Showing papers by "Dartmouth College published in 2004"

The functions of animal microRNAs

Abstract: MicroRNAs (miRNAs) are small RNAs that regulate the expression of complementary messenger RNAs. Hundreds of miRNA genes have been found in diverse animals, and many of these are phylogenetically conserved. With miRNA roles identified in developmental timing, cell death, cell proliferation, haematopoiesis and patterning of the nervous system, evidence is mounting that animal miRNAs are more numerous, and their regulatory impact more pervasive, than was previously suspected.

Do Institutions Cause Growth

Abstract: We revisit the debate over whether political institutions cause economic growth, or whether, alternatively, growth and human capital accumulation lead to institutional improvement. We find that most indicators of institutional quality used to establish the proposition that institutions cause growth are constructed to be conceptually unsuitable for that purpose. We also find that some of the instrumental variable techniques used in the literature are flawed. Basic OLS results, as well as a variety of additional evidence, suggest that (a) human capital is a more basic source of growth than are the institutions, (b) poor countries get out of poverty through good policies, often pursued by dictators, and (c) subsequently improve their political institutions.

Toward an aggregated understanding of enzymatic hydrolysis of cellulose: noncomplexed cellulase systems.

Abstract: Information pertaining to enzymatic hydrolysis of cellulose by noncomplexed cellulase enzyme systems is reviewed with a particular emphasis on development of aggregated understanding incorporating substrate features in addition to concentration and multiple cellulase components. Topics considered include properties of cellulose, adsorption, cellulose hydrolysis, and quantitative models. A classification scheme is proposed for quantitative models for enzymatic hydrolysis of cellulose based on the number of solubilizing activities and substrate state variables included. We suggest that it is timely to revisit and reinvigorate functional modeling of cellulose hydrolysis, and that this would be highly beneficial if not necessary in order to bring to bear the large volume of information available on cellulase components on the primary applications that motivate interest in the subject.

Neighbors as Negatives: Relative Earnings and Well-Being

Abstract: This paper investigates whether individuals feel worse off when others around them earn more In other words, do people care about relative position and does "lagging behind the Joneses" diminish well-being? To answer this question, I match individual-level panel data containing a number of indicators of well-being to information about local average earnings I find that, controlling for an individual's own income, higher earnings of neighbors are associated with lower levels of self-reported happiness The data's panel nature and rich set of measures of well-being and behavior indicate that this association is not driven by selection or by changes in the way people define happiness There is suggestive evidence that the negative effect of increases in neighbors' earnings on own well-being is most likely caused by interpersonal preferences, ie people having utility functions that depend on relative consumption in addition to absolute consumption

Expression profiling of mammalian microRNAs uncovers a subset of brain-expressed microRNAs with possible roles in murine and human neuronal differentiation

Abstract: Background: The microRNAs (miRNAs) are an extensive class of small noncoding RNAs (18 to 25 nucleotides) with probable roles in the regulation of gene expression. In Caenorhabditis elegans, lin-4 and let-7 miRNAs control the timing of fate specification of neuronal and hypodermal cells during larval development. lin-4, let-7 and other miRNA genes are conserved in mammals, and their potential functions in mammalian development are under active study. Results: In order to identify mammalian miRNAs that might function in development, we characterized the expression of 119 previously reported miRNAs in adult organs from mouse and human using northern blot analysis. Of these, 30 miRNAs were specifically expressed or greatly enriched in a particular organ (brain, lung, liver or skeletal muscle). This suggests organ- or tissuespecific functions for miRNAs. To test if any of the 66 brain-expressed miRNAs were present in neurons, embryonal carcinoma cells were treated with all-trans-retinoic acid to promote neuronal differentiation. A total of 19 brain-expressed miRNAs (including lin-4 and let-7 orthologs) were coordinately upregulated in both human and mouse embryonal carcinoma cells during neuronal differentiation. The mammalian ortholog of C. elegans lin-28, which is downregulated by lin-4 in worms via 3' untranslated region binding, was also repressed during neuronal differentiation of mammalian embryonal carcinoma cells. Mammalian lin-28 messenger RNAs contain conserved predicted binding sites in their 3' untranslated regions for neuron-expressed miR-125b (a lin-4 ortholog), let-7a, and miR-218. Conclusions: The identification of a subset of brain-expressed miRNAs whose expression behavior is conserved in both mouse and human differentiating neurons implicates these miRNAs in mammalian neuronal development or function.

