Showing papers by "University of Michigan published in 2001"

Initial sequencing and analysis of the human genome.

Abstract: The human genome holds an extraordinary trove of information about human development, physiology, medicine and evolution. Here we report the results of an international collaboration to produce and make freely available a draft sequence of the human genome. We also present an initial analysis of the data, describing some of the insights that can be gleaned from the sequence.

The role of positive emotions in positive psychology. The broaden-and-build theory of positive emotions.

Abstract: In this article, the author describes a new theoretical perspective on positive emotions and situates this new perspective within the emerging field of positive psychology. The broaden-and-build theory posits that experiences of positive emotions broaden people's momentary thought-action repertoires, which in turn serves to build their enduring personal resources, ranging from physical and intellectual resources to social and psychological resources. Preliminary empirical evidence supporting the broaden-and-build theory is reviewed, and open empirical questions that remain to be tested are identified. The theory and findings suggest that the capacity to experience positive emotions may be a fundamental human strength central to the study of human flourishing.

Stem cells, cancer, and cancer stem cells

Abstract: Stem cell biology has come of age. Unequivocal proof that stem cells exist in the haematopoietic system has given way to the prospective isolation of several tissue-specific stem and progenitor cells, the initial delineation of their properties and expressed genetic programmes, and the beginnings of their utility in regenerative medicine. Perhaps the most important and useful property of stem cells is that of self-renewal. Through this property, striking parallels can be found between stem cells and cancer cells: tumours may often originate from the transformation of normal stem cells, similar signalling pathways may regulate self-renewal in stem cells and cancer cells, and cancer cells may include 'cancer stem cells' - rare cells with indefinite potential for self-renewal that drive tumorigenesis.

A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease

Abstract: Crohn's disease is a chronic inflammatory disorder of the gastrointestinal tract, which is thought to result from the effect of environmental factors in a genetically predisposed host. A gene location in the pericentromeric region of chromosome 16, IBD1, that contributes to susceptibility to Crohn's disease has been established through multiple linkage studies, but the specific gene(s) has not been identified. NOD2, a gene that encodes a protein with homology to plant disease resistance gene products is located in the peak region of linkage on chromosome 16 (ref. 7). Here we show, by using the transmission disequilibium test and case-control analysis, that a frameshift mutation caused by a cytosine insertion, 3020insC, which is expected to encode a truncated NOD2 protein, is associated with Crohn's disease. Wild-type NOD2 activates nuclear factor NF-kappaB, making it responsive to bacterial lipopolysaccharides; however, this induction was deficient in mutant NOD2. These results implicate NOD2 in susceptibility to Crohn's disease, and suggest a link between an innate immune response to bacterial components and development of disease.

Modular chemistry: secondary building units as a basis for the design of highly porous and robust metal-organic carboxylate frameworks.

Abstract: Secondary building units (SBUs) are molecular complexes and cluster entities in which ligand coordination modes and metal coordination environments can be utilized in the transformation of these fragments into extended porous networks using polytopic linkers (1,4-benzenedicarboxylate, 1,3,5,7-adamantanetetracarboxylate, etc.). Consideration of the geometric and chemical attributes of the SBUs and linkers leads to prediction of the framework topology, and in turn to the design and synthesis of a new class of porous materials with robust structures and high porosity.

