Showing papers by "Dartmouth College published in 1999"

Interpreting patterns of gene expression with self-organizing maps: Methods and application to hematopoietic differentiation

Abstract: Array technologies have made it straightfor- ward to monitor simultaneously the expression pattern of thousands of genes. The challenge now is to interpret such massive data sets. The first step is to extract the fundamental patterns of gene expression inherent in the data. This paper describes the application of self-organizing maps, a type of mathematical cluster analysis that is particularly well suited for recognizing and classifying features in complex, multidi- mensional data. The method has been implemented in a publicly available computer package, GENECLUSTER, that per- forms the analytical calculations and provides easy data visualization. To illustrate the value of such analysis, the approach is applied to hematopoietic differentiation in four well studied models (HL-60, U937, Jurkat, and NB4 cells). Expression patterns of some 6,000 human genes were assayed, and an online database was created. GENECLUSTER was used to organize the genes into biologically relevant clusters that suggest novel hypotheses about hematopoietic differentia- tion—for example, highlighting certain genes and pathways involved in ''differentiation therapy'' used in the treatment of acute promyelocytic leukemia.

Conflict of Interest and the Credibility of Underwriter Analyst Recommendations

Abstract: Brokerage analysts frequently comment on and sometimes recommend companies that their firms have recently taken public. We show that stocks that underwriter analysts recommend perform more poorly than “buy” recommendations by unaffiliated brokers prior to, at the time of, and subsequent to the recommendation date. We conclude that the recommendations by underwriter analysts show significant evidence of bias. We show also that the market does not recognize the full extent of this bias. The results suggest a potential conflict of interest inherent in the different functions that investment bankers perform.

A ferric-chelate reductase for iron uptake from soils

Abstract: Iron deficiency afflicts more than three billion people worldwide, and plants are the principal source of iron in most diets. Low availability of iron often limits plant growth because iron forms insoluble ferric oxides, leaving only a small, organically complexed fraction in soil solutions. The enzyme ferric-chelate reductase is required for most plants to acquire soluble iron. Here we report the isolation of the FRO2 gene, which is expressed in iron-deficient roots of Arabidopsis. FRO2 belongs to a superfamily of flavocytochromes that transport electrons across membranes. It possesses intramembranous binding sites for haem and cytoplasmic binding sites for nucleotide cofactors that donate and transfer electrons. We show that FRO2 is allelic to the frd1 mutations that impair the activity of ferric-chelate reductase. There is a nonsense mutation within the first exon of FRO2 in frd1-1 and a missense mutation within FRO2 in frd1-3. Introduction of functional FRO2 complements the frd1-1 phenotype in transgenic plants. The isolation of FRO2 has implications for the generation of crops with improved nutritional quality and increased growth in iron-deficient soils.

The Influence of Organizational Acquisition Experience on Acquisition Performance: A Behavioral Learning Perspective

Abstract: Drawing on work from behavioral learning theory in psychology, this study examines the influence of prior organizational acquisition experience on the performance of acquisitions. This theory, which examines both the conditions preceding organization events and organizational responses, predicts that experience effects may range from positive to negative. Consistent with this theory, data from 449 acquisitions show an overall U-shaped relationship between organization acquisition experience and acquisition performance. In addition, the more similar a firm's acquisition targets are to its prior targets, the better they perform. These findings suggest that relatively inexperienced acquirers, after making their first acquisition, inappropriately generalize acquisition experience to subsequent dissimilar acquisitions, while more experienced acquirers appropriately discriminate between their acquisitions. Behavioral learning theory, then, may enhance understanding of organization experience effects.

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.

Evidence of active nerve cell degeneration in the substantia nigra of humans years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposure.

Abstract: This report provides the first detailed neuropathological study of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in humans. All 3 subjects self-administered the drug under the impression it was "synthetic heroin" and subsequently developed severe and unremitting parkinsonism, which was L-dopa responsive, at least in the earlier stages of illness. Survival times ranged from 3 to 16 years. Neuropathological examination revealed moderate to severe depletion of pigmented nerve cells in the substantia nigra in each case. Lewy bodies were not present. In Patients 1 and 2, there was gliosis and clustering of microglia around nerve cells. Patient 3 had a similar picture and also showed large amounts of extraneuronal melanin. These findings are indicative of active, ongoing nerve cell loss, suggesting that a time-limited insult to the nigrostriatal system can set in motion a self-perpetuating process of neurodegeneration. Although the mechanism by which this occurs is far from clear, the precedent set by the cases could have broad implications for human neurodegenerative disease.