Do Institutions Cause Growth

Abstract: We revisit the debate over whether political institutions cause economic growth, or whether, alternatively, growth and human capital accumulation lead to institutional improvement We find that most indicators of institutional quality used to establish the proposition that institutions cause growth are constructed to be conceptually unsuitable for that purpose We also find that some of the instrumental variable techniques used in the literature are flawed Basic OLS results, as well as a variety of additional evidence, suggest that a) human capital is a more basic source of growth than are the institutions, b) poor countries get out of poverty through good policies, often pursued by dictators, and c) subsequently improve their political institutions

The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress

Abstract: AMP-activated protein kinase (AMPK) is a highly conserved sensor of cellular energy status found in all eukaryotic cells. AMPK is activated by stimuli that increase the cellular AMP/ATP ratio. Essential to activation of AMPK is its phosphorylation at Thr-172 by an upstream kinase, AMPKK, whose identity in mammalian cells has remained elusive. Here we present biochemical and genetic evidence indicating that the LKB1 serine/threonine kinase, the gene inactivated in the Peutz-Jeghers familial cancer syndrome, is the dominant regulator of AMPK activation in several mammalian cell types. We show that LKB1 directly phosphorylates Thr-172 of AMPKα in vitro and activates its kinase activity. LKB1-deficient murine embryonic fibroblasts show nearly complete loss of Thr-172 phosphorylation and downstream AMPK signaling in response to a variety of stimuli that activate AMPK. Reintroduction of WT, but not kinase-dead, LKB1 into these cells restores AMPK activity. Furthermore, we show that LKB1 plays a biologically significant role in this pathway, because LKB1-deficient cells are hypersensitive to apoptosis induced by energy stress. On the basis of these results, we propose a model to explain the apparent paradox that LKB1 is a tumor suppressor, yet cells lacking LKB1 are resistant to cell transformation by conventional oncogenes and are sensitive to killing in response to agents that elevate AMP. The role of LKB1/AMPK in the survival of a subset of genetically defined tumor cells may provide opportunities for cancer therapeutics.

When Good Brands Do Bad

Abstract: This article reports results from a longitudinal field experiment examining the evolution of consumer-brand relationships. Development patterns differed, whereby relationships with sincere brands deepened over time in line with friendship templates, and relationships with exciting brands evinced a trajectory characteristic of short-lived flings. These patterns held only when the relationship proceeded without a transgression. Relationships with sincere brands suffered in the wake of transgressions, whereas relationships with exciting brands surprisingly showed signs of reinvigoration after such transgressions. Inferences concerning the brand’s partner quality mediated the results. Findings suggest a dynamic construal of brand personality, greater attention to interrupt events, and consideration of the relationship contracts formed at the hands of different brands.

The Capital Asset Pricing Model: Theory and Evidence

Abstract: T he capital asset pricing model (CAPM) of William Sharpe (1964) and John Lintner (1965) marks the birth of asset pricing theory (resulting in a Nobel Prize for Sharpe in 1990). Four decades later, the CAPM is still widely used in applications, such as estimating the cost of capital for firms and evaluating the performance of managed portfolios. It is the centerpiece of MBA investment courses. Indeed, it is often the only asset pricing model taught in these courses. The attraction of the CAPM is that it offers powerful and intuitively pleasing predictions about how to measure risk and the relation between expected return and risk. Unfortunately, the empirical record of the model is poor—poor enough to invalidate the way it is used in applications. The CAPM’s empirical problems may reflect theoretical failings, the result of many simplifying assumptions. But they may also be caused by difficulties in implementing valid tests of the model. For example, the CAPM says that the risk of a stock should be measured relative to a comprehensive “market portfolio” that in principle can include not just traded financial assets, but also consumer durables, real estate and human capital. Even if we take a narrow view of the model and limit its purview to traded financial assets, is it

