Showing papers by "Harvard University published in 1993"
TL;DR: Two small lin-4 transcripts of approximately 22 and 61 nt were identified in C. elegans and found to contain sequences complementary to a repeated sequence element in the 3' untranslated region (UTR) of lin-14 mRNA, suggesting that lin- 4 regulates lin- 14 translation via an antisense RNA-RNA interaction.
11,932 citations
TL;DR: The GAL4 system, a system for targeted gene expression that allows the selective activation of any cloned gene in a wide variety of tissue- and cell-specific patterns, has been designed and used to expand the domain of embryonic expression of the homeobox protein even-skipped.
Abstract: We have designed a system for targeted gene expression that allows the selective activation of any cloned gene in a wide variety of tissue- and cell-specific patterns. The gene encoding the yeast transcriptional activator GAL4 is inserted randomly into the Drosophila genome to drive GAL4 expression from one of a diverse array of genomic enhancers. It is then possible to introduce a gene containing GAL4 binding sites within its promoter, to activate it in those cells where GAL4 is expressed, and to observe the effect of this directed misexpression on development. We have used GAL4-directed transcription to expand the domain of embryonic expression of the homeobox protein even-skipped. We show that even-skipped represses wingless and transforms cells that would normally secrete naked cuticle into denticle secreting cells. The GAL4 system can thus be used to study regulatory interactions during embryonic development. In adults, targeted expression can be used to generate dominant phenotypes for use in genetic screens. We have directed expression of an activated form of the Dras2 protein, resulting in dominant eye and wing defects that can be used in screens to identify other members of the Dras2 signal transduction pathway.
9,460 citations
TL;DR: The APOE-epsilon 4 allele is associated with the common late onset familial and sporadic forms of Alzheimer9s disease (AD) in 42 families with late onset AD.
Abstract: The apolipoprotein E type 4 allele (APOE-epsilon 4) is genetically associated with the common late onset familial and sporadic forms of Alzheimer9s disease (AD). Risk for AD increased from 20% to 90% and mean age at onset decreased from 84 to 68 years with increasing number of APOE-epsilon 4 alleles in 42 families with late onset AD. Thus APOE-epsilon 4 gene dose is a major risk factor for late onset AD and, in these families, homozygosity for APOE-epsilon 4 was virtually sufficient to cause AD by age 80.
8,669 citations
TL;DR: A role for TNF-alpha in obesity and particularly in the insulin resistance and diabetes that often accompany obesity is indicated.
Abstract: Tumor necrosis factor-alpha (TNF-alpha) has been shown to have certain catabolic effects on fat cells and whole animals. An induction of TNF-alpha messenger RNA expression was observed in adipose tissue from four different rodent models of obesity and diabetes. TNF-alpha protein was also elevated locally and systemically. Neutralization of TNF-alpha in obese fa/fa rats caused a significant increase in the peripheral uptake of glucose in response to insulin. These results indicate a role for TNF-alpha in obesity and particularly in the insulin resistance and diabetes that often accompany obesity.
7,347 citations
TL;DR: In this article, the authors used haplotype analysis of linkage disequilibrium to spotlight a small segment of 4p16.3 as the likely location of the defect, which is expanded and unstable on HD chromosomes.
7,224 citations
TL;DR: It is suggested that fine-particulate air pollution, or a more complex pollution mixture associated with fine particulate matter, contributes to excess mortality in certain U.S. cities.
Abstract: Background Recent studies have reported associations between particulate air pollution and daily mortality rates. Population-based, cross-sectional studies of metropolitan areas in the United States have also found associations between particulate air pollution and annual mortality rates, but these studies have been criticized, in part because they did not directly control for cigarette smoking and other health risks. Methods In this prospective cohort study, we estimated the effects of air pollution on mortality, while controlling for individual risk factors. Survival analysis, including Cox proportional-hazards regression modeling, was conducted with data from a 14-to-16-year mortality follow-up of 8111 adults in six U.S. cities. Results Mortality rates were most strongly associated with cigarette smoking. After adjusting for smoking and other risk factors, we observed statistically significant and robust associations between air pollution and mortality. The adjusted mortality-rate ratio for the most po...