Osteoporosis prevention, diagnosis, and therapy

Abstract: OBJECTIVES To clarify the factors associated with prevention, diagnosis, and treatment of osteoporosis, and to present the most recent information available in these areas. PARTICIPANTS From March 27-29, 2000, a nonfederal, nonadvocate, 13-member panel was convened, representing the fields of internal medicine, family and community medicine, endocrinology, epidemiology, orthopedic surgery, gerontology, rheumatology, obstetrics and gynecology, preventive medicine, and cell biology. Thirty-two experts from these fields presented data to the panel and an audience of 699. Primary sponsors were the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Institutes of Health Office of Medical Applications of Research. EVIDENCE MEDLINE was searched for January 1995 through December 1999, and a bibliography of 2449 references provided to the panel. Experts prepared abstracts for presentations with relevant literature citations. Scientific evidence was given precedence over anecdotal experience. CONSENSUS PROCESS The panel, answering predefined questions, developed conclusions based on evidence presented in open forum and the literature. The panel composed a draft statement, which was read and circulated to the experts and the audience for public discussion. The panel resolved conflicts and released a revised statement at the end of the conference. The draft statement was posted on the Web on March 30, 2000, and updated with the panel's final revisions within a few weeks. CONCLUSIONS Though prevalent in white postmenopausal women, osteoporosis occurs in all populations and at all ages and has significant physical, psychosocial, and financial consequences. Risks for osteoporosis (reflected by low bone mineral density [BMD]) and for fracture overlap but are not identical. More attention should be paid to skeletal health in persons with conditions associated with secondary osteoporosis. Clinical risk factors have an important but poorly validated role in determining who should have BMD measurement, in assessing fracture risk, and in determining who should be treated. Adequate calcium and vitamin D intake is crucial to develop optimal peak bone mass and to preserve bone mass throughout life. Supplementation with these 2 nutrients may be necessary in persons not achieving recommended dietary intake. Gonadal steroids are important determinants of peak and lifetime bone mass in men, women, and children. Regular exercise, especially resistance and high-impact activities, contributes to development of high peak bone mass and may reduce risk of falls in older persons. Assessment of bone mass, identification of fracture risk, and determination of who should be treated are the optimal goals when evaluating patients for osteoporosis. Fracture prevention is the primary treatment goal for patients with osteoporosis. Several treatments have been shown to reduce the risk of osteoporotic fractures, including those that enhance bone mass and reduce the risk or consequences of falls. Adults with vertebral, rib, hip, or distal forearm fractures should be evaluated for osteoporosis and given appropriate therapy.

MiBench: A free, commercially representative embedded benchmark suite

Abstract: This paper examines a set of commercially representative embedded programs and compares them to an existing benchmark suite, SPEC2000. A new version of SimpleScalar that has been adapted to the ARM instruction set is used to characterize the performance of the benchmarks using configurations similar to current and next generation embedded processors. Several characteristics distinguish the representative embedded programs from the existing SPEC benchmarks including instruction distribution, memory behavior, and available parallelism. The embedded benchmarks, called MiBench, are freely available to all researchers.

Meta-analysis of theory-of-mind development: The truth about false belief.

Abstract: Research on theory of mind increasingly encompasses apparently contradictory findings. In particular, in initial studies, older preschoolers consistently passed false-belief tasks—a so-called “definitive” test of mentalstate understanding—whereas younger children systematically erred. More recent studies, however, have found evidence of false-belief understanding in 3-year-olds or have demonstrated conditions that improve children’s performance. A meta-analysis was conducted ( N � 178 separate studies) to address the empirical inconsistencies and theoretical controversies. When organized into a systematic set of factors that vary across studies, false-belief results cluster systematically with the exception of only a few outliers. A combined model that included age, country of origin, and four task factors (e.g., whether the task objects were transformed in order to deceive the protagonist or not) yielded a multiple R of .74 and an R 2 of .55; thus, the model accounts for 55% of the variance in false-belief performance. Moreover, false-belief performance showed a consistent developmental pattern, even across various countries and various task manipulations: preschoolers went from below-chance performance to above-chance performance. The findings are inconsistent with early competence proposals that claim that developmental changes are due to tasks artifacts, and thus disappear in simpler, revised false-belief tasks; and are, instead, consistent with theoretical accounts that propose that understanding of belief, and, relatedly, understanding of mind, exhibit genuine conceptual change in the preschool years.

Culture and systems of thought: holistic versus analytic cognition.