Why Some Firms Export

Abstract: This paper presents a dynamic model of the export decision by a profit-maximizing fi rm. Using ap anel of U.S. manufacturing plants, we test for the role of plant characteristics, spillovers from neighboring exporters, entry costs and government export promotion expenditures. Entry and exit in the export market by U.S. plants is substantial, past exporters are apt to reenter, and plants are likely to export in consecutive years. However, we find that entry costs are significant and spillovers from the export activity of other plants negligible. State export promotion expenditures have no significant effect on the probability of exporting. Plant characteristics, especially those indicative of past success, strongly increase the probability of exporting as do

Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex

Abstract: Mammalian target of rapamycin (mTOR) is a central regulator of protein synthesis whose activity is modulated by a variety of signals. Energy depletion and hypoxia result in mTOR inhibition. While energy depletion inhibits mTOR through a process involving the activation of AMP-activated protein kinase (AMPK) by LKB1 and subsequent phosphorylation of TSC2, the mechanism of mTOR inhibition by hypoxia is not known. Here we show that mTOR inhibition by hypoxia requires the TSC1/TSC2 tumor suppressor complex and the hypoxia-inducible gene REDD1/RTP801. Disruption of the TSC1/TSC2 complex through loss of TSC1 or TSC2 blocks the effects of hypoxia on mTOR, as measured by changes in the mTOR targets S6K and 4E-BP1, and results in abnormal accumulation of Hypoxia-inducible factor (HIF). In contrast to energy depletion, mTOR inhibition by hypoxia does not require AMPK or LKB1. Down-regulation of mTOR activity by hypoxia requires de novo mRNA synthesis and correlates with increased expression of the hypoxia-inducible REDD1 gene. Disruption of REDD1 abrogates the hypoxia-induced inhibition of mTOR, and REDD1 overexpression is sufficient to down-regulate S6K phosphorylation in a TSC1/TSC2-dependent manner. Inhibition of mTOR function by hypoxia is likely to be important for tumor suppression as TSC2-deficient cells maintain abnormally high levels of cell proliferation under hypoxia.

An illustrated consensus on the classification of pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms

Abstract: Invasive pancreatic ductal adenocarcinoma is an almost uniformly fatal disease. Several distinct noninvasive precursor lesions can give rise to invasive adenocarcinoma of the pancreas, and the prevention, detection, and treatment of these noninvasive lesions offers the potential to cure early pancreatic cancers. Noninvasive precursors of invasive ductal adenocarcinoma of the pancreas include pancreatic intraepithelial neoplasias (PanINs), intraductal papillary mucinous neoplasms (IPMNs), and mucinous cystic neoplasms. Diagnostic criteria, including a distinct ovarian-type stroma, and a consistent nomenclature are well established for mucinous cystic neoplasms. By contrast, consistent nomenclatures and diagnostic criteria have been more difficult to establish for PanINs and IPMNs. Because both PanINs and IPMNs consist of intraductal neoplastic proliferations of columnar, mucin-containing cells with a variable degree of papilla formation, the distinction between these two classes of precursor lesions remains problematic. Thus, considerable ambiguities still exist in the classification of noninvasive neoplasms in the pancreatic ducts. A meeting of international experts on precursor lesions of pancreatic cancer was held at The Johns Hopkins Hospital from August 18 to 19, 2003. The purpose of this meeting was to define an international acceptable set of diagnostic criteria for PanINs and IPMNs and to address a number of ambiguities that exist in the previously reported classification systems for these neoplasms. We present a consensus classification of the precursor lesions in the pancreatic ducts, PanINs and IPMNs.