7,194 citations
TL;DR: The last two decades indicate corporate internal control systems have failed to deal effectively with these changes, especially slow growth and the requirement for exit as mentioned in this paper, which is a major challenge for Western firms and political systems as these forces continue to work their way through the worldwide economy.
Abstract: Since 1973 technological, political, regulatory, and economic forces have been changing the worldwide economy in a fashion comparable to the changes experienced during the nineteenth century Industrial Revolution. As in the nineteenth century, we are experiencing declining costs, increasing average (but decreasing marginal) productivity of labor, reduced growth rates of labor income, excess capacity, and the requirement for downsizing and exit. The last two decades indicate corporate internal control systems have failed to deal effectively with these changes, especially slow growth and the requirement for exit. The next several decades pose a major challenge for Western firms and political systems as these forces continue to work their way through the worldwide economy.
7,121 citations
TL;DR: Tight genetic linkage between FALS and a gene that encodes a cytosolic, Cu/Zn-binding superoxide dismutase (SOD1), a homodimeric metalloenzyme that catalyzes the dismutation of the toxic superoxide anion O–2 to O2 and H2O2 is reported.
Abstract: Amyotrophic lateral sclerosis (ALS) is a degenerative disorder of motor neurons in the cortex, brainstem and spinal cord. Its cause is unknown and it is uniformly fatal, typically within five years. About 10% of cases are inherited as an autosomal dominant trait, with high penetrance after the sixth decade. In most instances, sporadic and autosomal dominant familial ALS (FALS) are clinically similar. We have previously shown that in some but not all FALS pedigrees the disease is linked to a genetic defect on chromosome 21q (refs 8, 9). Here we report tight genetic linkage between FALS and a gene that encodes a cytosolic, Cu/Zn-binding superoxide dismutase (SOD1), a homodimeric metalloenzyme that catalyzes the dismutation of the toxic superoxide anion O2.- to O2 and H2O2 (ref. 10). Given this linkage and the potential role of free radical toxicity in other neurodenegerative disorders, we investigated SOD1 as a candidate gene in FALS. We identified 11 different SOD1 missense mutations in 13 different FALS families.
6,733 citations
TL;DR: In this paper, the authors compare the geographic location of patent citations to those of cited patents, as evidence of the extent to which knowledge spillovers are geographically localized, and find that citations to U.S. patents are more likely to come from the U. S., and more likely than coming from the same state and SMSA as cited patents than one would expect based only on the preexisting concentration of related research activity.
Abstract: We compare the geographic location of patent citations to those of the cited patents, as evidence of the extent to which knowledge spillovers are geographically localized. We find that citations to U.S. patents are more likely to come from the U.S., and more likely to come from the same state and SMSA as the cited patents than one would expect based only on the preexisting concentration of related research activity. These effects are particularly significant at the local (SMSA) level, and are particularly apparent in early citations.
5,937 citations
TL;DR: In this article, an improved two-hybrid system was employed to isolate human genes encoding Cdk-interacting proteins (Cips) and found that CIP1 is a potent, tight-binding inhibitor of Cdks and can inhibit the phosphorylation of Rb by cyclin A-Cdk2.
5,726 citations
Journal Article•
TL;DR: Three critical issues must be addressed before a company can truly become a learning organization, writes HBS Professor David Garvin, who defines learning organizations as skilled at five main activities: systematic problem solving, experimentation with new approaches,learning from past experience, learning from the best practices of others, and transferring knowledge quickly and efficiently throughout the organization.