Abstract: The authors find East Asians to be holistic, attending to the entire field and assigning causality to it, making relatively little use of categories and formal logic, and relying on "dialectical" reasoning, whereas Westerners are more analytic, paying attention primarily to the object and the categories to which it belongs and using rules, including formal logic, to understand its behavior. The 2 types of cognitive processes are embedded in different naive metaphysical systems and tacit epistemologies. The authors speculate that the origin of these differences is traceable to markedly different social systems. The theory and the evidence presented call into question long-held assumptions about basic cognitive processes and even about the appropriateness of the process-content distinction.

Crafting a Job: Revisioning Employees as Active Crafters of Their Work

Abstract: We propose that employees craft their jobs by changing cognitive, task, and/or relational boundaries to shape interactions and relationships with others at work. These altered task and relational configurations change the design and social environment of the job, which, in turn, alters work meanings and work identity. We offer a model of job crafting that specifies (1) the individual motivations that spark this activity, (2) how opportunities to job craft and how individual work orientations determine the forms job crafting takes, and (3) its likely individual and organizational effects.

Does Oil Hinder Democracy

Abstract: Some scholars suggest that the Middle East's oil wealth helps explain its failure to democratize. This article examines three aspects of this “oil impedes democracy” claim. First, is it true? Does oil have a consistendy antidemocratic effect on states, once other factors are accounted for? Second, can this claim be generalized? Is it true only in the Middle East or elsewhere as well? Is it true for other types of mineral wealth and other types of commodity wealth or only for oil? Finally, if oil does have antidemocratic properties, what is the causal mechanism?The author uses pooled time-series cross-national data from 113 states between 1971 and 1997 to show that oil exports are strongly associated with authoritarian rule; that this effect is not limited to the Middle East; and that other types of mineral exports have a similar antidemocratic effect, while other types of commodity exports do not.The author also tests three explanations for this pattern: a “rentier effect,” which suggests that resource-rich governments use low tax rates and patronage to dampen democratic pressures; a “repression effect,” which holds that resource wealth enables governments to strengthen their internal security forces and hence repress popular movements; and a “modernization effect,” which implies that growth that is based on the export of oil and minerals will fail to bring about die social and cultural changes that tend to produce democratic government. He finds at least limited support for all three effects.

Gender Differences in Depression

Abstract: From early adolescence through adulthood, women are twice as likely as men to experience depression. Many different explanations for this gender difference in depression have been offered, but none seems to fully explain it. Recent research has focused on gender differences in stress responses, and in exposure to certain stressors. I review this research and describe how gender differences in stress experiences and stress reactivity may interact to create women's greater vulnerability to depression.

Racial Residential Segregation: A Fundamental Cause of Racial Disparities in Health:

Abstract: Racial residential segregation is a fundamental cause of racial disparities in health. The physical separation of the races by enforced residence in certain areas is an institutional mechanism of racism that was designed to protect whites from social interaction with blacks. Despite the absence of supportive legal statutes, the degree of residential segregation remains extremely high for most African Americans in the United States. The authors review evidence that suggests that segregation is a primary cause of racial differences in socioeconomic status (SES) by determining access to education and employment opportunities. SES in turn remains a fundamental cause of racial differences in health. Segregation also creates conditions inimical to health in the social and physical environment. The authors conclude that effective efforts to eliminate racial disparities in health must seriously confront segregation and its pervasive consequences.

Cluster algebras I: Foundations

Abstract: In an attempt to create an algebraic framework for dual canonical bases and total positivity in semisimple groups, we initiate the study of a new class of commutative algebras.

Managing the unexpected: Assuring high performance in an age of complexity.

Abstract: High reliability organizations (HROs) such as ER units in hospitals or firefighting units are designed to perform efficiently under extreme stress and pressure. Using HROs as the model for the 21st century organization, Karl Weick and Kathleen Sutcliffe show readers how to respond to unexpected challenges with flexibility rather than rigidity and to reduce the disruptive effects of change by using tools such as sensemaking, stress reduction, migrating decisions, and labeling. Introducing the powerful new concept of "mindfulness," the authors outline five qualities of the mindful organization and the organizational skills needed to achieve them. Each concept is clearly expressed in vivid case studies of organizations that demonstrate mindful practices in action. A Book in the University of Michigan Business School Series Voted Best HR Book of 2001 by HR.com

