31±0.86 events per year) and in affected family members (0.26±0.84 to 0.15±0.69 events per year) during 5-year matched periods. On-therapy survivorship analyses revealed that patients with cardiac symptoms before β-blockers (n=598) had a hazard ratio of 5.8 (95% CI, 3.7 to 9.1) for recurrent cardiac events (syncope, aborted cardiac arrest, or death) during β-blocker therapy compared with ...

Journal ArticleDOI
TL;DR: It is found that stepwise selection with a low alpha led to a relatively poor model performance, when evaluated on independent data, and shrinkage methods in full models including prespecified predictors and incorporation of external information are recommended, when prognostic models are constructed in small data sets.
Abstract: Logistic regression analysis may well be used to develop a prognostic model for a dichotomous outcome. Especially when limited data are available, it is difficult to determine an appropriate selection of covariables for inclusion in such models. Also, predictions may be improved by applying some sort of shrinkage in the estimation of regression coefficients. In this study we compare the performance of several selection and shrinkage methods in small data sets of patients with acute myocardial infarction, where we aim to predict 30-day mortality. Selection methods included backward stepwise selection with significance levels alpha of 0.01, 0.05, 0. 157 (the AIC criterion) or 0.50, and the use of qualitative external information on the sign of regression coefficients in the model. Estimation methods included standard maximum likelihood, the use of a linear shrinkage factor, penalized maximum likelihood, the Lasso, or quantitative external information on univariable regression coefficients. We found that stepwise selection with a low alpha (for example, 0.05) led to a relatively poor model performance, when evaluated on independent data. Substantially better performance was obtained with full models with a limited number of important predictors, where regression coefficients were reduced with any of the shrinkage methods. Incorporation of external information for selection and estimation improved the stability and quality of the prognostic models. We therefore recommend shrinkage methods in full models including prespecified predictors and incorporation of external information, when prognostic models are constructed in small data sets.

Journal ArticleDOI
TL;DR: Because of a broader antiviral spectrum, better tolerance, and less potential for emergence of resistance than is seen with the M2 inhibitors, the neuraminidase inhibitors represent an important advance in the treatment of influenza.

Journal ArticleDOI
TL;DR: Local Anesthetics and the Inflammatory Response: A New Therapeutic Indication?
Abstract: Local Anesthetics and the Inflammatory Response: A New Therapeutic Indication? Markus Hollmann;Marcel Durieux; Anesthesiology

Journal ArticleDOI
TL;DR: It is demonstrated that the pH of deaerated exhaled airway vapor condensate is over two log orders lower in patients with acute asthma than in control subjects and normalizes with corticosteroid therapy, and suggested that regulation of airway pH has a previously unsuspected role in asthma pathophysiology.
Abstract: Airway concentrations of many reactive nitrogen and oxygen species are high in asthma. The stability and bioactivities of these species are pH-dependent; however, the pH of the airway during acute asthma has not previously been studied. As with gastric and urinary acidification, asthmatic airway acidification could be expected dramatically to alter the concentrations and bioactivities/cytotoxicities of endogenous nitrogen oxides. Here, we demonstrate that the pH of deaerated exhaled airway vapor condensate is over two log orders lower in patients with acute asthma (5.23 ± 0.21, n = 22) than in control subjects (7.65 ± 0.20, n = 19, p < 0.001) and normalizes with corticosteroid therapy. Values are highly reproducible, unaffected by salivary or therapeutic artifact, and identical to samples taken directly from the lower airway. Further, at these low pH values, the endogenous airway compound, nitrite, is converted to nitric oxide (NO) in quantities sufficient largely to account for the concentrations of NO i...