BCMA Is Essential for the Survival of Long-lived Bone Marrow Plasma Cells

Abstract: Long-lived humoral immunity is manifested by the ability of bone marrow plasma cells (PCs) to survive for extended periods of time. Recent studies have underscored the importance of BLyS and APRIL as factors that can support the survival of B lineage lymphocytes. We show that BLyS can sustain PC survival in vitro, and this survival can be further enhanced by interleukin 6. Selective up-regulation of Mcl-1 in PCs by BLyS suggests that this α-apoptotic gene product may play an important role in PC survival. Blockade of BLyS, via transmembrane activator and cyclophilin ligand interactor–immunoglobulin treatment, inhibited PC survival in vitro and in vivo. Heightened expression of B cell maturation antigen (BCMA), and lowered expression of transmembrane activator and cyclophilin ligand interactor and BAFF receptor in PCs relative to resting B cells suggests a vital role of BCMA in PC survival. Affirmation of the importance of BCMA in PC survival was provided by studies in BCMA−/− mice in which the survival of long-lived bone marrow PCs was impaired compared with wild-type controls. These findings offer new insights into the molecular basis for the long-term survival of PCs.

Hospital costs associated with surgical complications: A report from the private-sector National Surgical Quality Improvement Program

Abstract: Background The National Surgical Quality Improvement Project (NSQIP) has reduced morbidity rates in Veterans Affairs Hospitals. As the NSQIP methods move to private-sector hospitals, funding responsibilities will shift to the medical center. The objective of the current study was to calculate hospital costs associated with postoperative complications, because reducing morbidity may offset the costs of using the NSQIP. Study design Patient data were obtained from a single private-sector center involved in the NSQIP from 2001 to 2002 (n=1,008). Cost data were derived from the hospital's internal cost-accounting database (TSI; Transitions Systems Inc). Total hospital costs associated with both minor complications and major complications were calculated. Multiple linear regression was used to determine the cost of each type of complication after adjusting for patient characteristics. Results Rates of minor complications (6.3%, 64 events) and major complications (6.6%, 67 events) were similar. Median hospital costs were lowest for patients without complications ($4,487) compared with those with minor ($14,094) and major complications ($28,356) (p Conclusions Given the substantial costs associated with major postoperative complications, reducing morbidity may provide sufficient cost savings to offset the resources needed to participate in the private-sector expansion of the NSQIP.

The Schizophrenia Patient Outcomes Research Team (PORT): Updated Treatment Recommendations 2003

Abstract: Since publication of the original Schizophrenia Patient Outcomes Research Team (PORT) treatment recommendations in 1998, considerable scientific advances have occurred in our knowledge about how to help persons with schizophrenia. Today an even stronger body of research supports the scientific basis of treatment. This evidence, taken in its entirety, points to the value of treatment approaches combining medications with psychosocial treatments, including psychological interventions, family interventions, supported employment, assertive community treatment, and skills training. The most significant advances lie in the increased options for pharmacotherapy, with the introduction of second generation antipsychotic medications, and greater confidence and specificity in the application of psychosocial interventions. Currently available treatment technologies, when appropriately applied and accessible, should provide most patients with significant relief from psychotic symptoms and improved opportunities to lead more fulfilling lives in the community. Nonetheless, major challenges remain, including the need for (1) better knowledge about the underlying etiologies of the neurocognitive impairments and deficit symptoms that account for much of the disability still associated with schizophrenia; (2) treatments that more directly address functional impairments and that promote recovery; and (3) approaches that facilitate access to scientifically based treatments for patients, the vast majority of whom currently do not have such access.

The Effect of Fixed Exchange Rates on Monetary Policy

Abstract: To investigate how a fixed exchange rate affects monetary policy, this paper classifies countries as pegged or nonpegged and examines whether a pegged country must follow the interest rate changes in the base country. Despite recent research which hints that all countries, not just pegged countries, lack monetary freedom, the evidence shows that pegs follow base country interest rates more than nonpegs. This study uses actual behavior, not declared status, for regime classification; expands the sample including base currencies other than the dollar; examines the impact of capital controls, as well as other control variables; considers the time series properties of the data carefully; and uses cointegration and other levels-relationship analysis to provide additional insights.