Neighborhood inequality, collective efficacy, and the spatial dynamics of urban violence

Abstract: Highlighting resource inequality, social processes, and spatial interdependence, this study combines structural characteristics from the 1990 census with a survey of 8,872 Chicago residents in 1995 to predict homicide variations in 1996–1998 across 343 neighborhoods. Spatial proximity to homicide is strongly related to increased homicide rates, adjusting for internal neighborhood characteristics and prior homicide. Concentrated disadvantage and low collective efficacy—defined as the linkage of social control and cohesion—also independently predict increased homicide. Local organizations, voluntary associations, and friend/kinship networks appear to be important only insofar as they promote the collective efficacy of residents in achieving social control and cohesion. Spatial dynamics coupled with neighborhood inequalities in social and economic capacity are therefore consequential for explaining urban violence.

Unified huntington’s disease rating scale: Reliability and consistency

Abstract: The Unified Huntington's disease Rating Scale (UHDRS) was developed as a clinical rating scale to assess four domains of clinical performance and capacity in HD: motor function, cognitive function, behavioral abnormalities, and functional capacity. We assessed the internal consistency and the intercorrelations for the four domains and examined changes in ratings over time. We also performed an interrater reliability study of the motor assessment. We found there was a high degree of internal consistency within each of the domains of the UHDRS and that there were significant intercorrelations between the domains of the UHDRS, with the exception of the total behavioral score. There was an excellent degree of interrater reliability for the motor scores. Our limited longitudinal database indicates that the UHDRS may be useful for tracking changes in the clinical features of HD over time. The UHDRS assesses relevant clinical features of HD and appears to be appropriate for repeated administration during clinical studies.

Polymeric system for dual growth factor delivery

Abstract: The development of tissues and organs is typically driven by the action of a number of growth factors. However, efforts to regenerate tissues (e.g., bone, blood vessels) typically rely on the delivery of single factors, and this may partially explain the limited clinical utility of many current approaches. One constraint on delivering appropriate combinations of factors is a lack of delivery vehicles that allow for a localized and controlled delivery of more than a single factor. We report a new polymeric system that allows for the tissue-specific delivery of two or more growth factors, with controlled dose and rate of delivery. The utility of this system was investigated in the context of therapeutic angiogenesis. We now demonstrate that dual delivery of vascular endothelial growth factor (VEGF)-165 and platelet-derived growth factor (PDGF)-BB, each with distinct kinetics, from a single, structural polymer scaffold results in the rapid formation of a mature vascular network. This is the first report of a vehicle capable of delivery of multiple angiogenic factors with distinct kinetics, and these results clearly indicate the importance of multiple growth factor action in tissue regeneration and engineering.

Delineation of prognostic biomarkers in prostate cancer

Abstract: Prostate cancer is the most frequently diagnosed cancer in American men1,2. Screening for prostate-specific antigen (PSA) has led to earlier detection of prostate cancer3, but elevated serum PSA levels may be present in non-malignant conditions such as benign prostatic hyperlasia (BPH). Characterization of gene-expression profiles that molecularly distinguish prostatic neoplasms may identify genes involved in prostate carcinogenesis, elucidate clinical biomarkers, and lead to an improved classification of prostate cancer4,5,6. Using microarrays of complementary DNA, we examined gene-expression profiles of more than 50 normal and neoplastic prostate specimens and three common prostate-cancer cell lines. Signature expression profiles of normal adjacent prostate (NAP), BPH, localized prostate cancer, and metastatic, hormone-refractory prostate cancer were determined. Here we establish many associations between genes and prostate cancer. We assessed two of these genes—hepsin, a transmembrane serine protease, and pim-1, a serine/threonine kinase—at the protein level using tissue microarrays consisting of over 700 clinically stratified prostate-cancer specimens. Expression of hepsin and pim-1 proteins was significantly correlated with measures of clinical outcome. Thus, the integration of cDNA microarray, high-density tissue microarray, and linked clinical and pathology data is a powerful approach to molecular profiling of human cancer.

