Showing papers by "Yale University published in 1998"

Crystallography & NMR System: A New Software Suite for Macromolecular Structure Determination

Abstract: A new software suite, called Crystallography & NMR System (CNS), has been developed for macromolecular structure determination by X-ray crystallography or solution nuclear magnetic resonance (NMR) spectroscopy. In contrast to existing structure-determination programs the architecture of CNS is highly flexible, allowing for extension to other structure-determination methods, such as electron microscopy and solid-state NMR spectroscopy. CNS has a hierarchical structure: a high-level hypertext markup language (HTML) user interface, task-oriented user input files, module files, a symbolic structure-determination language (CNS language), and low-level source code. Each layer is accessible to the user. The novice user may just use the HTML interface, while the more advanced user may use any of the other layers. The source code will be distributed, thus source-code modification is possible. The CNS language is sufficiently powerful and flexible that many new algorithms can be easily implemented in the CNS language without changes to the source code. The CNS language allows the user to perform operations on data structures, such as structure factors, electron-density maps, and atomic properties. The power of the CNS language has been demonstrated by the implementation of a comprehensive set of crystallographic procedures for phasing, density modification and refinement. User-friendly task-oriented input files are available for nearly all aspects of macromolecular structure determination by X-ray crystallography and solution NMR.

NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses

Abstract: ▪ Abstract The transcription factor NF-κB, more than a decade after its discovery, remains an exciting and active area of study. The involvement of NF-κB in the expression of numerous cytokines and adhesion molecules has supported its role as an evolutionarily conserved coordinating element in the organism's response to situations of infection, stress, and injury. Recently, significant advances have been made in elucidating the details of the pathways through which signals are transmitted to the NF-κB:IκB complex in the cytosol. The field now awaits the discovery and characterization of the kinase responsible for the inducible phosphorylation of IκB proteins. Another exciting development has been the demonstration that in certain situations NF-κB acts as an anti-apoptotic protein; therefore, elucidation of the mechanism by which NF-κB protects against cell death is an important goal. Finally, the generation of knockouts of members of the NF-κB/IκB family has allowed the study of the roles of these protein...

Neurons Containing Hypocretin (Orexin) Project to Multiple Neuronal Systems

Abstract: The novel neuropeptides called hypocretins (orexins) have recently been identified as being localized exclusively in cell bodies in a subregion of the tuberal part of the hypothalamus. The structure of the hypocretins, their accumulation in vesicles of axon terminals, and their excitatory effect on cultured hypothalamic neurons suggest that the hypocretins function in intercellular communication. To characterize these peptides further and to help understand what physiological functions they may serve, we undertook an immunohistochemical study to examine the distribution of preprohypocretin-immunoreactive neurons and fibers in the rat brain. Preprohypocretin-positive neurons were found in the perifornical nucleus and in the dorsal and lateral hypothalamic areas. These cells were distinct from those that express melanin-concentrating hormone. Although they represent a restricted group of cells, their projections were widely distributed in the brain. We observed labeled fibers throughout the hypothalamus. The densest extrahypothalamic projection was found in the locus coeruleus. Fibers were also seen in the septal nuclei, the bed nucleus of the stria terminalis, the paraventricular and reuniens nuclei of the thalamus, the zona incerta, the subthalamic nucleus, the central gray, the substantia nigra, the raphe nuclei, the parabrachial area, the medullary reticular formation, and the nucleus of the solitary tract. Less prominent projections were found in cortical regions, central and anterior amygdaloid nuclei, and the olfactory bulb. These results suggest that hypocretins are likely to have a role in physiological functions in addition to food intake such as regulation of blood pressure, the neuroendocrine system, body temperature, and the sleep–waking cycle.

Discovery of a supernova explosion at half the age of the Universe

Abstract: The ultimate fate of the Universe, infinite expansion or a big crunch, can be determined by using the redshifts and distances of very distant supernovae to monitor changes in the expansion rate. We can now find1 large numbers of these distant supernovae, and measure their redshifts and apparent brightnesses; moreover, recent studies of nearby type Ia supernovae have shown how to determine their intrinsic luminosities2,3,4—and therefore with their apparent brightnesses obtain their distances. The >50 distant supernovae discovered so far provide a record of changes in the expansion rate over the past several billion years5,6,7. However, it is necessary to extend this expansion history still farther away (hence further back in time) in order to begin to distinguish the causes of the expansion-rate changes—such as the slowing caused by the gravitational attraction of the Universe's mass density, and the possibly counteracting effect of the cosmological constant8. Here we report the most distant spectroscopically confirmed supernova. Spectra and photometry from the largest telescopes on the ground and in space show that this ancient supernova is strikingly similar to nearby, recent type Ia supernovae. When combined with previous measurements of nearer supernovae2,5, these new measurements suggest that we may live in a low-mass-density universe.

