Showing papers by "University of Virginia published in 1999"

Measuring Business Cycles: Approximate Band-Pass Filters for Economic Time Series

Abstract: Band-pass filters are useful in a wide range of economic contexts. This paper develops a set of approximate band-pass filters and illustrates their application to measuring the business-cycle component of macroeconomic activity. Detailed comparisons are made with several alternative filters commonly used for extracting business-cycle components.

Mitogen-activated protein kinases: specific messages from ubiquitous messengers

Abstract: Signal transduction networks allow cells to perceive changes in the extracellular environment and to mount an appropriate response. Mitogen-activated protein kinase (MAPK) cascades are among the most thoroughly studied of signal transduction systems and have been shown to participate in a diverse array of cellular programs, including cell differentiation, cell movement, cell division, and cell death. A key question in studies of this cascade is, how does a ubiquitously activated regulatory enzume generate a specific and biologically appropriate cellular response? In this review we describe recent findings that provide insight into ways that the regulation, structure, and localization of MAPKs and the participation of adapters and scaffolds can help determine biological outcomes. MAPK cascades are evolutionarily conserved in all eucaryotes and play a key role in the regulation of gene expression as well as cytoplasmic activities. They typically are organized in a three-kinase architecture consisting of a MAPK, a MAPK activator (MEK, MKK, or MAPK kinase), and a MEK activator (MEK kinase [MEKK] or MAPK kinase kinase). Transmission of signals is achieved by sequential phosphorylation and activation of the components specific to a respective cascade. In the yeast Saccharomyces cerevisiae, five MAPK modules have been described; they regulate mating, filamentation, high-osmolarity responses, cell wall remodeling, and sporulation (Fig. ​(Fig.1A)1A) (reviewed in references 56 and 77). In mammalian systems five distinguishable MAPK modules have been identified so far (Fig. ​(Fig.1B).1B). These include the extracellular signal-regulated kinase 1 and 2 (ERK1/2) cascade, which preferentially regulates cell growth and differentiation, as well as the c-Jun N-terminal kinase (JNK) and p38 MAPK cascades, which function mainly in stress responses like inflammation and apoptosis (reviewed in references 57, 74, and 103). Moreover, MAPK pathways control several developmental programs, such as morphogenesis and spatial patterning in Dictyostelium amoebae (17, 45), eye development in Drosophila melanogaster (124), vulva induction in Caenorhabditis elegans (113), and T-cell development in mammals (31). FIG. 1 Schematic overview of MAPK modules. (A) In S. cerevisiae, five MAPK modules regulate mating, filamentation, high-osmolarity responses, cell wall remodeling, and sporulation. (B) Mammalian MAPK modules regulate cell growth, differentiation, stress responses, ... Individual MAPK modules generally can signal independently from each other, and this specificity is manifested in distinct physiologic responses. This is most obvious when studying MAPK signaling in S. cerevisiae. Here a particular extracellular event characteristically activates a specific MAPK module and initiates a unique cellular program (reviewed in references 56 and 77). For example, stimulation of cells with pheromone leads to the activation of the pheromone response pathway (STE11, STE7, and FUS3) (Fig. ​(Fig.2),2), which ultimately results in cell cycle arrest and the induction of mating-specific genes. However, related MAPKs whose modules share some components with the pheromone response pathway are not affected by pheromone stimulation but are activated only in response to the appropriate stimulus. For example, under conditions of high osmolarity Ste11 can lead to activation of Hog1 but does not induce mating-specific genes. Conversely, conditions that activate the filamentation pathway (which utilizes STE11 and STE7) induce only genes that regulate filamentous growth without triggering pheromone responses or responses to high osmolarity. These observations suggest that yeast cells have developed efficient mechanisms to generate pathway specificity and to successfully suppress cross talk, even when individual components participate in more than one signaling pathway. FIG. 2 Scaffold and adapter molecules in MAPK pathways. MAPK scaffolds and adapters (gray shading) are thought to promote the formation of oligomeric protein complexes with components that function in a specific MAPK module. Scaffolds have been identified in ... In metazoan cells the problem is more complex because each cell is simultaneously exposed to multiple extracellular signals and must integrate these inputs to choose an appropriate response. Thus, the biological context of a signal plays a determinative role in the way that MAPK activation is interpreted. For example, although ERKs generally regulate cell growth and cell differentiation and JNKs participate in a stress response, this is not always the case and in certain cell types activation of JNKs can induce proliferation (110). This indicates that in mammalian systems physiologic responses associated with a certain MAPK module can be cell type specific. Moreover, in PC12 cells, transient stimulation of the ERK cascade leads to proliferation whereas sustained stimulation leads to differentiation, as measured by neurite outgrowth (81). Thus, activation of the ERK cascade can lead to contrasting physiological responses in the same cellular context, suggesting that signal specificity is also determined by regulatory mechanisms other than the selective activation of a MAPK module. In this short review, we outline recent advances in understanding of this signaling system that help to explain how MAPK cascades are regulated and how specificity can be generated. Because of the power of yeast genetics, understanding of MAPK signaling in S. cerevisiae is at an advanced level, and thus many examples that utilize this organism are given. However, analogous mechanisms appear to be operative in metazoans as well. We discuss in turn the role of enzyme-substrate interactions, scaffolding proteins, subcellular targeting and localization, temporal regulation, and signal integration in determining the biological outcome of MAPK activation.