CONSENSUS: Guidelines for Diagnosis and Therapy of MEN Type 1 and Type 2

Abstract: This is a consensus statement from an international group, mostly of clinical endocrinologists. MEN1 and MEN2 are hereditary cancer syndromes. The commonest tumors secrete PTH or gastrin in MEN1, and calcitonin or catecholamines in MEN2. Management strategies improved after the discoveries of their genes. MEN1 has no clear syndromic variants. Tumor monitoring in MEN1 carriers includes biochemical tests yearly and imaging tests less often. Neck surgery includes subtotal or total parathyroidectomy, parathyroid cryopreservation, and thymectomy. Proton pump inhibitors or somatostatin analogs are the main management for oversecretion of entero-pancreatic hormones, except insulin. The roles for surgery of most entero-pancreatic tumors present several controversies: exclusion of most operations on gastrinomas and indications for surgery on other tumors. Each MEN1 family probably has an inactivating MEN1 germline mutation. Testing for a germline MEN1 mutation gives useful information, but rarely mandates an intervention. The most distinctive MEN2 variants are MEN2A, MEN2B, and familial medullary thyroid cancer (MTC). They vary in aggressiveness of MTC and spectrum of disturbed organs. Mortality in MEN2 is greater from MTC than from pheochromocytoma. Thyroidectomy, during childhood if possible, is the goal in all MEN2 carriers to prevent or cure MTC. Each MEN2 index case probably has an activating germline RET mutation. RET testing has replaced calcitonin testing to diagnose the MEN2 carrier state. The specific RET codon mutation correlates with the MEN2 syndromic variant, the age of onset of MTC, and the aggressiveness of MTC; consequently, that mutation should guide major management decisions, such as whether and when to perform thyroidectomy.

Genotype-Phenotype Correlation in the Long-QT Syndrome Gene-Specific Triggers for Life-Threatening Arrhythmias

Abstract: Background The congenital long-QT syndrome (LQTS) is caused by mutations on several genes, all of which encode cardiac ion channels. The progressive understanding of the electrophysiological consequences of these mutations opens unforeseen possibilities for genotype-phenotype correlation studies. Preliminary observations suggested that the conditions ("triggers") associated with cardiac events may in large part be gene specific. Methods and results We identified 670 LQTS patients of known genotype (LQT1, n=371; LQT2, n=234; LQT3, n=65) who had symptoms (syncope, cardiac arrest, sudden death) and examined whether 3 specific triggers (exercise, emotion, and sleep/rest without arousal) differed according to genotype. LQT1 patients experienced the majority of their events (62%) during exercise, and only 3% occurred during rest/sleep. These percentages were almost reversed among LQT2 and LQT3 patients, who were less likely to have events during exercise (13%) and more likely to have events during rest/sleep (29% and 39%). Lethal and nonlethal events followed the same pattern. Corrected QT interval did not differ among LQT1, LQT2, and LQT3 patients (498, 497, and 506 ms, respectively). The percent of patients who were free of recurrence with ss-blocker therapy was higher and the death rate was lower among LQT1 patients (81% and 4%, respectively) than among LQT2 (59% and 4%, respectively) and LQT3 (50% and 17%, respectively) patients. Conclusions Life-threatening arrhythmias in LQTS patients tend to occur under specific circumstances in a gene-specific manner. These data allow new insights into the mechanisms that relate the electrophysiological consequences of mutations on specific genes to clinical manifestations and offer the possibility of complementing traditional therapy with gene-specific approaches.

Neurobiology of Pavlovian fear conditioning.

Abstract: ▪ Abstract Learning the relationships between aversive events and the environmental stimuli that predict such events is essential to the survival of organisms throughout the animal kingdom. Pavlovian fear conditioning is an exemplar of this form of learning that is exhibited by both rats and humans. Recent years have seen an incredible surge in interest in the neurobiology of fear conditioning. Neural circuits underlying fear conditioning have been mapped, synaptic plasticity in these circuits has been identified, and biochemical and genetic manipulations are beginning to unravel the molecular machinery responsible for the storage of fear memories. These advances represent an important step in understanding the neural substrates of a rapidly acquired and adaptive form of associative learning and memory in mammals.

Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura

Abstract: Thrombotic thrombocytopenic purpura (TTP) is a life-threatening systemic illness of abrupt onset and unknown cause. Proteolysis of the blood-clotting protein von Willebrand factor (VWF) observed in normal plasma is decreased in TTP patients. However, the identity of the responsible protease and its role in the pathophysiology of TTP remain unknown. We performed genome-wide linkage analysis in four pedigrees of humans with congenital TTP and mapped the responsible genetic locus to chromosome 9q34. A predicted gene in the identified interval corresponds to a segment of a much larger transcript, identifying a new member of the ADAMTS family of zinc metalloproteinase genes (ADAMTS13). Analysis of patients' genomic DNA identified 12 mutations in the ADAMTS13 gene, accounting for 14 of the 15 disease alleles studied. We show that deficiency of ADAMTS13 is the molecular mechanism responsible for TTP, and suggest that physiologic proteolysis of VWF and/or other ADAMTS13 substrates is required for normal vascular homeostasis.

Incivility in the workplace: Incidence and impact.

Abstract: This study extends the literature on interpersonal mistreatment in the workplace by examining the incidence, targets, instigators, and impact of incivility (eg, disrespect, condescension, degradation) Data were collected from 1,180 public-sector employees, 71% of whom reported some experience of workplace incivility in the previous 5 years As many as one third of the most powerful individuals within the organization instigated these uncivil acts Although women endured greater frequencies of incivility than did men, both genders experienced similarly negative effects on job satisfaction, job withdrawal, and career salience Uncivil workplace experiences were also associated with greater psychological distress; however, indices of psychological and physical health were relatively unaffected The authors discuss these findings in the context of organizational and cognitive stress theories

Color Separation of Galaxy Types in the Sloan Digital Sky Survey Imaging Data

Abstract: We study the optical colors of 147,920 galaxies brighter than g* = 21, observed in five bands by the Sloan Digital Sky Survey (SDSS) over ~100 deg2 of high Galactic latitude sky along the celestial equator. The distribution of galaxies in the g*-r* versus u*-g* color-color diagram is strongly bimodal, with an optimal color separator of u*-r* = 2.22. We use visual morphology and spectral classification of subsamples of 287 and 500 galaxies, respectively, to show that the two peaks correspond roughly to early- (E, S0, and Sa) and late-type (Sb, Sc, and Irr) galaxies, as expected from their different stellar populations. We also find that the colors of galaxies are correlated with their radial profiles, as measured by the concentration index and by the likelihoods of exponential and de Vaucouleurs' profile fits. While it is well known that late-type galaxies are bluer than early-type galaxies, this is the first detection of a local minimum in their color distribution. In all SDSS bands, the counts versus apparent magnitude relations for the two color types are significantly different and demonstrate that the fraction of blue galaxies increases toward the faint end.

The mass function of dark matter haloes

Abstract: We combine data from a number of N-body simulations to predict the abundance of dark haloes in cold dark matter (CDM) universes over more than four orders of magnitude in mass. A comparison of different simulations suggests that the dominant uncertainty in our results is systematic and is smaller than 10–30 per cent at all masses, depending on the halo definition used. In particular, our 'Hubble volume' simulations of τCDM and ΛCDM cosmologies allow the abundance of massive clusters to be predicted with uncertainties well below those expected in all currently planned observational surveys. We show that for a range of CDM cosmologies and for a suitable halo definition, the simulated mass function is almost independent of epoch, of cosmological parameters and of the initial power spectrum when expressed in appropriate variables. This universality is of exactly the kind predicted by the familiar Press–Schechter model, although this model predicts a mass function shape that differs from our numerical results, overestimating the abundance of 'typical' haloes and underestimating that of massive systems.