The Other Side of the Trade‐Off: The Impact of Risk on Executive Compensation

Abstract: The principal‐agent model of executive compensation is of central importance to the modern theory of the firm and corporate governance, yet the exiting empirical evidence supporting it is quite wea...

Perspective: the pace of modern life: measuring rates of contemporary microevolution.

Abstract: We evaluate methods for measuring and specifying rates of microevolution in the wild, with particular regard to studies of contemporary, often deemed "rapid," evolution. A considerable amount of ambiguity and inconsistency persists within the field, and we provide a number of suggestions that should improve study design, inference, and clarity of presentation. (1) Some studies measure change over time within a population (allochronic) and others measure the difference between two populations that had a common ancestor in the past (synchronic). Allochronic studies can be used to estimate rates of "evolution," whereas synchronic studies more appropriately estimate rates of "divergence." Rates of divergence may range from a small fraction to many times the actual evolutionary rates in the component populations. (2) Some studies measure change using individuals captured from the wild, whereas others measure differences after rearing in a common environment. The first type of study can be used to specify "phenotypic" rates and the later "genetic" rates. (3) The most commonly used evolutionary rate metric, the darwin, has a number of theoretical shortcomings. Studies of microevolution would benefit from specifying rates in standard deviations per generation, the haldane. (4) Evolutionary rates are typically specified without an indication of their precision. Readily available methods for specifying confidence intervals and statistical significance (regression, bootstrapping, randomization) should be implemented. (5) Microevolutionists should strive to accumulate time series, which can reveal temporal shifts in the rate of evolution and can be used to identify evolutionary patterns. (6) Evolutionary rates provide a convenient way to compare the tempo of evolution across studies, traits, taxa, and time scales, but such comparisons are subject to varying degrees of confidence. Comparisons across different time scales are particularly tenuous. (7) A number of multivariate rate measures exist, but considerable theoretical development is required before their utility can be determined. We encourage the continued investigation of evolutionary rates because the information they provide is relevant to a wide range of theoretical and practical issues.

Calcium Supplements for the Prevention of Colorectal Adenomas

Abstract: Background and Methods Laboratory, clinical, and epidemiologic evidence suggests that calcium may help prevent colorectal adenomas. We conducted a randomized, double-blind trial of the effect of supplementation with calcium carbonate on the recurrence of colorectal adenomas. We randomly assigned 930 subjects (mean age, 61 years; 72 percent men) with a recent history of colorectal adenomas to receive either calcium carbonate (3 g [1200 mg of elemental calcium] daily) or placebo, with follow-up colonoscopies one and four years after the qualifying examination. The primary end point was the proportion of subjects in whom at least one adenoma was detected after the first follow-up endoscopy but up to (and including) the second follow-up examination. Risk ratios for the recurrence of adenomas were adjusted for age, sex, lifetime number of adenomas before the study, clinical center, and length of the surveillance period. Results The subjects in the calcium group had a lower risk of recurrent adenomas. Among the...

Transfusion medicine. First of two parts--blood transfusion.

Abstract: Blood transfusion and blood conservation (techniques or strategies to avoid the need for blood) are complementary activities that constitute the clinical arena of transfusion medicine. Recent improvements in the safety of the blood supply and the increasing costs associated with transfusion therapies have led to a reevaluation of the clinical practices of blood transfusion and blood conservation. Among the issues that have been reevaluated are the threshold for transfusion at which the benefits outweigh the risks and the identification of patients most likely to benefit from blood conservation. This review summarizes recent developments in transfusion medicine that have affected the . . .

Synergism and antagonism among multiple stressors

Abstract: This study was designed to test for synergism (increased stress) or antagonism (decreased stress) among multiple environmental stressors using additive, multiplicative, and simple comparative effects models. Model predictions were compared to empirical results of laboratory experiments measuring interactions among thermal stress, toxin exposure, and low food on reproduction and survival of two species of cladoceran zooplankton. Stress was defined operationally as a reduction in reproduction or survival relative to optimal conditions over a 7-d period. These experiments are particularly applicable to episodic stresses such as those associated with short-term heat waves. Toxin or low food in combination with 30°C temperatures were generally more harmful than high temperature alone. However, most multiple stress effects were antagonistic, in that effects in combination were not as severe as predicted based on the sum or the product of their individual effects. In rare cases, interaction among stressors even diminished effects of the worst single stressor. Optimal conditions for reproduction and survival occurred at 25°C, high food and 0 mg liter ' toxin (a surfactant, sodium dodecyl sulfate). Suppressive effects of stressors examined individually ranked: high temperature (30°C) > SDS (10 mg liter -1 ≥ low food (∼100 μg C liter -1 ) > low temperature (20°C). Daphnia pulex isolated from a pond which experiences high summer temperatures throughout was more tolerant of 30°C conditions than Daphnia pulicaria isolated from a lake with a cold-water refuge. Differences were observed in individuals exposed as either adults or as 24-h neonates.