Anti-inflammatory Properties of Cytochrome P450 Epoxygenase-Derived Eicosanoids

Abstract: The epoxyeicosatrienoic acids (EETs) are products of cytochrome P450 epoxygenases that have vasodilatory properties similar to that of endothelium-derived hyperpolarizing factor. The cytochrome P450 isoform CYP2J2 was cloned and identified as a potential source of EETs in human endothelial cells. Physiological concentrations of EETs or overexpression of CYP2J2 decreased cytokine-induced endothelial cell adhesion molecule expression, and EETs prevented leukocyte adhesion to the vascular wall by a mechanism involving inhibition of transcription factor NF-κB and IκB kinase. The inhibitory effects of EETs were independent of their membrane-hyperpolarizing effects, suggesting that these molecules play an important nonvasodilatory role in vascular inflammation.

Stakeholders, social responsibility, and performance: empirical evidence and theoretical perspectives

Abstract: The management of competing stakeholder interests has emerged as a significant topic in the management literature. Related issues are the relationship between stakeholder management and the perception that a firm is socially responsible, and the performance implications of both stakeholder management and social responsibility. Theory and models surrounding these issues are abundant, but empirical research is in an early stage. This research forum reports six excellent efforts to tackle fundamental ideas about stakeholders, social responsibility, and performance.

Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia

Abstract: Familial platelet disorder with predisposition to acute myelogenous leukaemia (FPD/AML, MIM 601399) is an autosomal dominant disorder characterized by qualitative and quantitative platelet defects, and propensity to develop acute myelogenous leukaemia (AML). Informative recombination events in 6 FPD/AML pedigrees with evidence of linkage to markers on chromosome 21q identified an 880-kb interval containing the disease gene. Mutational analysis of regional candidate genes showed nonsense mutations or intragenic deletion of one allele of the haematopoietic transcription factor CBFA2 (formerly AML1) that co-segregated with the disease in four FPD/AML pedigrees. We identified heterozygous CBFA2 missense mutations that co-segregated with the disease in the remaining two FPD/AML pedigrees at phylogenetically conserved amino acids R166 and R201, respectively. Analysis of bone marrow or peripheral blood cells from affected FPD/AML individuals showed a decrement in megakaryocyte colony formation, demonstrating that CBFA2 dosage affects megakaryopoiesis. Our findings support a model for FPD/AML in which haploinsufficiency of CBFA2 causes an autosomal dominant congenital platelet defect and predisposes to the acquisition of additional mutations that cause leukaemia.

Characterization of the human cysteinyl leukotriene CysLT1 receptor.

Abstract: The cysteinyl leukotrienes-leukotriene C4(LTC4), leukotriene D4(LTD4) and leukotriene E4(LTE4)-are important mediators of human bronchial asthma. Pharmacological studies have determined that cysteinyl leukotrienes activate at least two receptors, designated CysLT1 and CysLT2. The CysLT1-selective antagonists, such as montelukast (Singulair), zafirlukast (Accolate) and pranlukast (Onon), are important in the treatment of asthma. Previous biochemical characterization of CysLT1 antagonists and the CysLT1 receptor has been in membrane preparations from tissues enriched for this receptor. Here we report the molecular and pharmacological characterization of the cloned human CysLT1 receptor. We describe the functional activation (calcium mobilization) of this receptor by LTD4 and LTC4, and competition for radiolabelled LTD4 binding to this receptor by the cysteinyl leukotrienes and three structurally distinct classes of CysLT1-receptor antagonists. We detected CysLT1-receptor messenger RNA in spleen, peripheral blood leukocytes and lung. In normal human lung, expression of the CysLT1-receptor mRNA was confined to smooth muscle cells and tissue macrophages. Finally, we mapped the human CysLT1-receptor gene to the X chromosome.