Human Amygdala Responsivity to Masked Fearful Eye Whites

Abstract: The amygdala was more responsive to fearful (larger) eye whites than to happy (smaller) eye whites presented in a masking paradigm that mitigated subjects' awareness of their presence and aberrant nature. These data demonstrate that the amygdala is responsive to elements of.

Biomechanics of locked plates and screws.

Abstract: Objective:To review the biomechanical principles that guide fracture fixation with plates and screws; specifically to compare and contrast the function and roles of conventional unlocked plates to locked plates in fracture fixation. We review basic plate and screw function, discuss the design ration

The Essential Basic Helix-Loop-Helix Protein FIT1 Is Required for the Iron Deficiency Response

Abstract: Regulation of iron uptake is critical for plant survival. Although the activities responsible for reduction and transport of iron at the plant root surface have been described, the genes controlling these activities are largely unknown. We report the identification of the essential gene Fe-deficiency Induced Transcription Factor 1 (FIT1), which encodes a putative transcription factor that regulates iron uptake responses in Arabidopsis thaliana. Like the Fe(III) chelate reductase FRO2 and high affinity Fe(II) transporter IRT1, FIT1 mRNA is detected in the outer cell layers of the root and accumulates in response to iron deficiency. fit1 mutant plants are chlorotic and die as seedlings but can be rescued by the addition of supplemental iron, pointing to a defect in iron uptake. fit1 mutant plants accumulate less iron than wild-type plants in root and shoot tissues. Microarray analysis shows that expression of many (72 of 179) iron-regulated genes is dependent on FIT1. We demonstrate that FIT1 regulates FRO2 at the level of mRNA accumulation and IRT1 at the level of protein accumulation. We propose a new model for iron uptake in Arabidopsis where FRO2 and IRT1 are differentially regulated by FIT1.

CD40/CD154 interactions at the interface of tolerance and immunity

Abstract: Development of the acquired immune response is dependent on the signaling of CD40 by its ligand, CD154. These molecules govern both the magnitude and quality of humoral- and cell-mediated immunity. A litany of studies have conclusively documented that blockade of this ligand-receptor pair can prevent, and also intervene in, the progression of antibody- and cell-mediated autoimmune diseases, and can instill long-lived allogeneic and xenogeneic graft tolerance. Many effector mechanisms of inflammation are abolished as a result of CD154 blockade, but we are now beginning to understand that CD154 blockade may, in some instances, engender long-lived, antigen-specific tolerance. In the context of transplantation tolerance, we present a hypothesis that alpha CD154 blockade is most effective at inducing long-lived allospecific tolerance if anergy and regulation can be elicited prior to the onslaught of inflammation that is induced by grafting (preemptive tolerance). This facet of alpha CD154-induced tolerance appears to co-opt the normal processes of peripheral tolerance induced by immature DCs and can be exploited to induce long-lived antigen-specific tolerance. The underlying science and the prospects for inducing long-lived antigen-specific tolerance in a model of allograft tolerance through CD154 blockade are presented and discussed.

Effect of Xylan and Lignin Removal by Batch and Flowthrough Pretreatment on the Enzymatic Digestibility of Corn Stover Cellulose