Abstract: Continuous improvement programs are proliferating as corporations seek to better themselves and gain an edge. Unfortunately, however, failed programs far outnumber successes, and improvement rates remain low. That's because most companies have failed to grasp a basic truth. Before people and companies can improve, they first must learn. And to do this, they need to look beyond rhetoric and high philosophy and focus on the fundamentals. Three critical issues must be addressed before a company can truly become a learning organization, writes HBS Professor David Garvin. First is the question of meaning: a well-grounded, easy-to-apply definition of a learning organization. Second comes management: clearer operational guidelines for practice. Finally, better tools for measurement can assess an organization's rate and level of learning. Using these "three Ms" as a framework, Garvin defines learning organizations as skilled at five main activities: systematic problem solving, experimentation with new approaches, learning from past experience, learning from the best practices of others, and transferring knowledge quickly and efficiently throughout the organization. And since you can't manage something if you can't measure it, a complete learning audit is a must. That includes measuring cognitive and behavioral changes as well as tangible improvements in results. No learning organization is built overnight. Success comes from carefully cultivated attitudes, commitments, and management processes that accrue slowly and steadily. The first step is to foster an environment conducive to learning. Analog Devices, Chaparral Steel, Xerox, GE, and other companies provide enlightened examples.
Journal Article•
TL;DR: The international index and the age-adjusted international index should be used in the design of future therapeutic trials in patients with aggressive non-Hodgkin's lymphoma and in the selection of appropriate therapeutic approaches for individual patients.
Abstract: BACKGROUND
Although many patients with intermediate-grade or high-grade (aggressive) non-Hodgkin's lymphoma are cured by combination chemotherapy, the remainder are not cured and ultimately die of their disease. The Ann Arbor classification, used to determine the stage of this disease, does not consistently distinguish between patients with different long-term prognoses. This project was undertaken to develop a model for predicting outcome in patients with aggressive non-Hodgkin's lymphoma on the basis of the patients' clinical characteristics before treatment.
METHODS
Adults with aggressive non-Hodgkin's lymphoma from 16 institutions and cooperative groups in the United States, Europe, and Canada who were treated between 1982 and 1987 with combination-chemotherapy regimens containing doxorubicin were evaluated for clinical features predictive of overall survival and relapse-free survival. Features that remained independently significant in step-down regression analyses of survival were incorporated into models that identified groups of patients of all ages and groups of patients no more than 60 years old with different risks of death.
RESULTS
In 2031 patients of all ages, our model, based on age, tumor stage, serum lactate dehydrogenase concentration, performance status, and number of extranodal disease sites, identified four risk groups with predicted five-year survival rates of 73 percent, 51 percent, 43 percent, and 26 percent. In 1274 patients 60 or younger, an age-adjusted model based on tumor stage, lactate dehydrogenase level, and performance status identified four risk groups with predicted five-year survival rates of 83 percent, 69 percent, 46 percent, and 32 percent. In both models, the increased risk of death was due to both a lower rate of complete responses and a higher rate of relapse from complete response. These two indexes, called the international index and the age-adjusted international index, were significantly more accurate than the Ann Arbor classification in predicting long-term survival.
CONCLUSIONS
The international index and the age-adjusted international index should be used in the design of future therapeutic trials in patients with aggressive non-Hodgkin's lymphoma and in the selection of appropriate therapeutic approaches for individual patients.
TL;DR: The frequency of use of unconventional therapy in the United States is far higher than previously reported and expenditure associated with use in 1990 amounted to approximately $13.7 billion, comparable to the $12.8 billion spent out of pocket annually for all hospitalizations in theUnited States.
Abstract: Background Many people use unconventional therapies for health problems, but the extent of this use and the costs are not known. We conducted a national survey to determine the prevalence, costs, and patterns of use of unconventional therapies, such as acupuncture and chiropractic. Methods We limited the therapies studied to 16 commonly used interventions neither taught widely in U.S. medical schools nor generally available in U.S. hospitals. We completed telephone interviews with 1539 adults (response rate, 67 percent) in a national sample of adults 18 years of age or older in 1990. We asked respondents to report any serious or bothersome medical conditions and details of their use of conventional medical services; we then inquired about their use of unconventional therapy. Results One in three respondents (34 percent) reported using at least one unconventional therapy in the past year, and a third of these saw providers for unconventional therapy. The latter group had made an average of 19 visits to suc...