Divergent Stakeholder Theory

Abstract: The article focuses on a proposal concerning convergent stakeholder theory. It states that what is needed are theories that are divergent and thus utilize the point of view of stakeholder terms in showing different but useful methods of understanding organizations. It suggests that the theory in previous comments are derived in descriptive, instrumental, and normative theory. It mentions that philosophers and ethical theorists have argued that there isn't a meaningful distinction between normative and descriptive except by relying on the distinction itself.

Differential distribution of three members of a gene family encoding low voltage-activated (T-type) calcium channels.

Abstract: Low voltage-activated (T-type) calcium currents are observed in many central and peripheral neurons and display distinct physiological and functional properties. Using in situ hybridization, we have localized central and peripheral nervous system expression of three transcripts (α1G, α1H, and α1I) of the T-type calcium channel family (CaVT). Each mRNA demonstrated a unique distribution, and expression of the three genes was largely complementary. We found high levels of expression of these transcripts in regions associated with prominent T-type currents, including inferior olivary and thalamic relay neurons (which expressed α1G), sensory ganglia, pituitary, and dentate gyrus granule neurons (α1H), and thalamic reticular neurons (α1I and α1H). Other regions of high expression included the Purkinje cell layer of the cerebellum, the bed nucleus of the stria terminalis, the claustrum (α1G), the olfactory tubercles (α1H and α1I), and the subthalamic nucleus (α1I and α1G). Some neurons expressed high levels of all three genes, including hippocampal pyramidal neurons and olfactory granule cells. Many brain regions showed a predominance of labeling for α1G, including the amygdala, cerebral cortex, rostral hypothalamus, brainstem, and spinal cord. Exceptions included the basal ganglia, which showed more prominent labeling for α1H and α1I, and the olfactory bulb, the hippocampus, and the caudal hypothalamus, which showed more even levels of all three transcripts. Our results are consistent with the hypothesis that differential gene expression underlies pharmacological and physiological heterogeneity observed in neuronal T-type calcium currents, and they provide a molecular basis for the study of T-type channels in particular neurons.

Cross-Cultural Variations in Predictors of Life Satisfaction: Perspectives from Needs and Values

Abstract: The authors tested for cross-cultural difference in predictors of life satisfaction. In Study 1 (39 nations, N = 54, 446), they found that financial satisfaction was more strongly associated with life satisfaction in poorer nations, whereas home life satisfaction was more strongly related to life satisfaction in wealthy nations. In Study 2 (39 nations, N = 6,782), the authors found that satisfaction with esteem needs (e.g., the self and freedom) predicted global life satisfaction more strongly among people in individualist nations than people in collectivist nations. The present investigation provides support for the needs and values-as-moderators model of subjective well-being at the cultural level. The need for theories that account for culture-specific as well as universal predictors of life satisfaction will be discussed.

It's Time to Revise the Definition of Status Epilepticus

Abstract: Generalized, tonic-clonic status epilepticus is well recognized as a common neurologic emergency requir- ing prompt treatment. The diagnosis is usually not diffi- cult, other than for patients with prolonged seizures, who often develop increasingly subtle clinical features (1,2). There also appears to be a consensus among physicians regarding treatment (3). Nonetheless, there is a major, persistent dilemma regarding status epilepticus: its defi- nition. Discussions concerning the precise definition of status epilepticus all too often result in agreement that current “textbook” definitions are either imprecise, at odds with clinical practice, or both. Here we propose a revised system for defining status epilepticus that ad- dresses these problems. References to status epilepticus prior to the mid- 19th century focused on cases in which seizures lasted many hours to days (4). In 1904, Clark and Prout (5) defined status epilepticus as a state in which seizures occur so frequently that ‘‘the coma and exhaustion are continuous between the seizures.” In his general textbook of neu- rology published in 1940, Kinnier Wilson (6) referred to status epilepticus as the severest form of seizures in which “the post-convulsive sleep of one attack is cut short by development of the next.” Aspects of these definitions were mirrored in the first International Clas- sification of Epileptic Seizures that was developed in 1964 by the International League Against Epilepsy (ILAE). Status epilepticus was defined as the situation in which “a seizure persists for a sufficient length of time or is repeated frequently enough to produce a fixed and enduring epileptic condition” (7). The same definition was retained in the revised classification published in 1970 (8), and it was modified slightly in 1981 to refer to the situation in which “a seizure persists for a sufficient length of time or is repeated frequently enough that re- covery between attacks does not occur” (9).