Investor Protection and Corporate Governance

Abstract: Recent research on corporate governance has documented large differences between countries in ownership concentration in publicly traded firms, in the breadth and depth of financial markets, and in the access of firms to external finance. We suggest that there is a common element to the explanations of these differences, namely how well investors, both shareholders and creditors, are protected by law from expropriation by the managers and controlling shareholders of firms. We describe the differences in laws and the effectiveness of their enforcement across countries, summarize the consequences of these differences, and suggest potential strategies of reform of corporate governance. We argue that the legal approach is a more fruitful way to understand corporate governance and its reform than the conventional distinction between bank-centered and market-centered financial systems.

The IRT1 protein from Arabidopsis thaliana is a metal transporter with a broad substrate range

Abstract: The molecular basis for the transport of manganese across membranes in plant cells is poorly understood. We have found that IRT1, an Arabidopsis thaliana metal ion transporter, can complement a mutant Saccharomyces cerevisiae strain defective in high-affinity manganese uptake (smf1 delta). The IRT1 protein has previously been identified as an iron transporter. The current studies demonstrated that IRT1, when expressed in yeast, can transport manganese as well. This manganese uptake activity was inhibited by cadmium, iron(II) and zinc, suggesting that IRT1 can transport these metals. The IRT1 cDNA also complements a zinc uptake-deficient yeast mutant strain (zrt1zrt2), and IRT1-dependent zinc transport in yeast cells is inhibited by cadmium, copper, cobalt and iron(III). However, IRT1 did not complement a copper uptake-deficient yeast mutant (ctr1), implying that this transporter is not involved in the uptake of copper in plant cells. The expression of IRT1 is enhanced in A. thaliana plants grown under iron deficiency. Under these conditions, there were increased levels of root-associated manganese, zinc and cobalt, suggesting that, in addition to iron, IRT1 mediates uptake of these metals into plant cells. Taken together, these data indicate that the IRT1 protein is a broad-range metal ion transporter in plants.

Forecasting Profitability And Earnings

Abstract: There is a strong presumption in economics that, in a competitive environment, profitability is mean reverting. We provide corroborating evidence. In a simple partial adjustment model, the estimated rate of mean reversion is about 40 percent per year. But a simple partial adjustment model with a uniform rate of mean reversion misses rich non-linear patterns in the behavior of profitability. Specifically, we find that mean reversion is faster when profitability is below its mean and when it is further from its mean in either direction. We also show that the mean reversion in profitability produces predictable variation in earnings.

Characteristics, Covariances, and Average Returns: 1929-1997

Abstract: The value premium in U.S. stocks returns is robust. The positive relation between average return and book-to-market equity (BE/ME) is as strong for 1929-63 as for the subsequent period studied in previous papers. Like others, we also find a size premium in stock returns. Small stocks have higher average returns than big stocks. The size premium is, however, weaker and less reliable than the value premium. The relations between average return and firm characteristics (size and BE/ME) are better explained by a three-factor risk model than by the behavioral hypothesis that investor overreaction causes characteristics to be compensated irrespective of risk loadings.

Investor Protection and Corporate Valuation

Abstract: We present a model of the effects of legal protection of minority shareholders and of cash flow ownership by a controlling shareholder on the valuation of firms. We then test this model using a sample of 371 large firms from 27 wealthy economies. Consistent with the model, we find evidence of higher valuation of firms in countries with better protection of minority shareholders, and weaker evidence of the benefits of higher cash flow ownership by controlling shareholders for corporate valuation.

Cbfa2 is required for the formation of intra-aortic hematopoietic clusters.

Abstract: Cbfa2 (AML1) encodes the DNA-binding subunit of a transcription factor in the small family of core-binding factors (CBFs). Cbfa2 is required for the differentiation of all definitive hematopoietic cells, but not for primitive erythropoiesis. Here we show that Cbfa2 is expressed in definitive hematopoietic progenitor cells, and in endothelial cells in sites from which these hematopoietic cells are thought to emerge. Endothelial cells expressing Cbfa2 are in the yolk sac, the vitelline and umbilical arteries, and in the ventral aspect of the dorsal aorta in the aorta/genital ridge/mesonephros (AGM) region. Endothelial cells lining the dorsal aspect of the aorta, and elsewhere in the embryo, do not express Cbfa2. Cbfa2 appears to be required for maintenance of Cbfa2 expression in the endothelium, and for the formation of intra-aortic hematopoietic clusters from the endothelium.