TL;DR: It is demonstrated that a temporal gradient in Lin-14 protein is generated posttranscriptionally by multiple elements in the lin-14 3'UTR that are regulated by the heterochronic gene Lin-4.
TL;DR: Two broad mechanisms--oxidative stress and excessive activation of glutamate receptors--are converging and represent sequential as well as interacting processes that provide a final common pathway for cell vulnerability in the brain.
Abstract: There is an increasing amount of experimental evidence that oxidative stress is a causal, or at least an ancillary, factor in the neuropathology of several adult neurodegenerative disorders, as well as in stroke, trauma, and seizures. At the same time, excessive or persistent activation of glutamate-gated ion channels may cause neuronal degeneration in these same conditions. Glutamate and related acidic amino acids are thought to be the major excitatory neurotransmitters in brain and may be utilized by 40 percent of the synapses. Thus, two broad mechanisms--oxidative stress and excessive activation of glutamate receptors--are converging and represent sequential as well as interacting processes that provide a final common pathway for cell vulnerability in the brain. The broad distribution in brain of the processes regulating oxidative stress and mediating glutamatergic neurotransmission may explain the wide range of disorders in which both have been implicated. Yet differential expression of components of the processes in particular neuronal systems may account for selective neurodegeneration in certain disorders.
Book•
01 Mar 1993TL;DR: The Theory of Multiple Intelligences In a Nutshell A Rounded Version (with Joseph Walters) Questions and Answers About MultipleIntelligences Theory (withJoseph Walters) The Relation of Intelligence to Other Valued Human Capacities Educating The Intelligence A School of the Future (with Tina Blythe) Interlude: The Two Rhetorics of School Reform: Complex Theories versus the Quick Fix The Emergence and Nurturance of MultipleIntelligence in Early Childhood: The Project Spectrum Approach (with Mara Krechevsky) The Elementary Years
Abstract: The Theory Of Multiple Intelligences In a Nutshell A Rounded Version (with Joseph Walters) Questions and Answers About Multiple Intelligences Theory (with Joseph Walters) The Relation of Intelligence to Other Valued Human Capacities Educating The Intelligences A School of the Future (with Tina Blythe) Interlude: The Two Rhetorics of School Reform: Complex Theories versus the Quick Fix The Emergence and Nurturance of Multiple Intelligences in Early Childhood: The Project Spectrum Approach (with Mara Krechevsky) The Elementary Years: The Project Approach in the Key School Setting Approaching School Intelligently: Practical Intelligence at the Middle School Level (with Mara Krechevsky) Disciplined Inquiry in the High School: An Introduction to Arts PROPEL Interlude: On Implementing Educational Programs: Obstacles and Opportunities Assessment And Beyond: The Components Of An MI Education Assessment in Context: The Alternative to Standardized Testing Interlude: A Portfolio Approach to College Admissions Beyond Assessment: The Aims and Means of Education The Future of Work on Multiple Intelligences Intelligences in Seven Phases Engaging Intelligence (with Mindy Kornhaber and Mara Krechevsky) Epilogue: Multiple Intelligences Theory in 2013.
TL;DR: Data support the involvement of ApoE ϵ4 in the pathogenesis of late-onset familial and sporadic AD and suggest it may operate as a susceptibility gene (risk factor) for the clinical expression of AD.