IL-18, a Novel Immunoregulatory Cytokine, Is Up-Regulated in Crohn’s Disease: Expression and Localization in Intestinal Mucosal Cells

Abstract: IL-18, a novel immunoregulatory cytokine with potent IFN-gamma-inducing activities, may play an important role in Th1-mediated chronic inflammatory disorders. The aim of the present study was to characterize the expression and localization of IL-18 in colonic specimens and isolated mucosal cell populations from patients with Crohn's disease (CD), a prototypic Th1-mediated disorder. Using a semiquantitative RT-PCR protocol, IL-18 mRNA transcripts were found to be increased in freshly isolated intestinal epithelial cells (IEC) and lamina propria mononuclear cells (LPMC) from CD compared with ulcerative colitis (UC) and noninflamed control (cont) patients, and were more abundant in IEC compared with LPMC. Immunohistochemical analysis of surgically resected colonic tissues localized IL-18 to both LPMC (specifically, macrophages and dendritic cells) as well as IEC. Staining was more intense in CD compared with UC and cont, and in involved (inv) vs noninvolved (n inv) areas. Western blot analysis revealed that an 18. 3-kDa band, consistent with both recombinant and mature human IL-18 protein, was found predominantly in CD vs UC intestinal mucosal biopsies; a second band of 24 kDa, consistent with the inactive IL-18 precursor, was detected in n inv areas from both CD and UC biopsies and was the sole form found in noninflamed cont. To our knowledge, this report is the first describing increased expression of IL-18 in a human Th1-mediated chronic inflammatory disease. In addition, our studies further support the concept that IEC and dendritic cells may possess important immunoregulatory functions in both normal, as well as pathological, mucosal immunity.

Structural Rearrangements Underlying K+-Channel Activation Gating

Abstract: The intramembrane molecular events underlying activation gating in the Streptomyces K+ channel were investigated by site-directed spin-labeling methods and electron paramagnetic resonance spectroscopy. A comparison of the closed and open conformations of the channel revealed periodic changes in spin-label mobility and intersubunit spin-spin interaction consistent with rigid-body movements of the two transmembrane helices TM1 and TM2. These changes involve translations and counterclockwise rotations of both helices relative to the center of symmetry of the channel. The movement of TM2 increases the diameter of the permeation pathway along the point of convergence of the four subunits, thus opening the pore. Although the extracellular residues flanking the selectivity filter remained immobile during gating, small movements were detected at the C-terminal end of the pore helix, with possible implications to the gating mechanism.