Abstract: Compared with batch systems, flowthrough and countercurrent reactors have important potential advan- tages for pretreating cellulosic biomass, including higher hemicellulose sugar yields, enhanced cellulose digestibility, and reduced chemical additions. Unfortunately, they suffer from high water and energy use. To better understand these trade-offs, comparative data are reported on xylan and lignin removal and enzymatic digestibility of cellu- lose for corn stover pretreated in batch and flowthrough reactors over a range of flow rates between 160j and 220jC, with water only and also with 0.1 wt% sulfuric acid. Increasing flow with just water enhanced the xylan dissolution rate, more than doubled total lignin removal, and increased cellulose digestibility. Furthermore, adding dilute sulfuric acid increased the rate of xylan removal for both batch and flowthrough systems. Interestingly, adding acid also increased the lignin removal rate with flow, but less lignin was left in solution when acid was added in batch. Although the enzymatic hydrolysis of pretreated cellulose was related to xylan removal, as others have shown, the digestibility was much better for flowthrough compared with batch systems, for the same degree of xylan removal. Cellulose digestibility for flowthrough reactors was related to lignin removal as well. These results suggest that altering lignin also affects the enzymatic digestibility of corn stover. B 2004 Wiley Periodicals, Inc.

Experimental evaluation of wireless simulation assumptions

Abstract: All analytical and simulation research on ad~hoc wireless networks must necessarily model radio propagation using simplifying assumptions. We provide a comprehensive review of six assumptions that are still part of many ad hoc network simulation studies, despite increasing awareness of the need to represent more realistic features, including hills, obstacles, link asymmetries, and unpredictable fading. We use an extensive set of measurements from a large outdoor routing experiment to demonstrate the weakness of these assumptions, and show how these assumptions cause simulation results to differ significantly from experimental results. We close with a series of recommendations for researchers, whether they develop protocols, analytic models, or simulators for ad~hoc wireless networks.

Lessons from the Genome Sequence of Neurospora crassa: Tracing the Path from Genomic Blueprint to Multicellular Organism

Abstract: We present an analysis of over 1,100 of the approximately 10,000 predicted proteins encoded by the genome sequence of the filamentous fungus Neurospora crassa. Seven major areas of Neurospora genomics and biology are covered. First, the basic features of the genome, including the automated assembly, gene calls, and global gene analyses are summarized. The second section covers components of the centromere and kinetochore complexes, chromatin assembly and modification, and transcription and translation initiation factors. The third area discusses genome defense mechanisms, including repeat induced point mutation, quelling and meiotic silencing, and DNA repair and recombination. In the fourth section, topics relevant to metabolism and transport include extracellular digestion; membrane transporters; aspects of carbon, sulfur, nitrogen, and lipid metabolism; the mitochondrion and energy metabolism; the proteasome; and protein glycosylation, secretion, and endocytosis. Environmental sensing is the focus of the fifth section with a treatment of two-component systems; GTP-binding proteins; mitogen-activated protein, p21-activated, and germinal center kinases; calcium signaling; protein phosphatases; photobiology; circadian rhythms; and heat shock and stress responses. The sixth area of analysis is growth and development; it encompasses cell wall synthesis, proteins important for hyphal polarity, cytoskeletal components, the cyclin/cyclin-dependent kinase machinery, macroconidiation, meiosis, and the sexual cycle. The seventh section covers topics relevant to animal and plant pathogenesis and human disease. The results demonstrate that a large proportion of Neurospora genes do not have homologues in the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe. The group of unshared genes includes potential new targets for antifungals as well as loci implicated in human and plant physiology and disease.

Transport of solar wind into Earth's magnetosphere through rolled-up Kelvin–Helmholtz vortices

Abstract: Establishing the mechanisms by which the solar wind enters Earth's magnetosphere is one of the biggest goals of magnetospheric physics, as it forms the basis of space weather phenomena such as magnetic storms and aurorae1. It is generally believed that magnetic reconnection is the dominant process, especially during southward solar-wind magnetic field conditions when the solar-wind and geomagnetic fields are antiparallel at the low-latitude magnetopause2. But the plasma content in the outer magnetosphere increases during northward solar-wind magnetic field conditions3,4, contrary to expectation if reconnection is dominant. Here we show that during northward solar-wind magnetic field conditions—in the absence of active reconnection at low latitudes—there is a solar-wind transport mechanism associated with the nonlinear phase of the Kelvin–Helmholtz instability5. This can supply plasma sources for various space weather phenomena.