Abstract: Apolipoprotein E, type epsilon 4 allele (APOE epsilon 4), is associated with late-onset familial Alzheimer's disease (AD). There is high avidity and specific binding of amyloid beta-peptide with the protein ApoE. To test the hypothesis that late-onset familial AD may represent the clustering of sporadic AD in families large enough to be studied, we extended the analyses of APOE alleles to several series of sporadic AD patients. APOE epsilon 4 is significantly associated with a series of probable sporadic AD patients (0.36 +/- 0.042, AD, versus 0.16 +/- 0.027, controls [allele frequency estimate +/- standard error], p = 0.00031). Spouse controls did not differ from CEPH grandparent controls from the Centre d'Etude du Polymorphisme Humain (CEPH) or from literature controls. A large combined series of autopsy-documented sporadic AD patients also demonstrated highly significant association with the APOE epsilon 4 allele (0.40 +/- 0.026, p < or = 0.00001). These data support the involvement of ApoE epsilon 4 in the pathogenesis of late-onset familial and sporadic AD. ApoE isoforms may play an important role in the metabolism of beta-peptide, and APOE epsilon 4 may operate as a susceptibility gene (risk factor) for the clinical expression of AD.
TL;DR: In this article, the authors describe a comprehensive theory of trust in market research relationships. But they do not consider the impact of trust on exchange relationships in the context of financial transactions, where trust is critical in facilitating exchange relationships.
Abstract: Building on previous work suggesting that trust is critical in facilitating exchange relationships, the authors describe a comprehensive theory of trust in market research relationships. This theor...
TL;DR: The results suggest that integrins act as mechanoreceptors and transmit mechanical signals to the cytoskeleton, which may be mediated simultaneously at multiple locations inside the cell through force-induced rearrangements within a tensionally integrated cytos skeleton.
Abstract: Mechanical stresses were applied directly to cell surface receptors with a magnetic twisting device. The extracellular matrix receptor, integrin beta 1, induced focal adhesion formation and supported a force-dependent stiffening response, whereas nonadhesion receptors did not. The cytoskeletal stiffness (ratio of stress to strain) increased in direct proportion to the applied stress and required intact microtubules and intermediate filaments as well as microfilaments. Tensegrity models that incorporate mechanically interdependent struts and strings that reorient globally in response to a localized stress mimicked this response. These results suggest that integrins act as mechanoreceptors and transmit mechanical signals to the cytoskeleton. Mechanotransduction, in turn, may be mediated simultaneously at multiple locations inside the cell through force-induced rearrangements within a tensionally integrated cytoskeleton.
TL;DR: Majors topics addressed in this review on zinc physiology are chemistry and biochemistry; interface of biochemistry and physiology of zinc; physiology and cell and molecular biology; and pathology.
Abstract: Majors topics addressed in this review on zinc physiology are ; 1) chemistry and biochemistry; 2) interface of biochemistry and physiology of zinc; 3) physiology and cell and molecular biology; 4) pathology
TL;DR: The variability in SH2 domain sequences at likely sites of contact provides a structural basis for the phosphopeptide selectivity of these families.
TL;DR: Data and reports indicating that S. cerevisiae msh2 mutations cause an instability of dinucleotide repeats like those associated with H NPCC suggest that hMSH2 is the HNPCC gene.
TL;DR: It is proposed that the CED-3 protein acts as a cysteine protease in the initiation of programmed cell death in C. elegans and that cysteINE proteases also function in programmed cell deaths in mammals.
TL;DR: It is reported that NO.-mediated neurotoxicity is engendered, at least in part, by reaction with superoxide anion (O.-2), apparently leading to formation of peroxynitrite (ONOO−), and not by NO.
Abstract: Congeners of nitrogen monoxide (NO) are neuroprotective and neurodestructive. To address this apparent paradox, we considered the effects on neurons of compounds characterized by alternative redox states of NO: nitric oxide (NO.) and nitrosonium ion (NO+). Nitric oxide, generated from NO. donors or synthesized endogenously after NMDA (N-methyl-D-aspartate) receptor activation, can lead to neurotoxicity. Here, we report that NO.- mediated neurotoxicity is engendered, at least in part, by reaction with superoxide anion (O2.-), apparently leading to formation of peroxynitrite (ONOO-), and not by NO. alone. In contrast, the neuroprotective effects of NO result from downregulation of NMDA-receptor activity by reaction with thiol group(s) of the receptor's redox modulatory site. This reaction is not mediated by NO. itself, but occurs under conditions supporting S-nitrosylation of NMDA receptor thiol (reaction or transfer of NO+). Moreover, the redox versatility of NO allows for its interconversion from neuroprotective to neurotoxic species by a change in the ambient redox milieu. The details of this complex redox chemistry of NO may provide a mechanism for harnessing neuroprotective effects and avoiding neurotoxicity in the central nervous system.