Jensen's inequality predicts effects of environmental variation.

Abstract: Many biologists now recognize that environmental variance can exert important effects on patterns and processes in nature that are independent of average conditions. Jensen’s inequality is a mathematical proof that is seldom mentioned in the ecological literature but which provides a powerful tool for predicting some direct effects of environmental variance in biological systems. Qualitative predictions can be derived from the form of the relevant response functions (accelerating versus decelerating). Knowledge of the frequency distribution (especially the variance) of the driving variables allows quantitative estimates of the effects. Jensen’s inequality has relevance in every field of biology that includes nonlinear processes.

The Quality of Government

Abstract: We investigate empirically the determinants of the quality of governments in a large cross-section of countries. We assess government performance using measures of government intervention, public sector efficiency, public good provision, size of government, and political freedom. We find that countries that are poor, close to the equator, ethnolinguistically heterogeneous, use French or socialist laws, or have high proportions of Catholics or Muslims exhibit inferior government performance. We also find that the larger governments tend to be the better performing ones. The importance of historical factors in explaining the variation in government performance across countries sheds light on the economic, political, and cultural theories of institutions.

BIOMASS ETHANOL: Technical Progress, Opportunities, and Commercial Challenges

Abstract: ▪ Abstract Ethanol made from lignocellulosic biomass sources, such as agricultural and forestry residues and herbaceous and woody crops, provides unique environmental, economic, and strategic benefits. Through sustained research funding, primarily by the U.S. Department of Energy, the estimated cost of biomass ethanol production has dropped from ∼$4.63/gallon in 1980 to ∼$1.22/gallon today, and it is now potentially competitive for blending with gasoline. Advances in pretreatment by acid-catalyzed hemicellulose hydrolysis and enzymes for cellulose breakdown coupled with recent development of genetically engineered bacteria that ferment all five sugars in biomass to ethanol at high yields have been the key to reducing costs. However, through continued advances in accessing the cellulose and hemicellulose fractions, the cost of biomass ethanol can be reduced to the point at which it is competitive as a pure fuel without subsidies. A major challenge to realizing the great benefits of biomass ethanol remains ...

Malonyl-CoA, fuel sensing, and insulin resistance

Abstract: Malonyl-CoA is an allosteric inhibitor of carnitine palmitoyltransferase (CPT) I, the enzyme that controls the transfer of long-chain fatty acyl (LCFA)-CoAs into the mitochondria where they are oxi...

Executive Compensation, Strategic Competition, and Relative Performance Evaluation: Theory and Evidence

Abstract: We examine compensation contracts for managers in imperfectly competitive product markets. We show that strategic interactions among firms can explain the lack of relative performance-based incentives in which compensation decreases with rival firm performance. The need to soften product market competition generates an optimal compensation contract that places a positive weight on both own and rival performance. Firms in more competitive industries place greater weight on rival firm performance relative to own firm performance. We find empirical evidence of a positive sensitivity of compensation to rival firm performance that is increasing in the degree of competition in the industry.

Consensus Statement on the Upcoming Crisis in Geriatric Mental Health: Research Agenda for the Next 2 Decades

Abstract: It is anticipated that the number of people older than 65 years with psychiatric disorders in the United States will increase from about 4 million in 1970 to15 million in 2030. The current health care system serves mentally ill older adults poorly and is unprepared to meet the upcoming crisis in geriatric mental health. We recommend the formulation of a 15- to 25-year plan for research on mental disorders in elderly persons. It should include studies of prevention, translation of findings from bench to bedside, large-scale intervention trials with meaningful outcome measures, and health services research. Innovative strategies are needed to formulate new conceptualizations of psychiatric disorders, especially those given scant attention in the past. New methods of clinical and research training involving specialists, primary care clinicians, and the lay public are warranted.

Impact of drought on desert shrubs : Effects of seasonality and degree of resource island development

Abstract: Large areas of semiarid grasslands in the southwestern United States have been virtually replaced by shrubs during the past century. Understanding the causes and consequences of such vegetation dynamics requires that we elucidate the interplay between external forces of change (e.g., climate, human impacts) and the internal forces within these ecosystems that foster resilience and/or stability. Several conceptual models of arid ecosystems address this interplay by including the potential role of autogenic shrub effects on ecosystem processes, which lead to the formation of “resource islands” and tend to promote shrub persistence. Specifically, during the process of shrub establishment and maturation, the cycling of nutrients is progressively confined to the zones of litter accumulation beneath shrubs, while bare intershrub spaces become increasingly nutrient poor. As shrub resource islands develop, there is increased interception and stemflow by shrub canopies, confining infiltration of nutrient-enriched ...