Heavy-Element Abundances in Blue Compact Galaxies

Abstract: We present high-quality ground-based spectroscopic observations of 54 supergiant H II regions in 50 low-metallicity blue compact galaxies with oxygen abundances 12+log O/H between 7.1 and 8.3. We use the data to determine abundances for the elements N, O, Ne, S, Ar, and Fe. We also analyze Hubble Space Telescope (HST) Faint Object Spectrograph archival spectra of 10 supergiant H II regions to derive C and Si abundances in a subsample of seven BCGs. The main result of the present study is that none of the heavy element-to-oxygen abundance ratios studied here (C/O, N/O, Ne/O, Si/O, S/O, Ar/O, Fe/O) depend on oxygen abundance for BCGs with 12+log O/H≤7.6 (Z≤Z☉/20). This constancy implies that all of these heavy elements have a primary origin and are produced by the same massive (M≥10 M☉) stars responsible for O production. The dispersion of the ratios C/O and N/O in these galaxies is found to be remarkably small, being only ±0.03 and ±0.02 dex, respectively. This very small dispersion is strong evidence against any time-delayed production of C and primary N in the lowest metallicity BCGs (secondary N production is negligible at these low metallicities). The absence of a time-delayed production of C and N is consistent with the scenario that galaxies with 12+logO/H≤7.6 are now undergoing their first burst of star formation, and that they are therefore young, with ages not exceeding 40 Myr. If very low metallicity BCGs are indeed young, this would argue against the commonly held belief that C and N are produced by intermediate-mass (3 M☉≤M≤9 M☉) stars at very low metallicities, as these stars would not have yet completed their evolution in these lowest metallicity galaxies. In higher metallicity BCGs (7.6 7.6; (3) by the time intermediate-mass stars have evolved and released their nucleosynthetic products (100-500 Myr), all galaxies have become enriched to 7.6 8.2, secondary N production becomes important. BCGs show the same O/Fe overabundance with respect to the Sun (~0.4 dex) as Galactic halo stars, suggesting the same chemical enrichment history. We compare heavy elements yields derived from the observed abundance ratios with theoretical yields for massive stars and find general good agreement. However, the theoretical models are unable to reproduce the observed N/O and Fe/O. Further theoretical developments are necessary, in particular to solve the problem of primary nitrogen production in low-metallicity massive stars. We discuss the apparent discrepancy between abundance ratios N/O measured in BCGs and those in high-redshift damped Lyα galaxies, which are up to 1 order of magnitude smaller. We argue that this large discrepancy may arise from the unknown physical conditions of the gas responsible for the metallic absorption lines in high-redshift damped Lyα systems. While it is widely assumed that the absorbing gas is neutral, we propose that it could be ionized. In this case, ionization correction factors can boost N/O in damped Lyα galaxies into the range of those measured in BCGs.

Activation of mitogen-activated protein kinase associated with prostate cancer progression

Abstract: Using an antibody specific for dually phosphorylated extracellular-regulated kinases 1 and 2, we have examined 82 primary and metastatic prostate tumor specimens for the presence of activated mitogen-activated protein (MAP) kinase. Nonneoplastic prostate tissue showed little or no staining with activated MAP kinase antiserum. In prostate tumors, the level of activated MAP kinase increased with increasing Gleason score and tumor stage. In a separate analysis, tumor samples from two patients showed no activation of MAP kinase before androgen ablation therapy; however, following androgen ablation treatment, high levels of activated MAP kinase were detected in the recurrent tumors. Collectively, these data suggest an increase in the activation of the MAP kinase signal transduction pathway as prostate cancer progresses to a more advanced and androgen-independent disease.

Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza: randomized controlled trials for prevention and treatment.

Abstract: ContextInfluenza virus neuraminidase is thought to be essential for virus replication in humans; however, to date, available neuraminidase inhibitors are limited to zanamivir, which is topically administered.ObjectiveTo determine the safety, tolerability, and antiviral activity of oral neuraminidase inhibitor oseltamivir (GS4104/Ro64-0796) for prevention and the early treatment of influenza in experimentally infected humans.DesignTwo randomized, double-blind, placebo-controlled trials conducted between June and July 1997.SettingIndividual hotel rooms; 2 large US university medical schools.ParticipantsA total of 117 healthy adult volunteers (aged 18-40 years; median age, 21 years) who were susceptible (hemagglutination-inhibition antibody titer ≤1:8).InterventionsAll subjects were inoculated intranasally with influenza A/Texas/36/91(H1N1) virus. For the prophylaxis study, oral oseltamivir (100 mg once daily [n=12], 100 mg twice daily [n=12], or matching placebo [n=13], starting 26 hours before virus inoculation) was administered. For the treatment study, the same drug was given (20 mg, 100 mg, or 200 mg twice daily, 200 mg once daily, or matching placebo [n=16], in each group starting 28 hours after inoculation). All regimens were continued for 5 days.Main Outcome MeasuresComparing placebo groups with pooled treatment groups, for prophylaxis, outcomes included frequency of infection and viral shedding; for treatment, viral shedding in titers.ResultsIn the prophylaxis study, 8 (67%) of 12 placebo and 8 (38%) of 21 oseltamivir recipients became infected (P=.16; efficacy, 61%); 6 (50%) placebo compared with 0 oseltamivir recipients shed virus (P<.001; efficacy, 100%), and 33% of placebo but no oseltamivir recipient had infection-related respiratory illness (P<.01). Among infected subjects in the treatment study (n=69), the viral titer area under the curve of the combined oseltamivir groups (n=56) was lower (median [interquartile range {IQR}], 80 [23-151] vs 273 [79-306] log10 tissue culture-infective doses50 per milliliter×hour; P=.02) than the placebo group (n=13), and the median (IQR) duration of viral shedding with therapy was reduced from 107 (83-131) to 58 (35-59) hours (P=.003). Oseltamivir treatment also reduced symptom scores (median [IQR] score-hours, 225 [97-349] vs 400 [189-645]; P=.05), and nasal proinflammatory cytokine levels. Transient mild to moderate nausea after dosing was observed in 15 (17%) of 88 oseltamivir and 2 (7%) of 29 placebo recipients (95% confidence interval for difference, −11% to 68%), which was largely prevented by ingestion with food.ConclusionsIn these trials, prophylaxis and early treatment with oral oseltamivir were both associated with significant antiviral and clinical effects in experimental human influenza.