TL;DR: A vertebrate gene related to the Drosophila segment polarity gene hedgehog, which is expressed specifically in the ZPA and in other regions of the embryo, that is capable of polarizing limbs in grafting experiments is isolated.
TL;DR: Evidence is provided of an association between a high intake of vitamin E and a lower risk of coronary heart disease in men, and public policy recommendations with regard to the use ofitamin E supplements should await the results of additional studies.
Abstract: Background The oxidative modification of low-density lipoproteins increases their incorporation into the arterial intima, an essential step in atherogenesis. Although dietary antioxidants, such as vitamin C, carotene, and vitamin E, have been hypothesized to prevent coronary heart disease, prospective epidemiologic data are sparse. Methods In 1986, 39,910 U.S. male health professionals 40 to 75 years of age who were free of diagnosed coronary heart disease, diabetes, and hypercholesterolemia completed detailed dietary questionnaires that assessed their usual intake of vitamin C, carotene, and vitamin E in addition to other nutrients. During four years of follow-up, we documented 667 cases of coronary disease. Results After controlling for age and several coronary risk factors, we observed a lower risk of coronary disease among men with higher intakes of vitamin E (P for trend = 0.003). For men consuming more than 60 IU per day of vitamin E, the multivariate relative risk was 0.64 (95 percent confidence in...
TL;DR: A dimer of the class II αβ heterodimers is seen in the crystal forms of HLA-DR1, suggesting class II HLA dimerization as a mechanism for initiating the cytoplasmic signalling events in T-cell activation.
Abstract: The three-dimensional structure of the class II histocompatibility glycoprotein HLA-DR1 from human B-cell membranes has been determined by X-ray crystallography and is similar to that of class I HLA. Peptides are bound in an extended conformation that projects from both ends of an 'open-ended' antigen-binding groove. A prominent non-polar pocket into which an 'anchoring' peptide side chain fits is near one end of the binding groove. A dimer of the class II alpha beta heterodimers is seen in the crystal forms of HLA-DR1, suggesting class II HLA dimerization as a mechanism for initiating the cytoplasmic signalling events in T-cell activation.
TL;DR: In recent years, academic and practitioner interest has focused on market orientation and factors that engender this orientation in organizations as mentioned in this paper, however, much less attention has been devoted to d...
Abstract: In recent years, academic and practitioner interest has focused on market orientation and factors that engender this orientation in organizations. However, much less attention has been devoted to d...
TL;DR: The European Community (EC) is the most successful example of institutionalized international policy coordination in the modem world, yet there is little agreement about the proper explanation for its evolution as discussed by the authors.
Abstract: The European Community (EC) is the most successful example of institutionalized international policy co-ordination in the modem world, yet there is little agreement about the proper explanation for its evolution. From the signing of the Treaty of Rome to the making of Maastricht, the EC has developed through a series of celebrated intergovernmental bargains, each of which set the agenda for an intervening period of consolidation. The most fundamental task facing a theoretical account of European integration is to explain these bargains. Today many would revive neo-functionalism’s emphasis on sui generis characteristics of EC institutions, in particular the importance of unintended consequences of previous decisions and the capacity of supranational officials to provide leadership. This article joins the debate by reasserting the self-critique, advanced almost two decades ago by Emst Haas and other leading neo-functionalists, who
TL;DR: Three members of a mouse gene family related to the Drosophila segment polarity gene, hedgehog (hh), are identified and it is suggested that Shh may play a role in the normal inductive interactions that pattern the ventral CNS.