Is Anybody Still a Realist

Abstract: Realism, the oldest and most prominent theoretical paradigm in international relations, is in trouble. The problem is not lack of interest. Realism remains the primary or alternative theory in virtually every major book and article addressing general theories of world politics, particularly in security affairs. Controversies between neorealism and its critics continue to dominate international relations theory debates. Nor is the problem realism’s purported inability to make point predictions. Many speciac realist theories are testable, and there remains much global conoict about which realism offers powerful insights. Nor is the problem the lack of empirical support for simple realist predictions, such as recurrent balancing; or the absence of plausible realist explanations of certain salient phenomena, such as the Cold War, the “end of history,”1or systemic change in general. Research programs advance, after all, by the reanement and improvement of previous theories to account for anomalies. There can be little doubt that realist theories rightfully retain a salient position in international relations theory.

PTEN Mutation Spectrum and Genotype-Phenotype Correlations in Bannayan-Riley-Ruvalcaba Syndrome Suggest a Single Entity With Cowden Syndrome

Abstract: Germline mutations in the tumour suppressor gene PTEN have been implicated in two hamartoma syndromes that exhibit some clinical overlap, Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRR). PTEN maps to 10q23 and encodes a dual specificity phosphatase, a substrate of which is phosphatidylinositol 3,4,5-triphosphate, a phospholipid in the phosphatidylinositol 3-kinase pathway. CS is characterized by multiple hamartomas and an increased risk of benign and malignant disease of the breast, thyroid and central nervous system, whilst the presence of cancer has not been formally documented in BRR. The partial clinical overlap in these two syndromes is exemplified by the hallmark features of BRR: macrocephaly and multiple lipomas, the latter of which occur in a minority of individuals with CS. Additional features observed in BRR, which may also occur in a minority of CS patients, include Hashimoto's thyroiditis, vascular malformations and mental retardation. Pigmented macules of the glans penis, delayed motor development and neonatal or infant onset are noted only in BRR. In this study, constitutive DNA samples from 43 BRR individuals comprising 16 sporadic and 27 familial cases, 11 of which were families with both CS and BRR, were screened for PTEN mutations. Mutations were identified in 26 of 43 (60%) BRR cases. Genotype-phenotype analyses within the BRR group suggested a number of correlations, including the association of PTEN mutation and cancer or breast fibroadenoma in any given CS, BRR or BRR/CS overlap family ( P = 0.014), and, in particular, truncating mutations were associated with the presence of cancer and breast fibroadenoma in a given family ( P = 0.024). Additionally, the presence of lipomas was correlated with the presence of PTEN mutation in BRR patients ( P = 0.028). In contrast to a prior report, no significant difference in mutation status was found in familial versus sporadic cases of BRR ( P = 0.113). Comparisons between BRR and a previously studied group of 37 CS families suggested an increased likelihood of identifying a germline PTEN mutation in families with either CS alone or both CS and BRR when compared with BRR alone ( P = 0.002). Among CS, BRR and BRR/CS overlap families that are PTEN mutation positive, the mutation spectra appear similar. Thus, PTEN mutation-positive CS and BRR may be different presentations of a single syndrome and, hence, both should receive equal attention with respect to cancer surveillance.

Methylation of histone H3 at lysine 4 is highly conserved and correlates with transcriptionally active nuclei in Tetrahymena

Abstract: Studies into posttranslational modifications of histones, notably acetylation, have yielded important insights into the dynamic nature of chromatin structure and its fundamental role in gene expression. The roles of other covalent histone modifications remain poorly understood. To gain further insight into histone methylation, we investigated its occurrence and pattern of site utilization in Tetrahymena, yeast, and human HeLa cells. In Tetrahymena, transcriptionally active macronuclei, but not transcriptionally inert micronuclei, contain a robust histone methyltransferase activity that is highly selective for H3. Microsequence analyses of H3 from Tetrahymena, yeast, and HeLa cells indicate that lysine 4 is a highly conserved site of methylation, which to date, is the major site detected in Tetrahymena and yeast. These data document a nonrandom pattern of H3 methylation that does not overlap with known acetylation sites in this histone. In as much as H3 methylation at lysine 4 appears to be specific to macronuclei in Tetrahymena, we suggest that this modification pattern plays a facilitatory role in the transcription process in a manner that remains to be determined. Consistent with this possibility, H3 methylation in yeast occurs preferentially in a subpopulation of H3 that is preferentially acetylated.

The Adjustment of Children with Divorced Parents: A Risk and Resiliency Perspective

Abstract: This review addresses major questions about divorce, around which much contemporary research is oriented. These involve questions of the consequences of divorce for the adjustment of children and the vulnerability and resiliency of children in coping with divorce, whether children are better off in a conflictual intact family situation or a divorced family, and how mothers, fathers, and clinical or educational interventions can moderate the effects of divorce. Although research in the past decade has yielded considerable information about these questions, issues that need further investigation are also presented.

Space Velocities of Globular Clusters. III. Cluster Orbits and Halo Substructure

Abstract: We have compiled a catalog of absolute proper motions of globular clusters from various sources. The sample consists of 38 clusters, from which most of the southern ones (15 clusters) were measured in our previous papers in this series. We have integrated orbits assuming two different Galactic potential models adopted from the literature and have calculated orbital parameters. The uncertainties associated with the orbital parameters were derived in a Monte Carlo approach, and we conclude that, overall, at the present level of measurement errors, orbital differences due to Galactic potential models are not significant. Three metal-poor clusters are found to have orbits similar to prototypical metal-rich disk clusters. These clusters are NGC 6254 (M10), NGC 6626 (M28), and NGC 6752. We interpret this as a potentially significant constraint on the formation of the disk. It is thus possible that part of the inner metal-poor halo is the low-metallicity tail of the thick disk. In this case, the ages of these clusters indicate that the formation of the disk partially overlapped with that of the halo. The clusters classified as young halo or red horizontal-branch by Zinn show a radially anisotropic velocity distribution, their orbits are of high total energy, with apocentric radii larger than 10 kpc and highly eccentric. In this sense they may represent an accreted component of our Galaxy. We also discuss ω Cen's orbit characteristics in the view of an accreted origin. We investigate the effect of the orbital motion on the internal dynamics of clusters. Adopting the formalism from Gnedin & Ostriker and their destruction rates due to two-body relaxation, we find that, in most cases, this internal process is more important than the destruction processes due to disk and bulge shocking. Hubble Space Telescope (HST) observations argue that NGC 6397's luminosity function is depleted at the faint end, and this is blamed on its high total destruction rate. We propose a list of clusters with similar destruction rates that may also have depleted luminosity functions. We also note the bias toward deriving higher destruction rates in studies that statistically assign tangential velocities based on a kinematic model of the globular cluster system, in contrast to the rates derived from the measured tangential velocities. Clusters prone to such biases are those that have circular orbits (kinematically thick-disk clusters) and some of those with orbits of high total energy.

Requirement of Rsk-2 for epidermal growth factor-activated phosphorylation of histone H3.

Abstract: During the immediate-early response of mammalian cells to mitogens, histone H3 is rapidly and transiently phosphorylated by one or more unidentified kinases. Rsk-2, a member of the pp90rsk family of kinases implicated in growth control, was required for epidermal growth factor (EGF)–stimulated phosphorylation of H3. RSK-2mutations in humans are linked to Coffin-Lowry syndrome (CLS). Fibroblasts derived from a CLS patient failed to exhibit EGF-stimulated phosphorylation of H3, although H3 was phosphorylated during mitosis. Introduction of the wild-type RSK-2 gene restored EGF-stimulated phosphorylation of H3 in CLS cells. In addition, disruption of the RSK-2 gene by homologous recombination in murine embryonic stem cells abolished EGF-stimulated phosphorylation of H3. H3 appears to be a direct or indirect target of Rsk-2, suggesting that chromatin remodeling might contribute to mitogen-activated protein kinase–regulated gene expression.