The concept of creativity: Prospects and paradigms.

Abstract: If one wanted to select the best novelist, artist, entrepreneur, or even chief executive officer, one would most likely want someone who is creative. Indeed, today many CEOs are selected not for their pleasant personalities (it's hard to be perceived as pleasant when you may have to fire 20% of the company) or their learning and memory skills (they use computers or subordinates to remember the details for them), but for their creative vision of how to turn a company around. Creativity is the ability to produce work that is both novel (i.e., original, unexpected) and appropriate (i.e., useful, adaptive concerning task constraints) (Lubart, 1994; Ochse, 1990; Sternberg, 1988a; Sternberg & Lubart, 1991, 1995, 1996). Creativity is a topic of wide scope that is important at both the individual and societal levels for a wide range of task domains. At an individual level, creativity is relevant, for example, when one is solving problems on the job and in daily life. At a societal level, creativity can lead to new scientific findings, new movements in art, new inventions, and new social programs. The economic importance of creativity is clear because new products or services create jobs. Furthermore, individuals, organizations, and societies must adapt existing resources to changing task demands to remain competitive.

Control of apoptosis and mitotic spindle checkpoint by survivin.

Abstract: Progression of the cell cycle and control of apoptosis (programmed cell death) are thought to be intimately linked processes, acting to preserve homeostasis and developmental morphogenesis. Although proteins that regulate apoptosis have been implicated in restraining cell-cycle entry and controlling ploidy (chromosome number), the effector molecules at the interface between cell proliferation and cell survival have remained elusive. Here we show that a new inhibitor of apoptosis (IAP) protein, survivin, is expressed in the G2/M phase of the cell cycle in a cycle-regulated manner. At the beginning of mitosis, survivin associates with microtubules of the mitotic spindle in a specific and saturable reaction that is regulated by microtubule dynamics. Disruption of survivin-microtubule interactions results in loss of survivin's anti-apoptosis function and increased caspase-3 activity, a mechanism involved in cell death, during mitosis. These results indicate that survivin may counteract a default induction of apoptosis in G2/M phase. The overexpression of survivin in cancer may overcome this apoptotic checkpoint and favour aberrant progression of transformed cells through mitosis.

Disruption of IRS-2 causes type 2 diabetes in mice

Abstract: Human type 2 diabetes is characterized by defects in both insulin action and insulin secretion. It has been difficult to identify a single molecular abnormality underlying these features. Insulin-receptor substrates (IRS proteins) may be involved in type 2 diabetes: they mediate pleiotropic signals initiated by receptors for insulin and other cytokines1. Disruption of IRS-1 in mice retards growth, but diabetes does not develop because insulin secretion increases to compensate for the mild resistance to insulin2,3. Here we show that disruption of IRS-2 impairs both peripheral insulin signalling and pancreatic β-cell function. IRS-2-deficient mice show progressive deterioration of glucose homeostasis because of insulin resistance in the liver and skeletal muscle and a lack of β-cell compensation for this insulin resistance. Our results indicate that dysfunction of IRS-2 may contribute to the pathophysiology of human type 2 diabetes.

Mutation detection and single-molecule counting using isothermal rolling-circle amplification

Abstract: Rolling-circle amplification (RCA) driven by DNA polymerase can replicate circularized oligonucleotide probes with either linear or geometric kinetics under isothermal conditions. In the presence of two primers, one hybridizing to the + strand, and the other, to the - strand of DNA, a complex pattern of DNA strand displacement ensues that generates 10(9) or more copies of each circle in 90 minutes, enabling detection of point mutations in human genomic DNA. Using a single primer, RCA generates hundreds of tandemly linked copies of a covalently closed circle in a few minutes. If matrix-associated, the DNA product remains bound at the site of synthesis, where it may be tagged, condensed and imaged as a point light source. Linear oligonucleotide probes bound covalently on a glass surface can generate RCA signals, the colour of which indicates the allele status of the target, depending on the outcome of specific, target-directed ligation events. As RCA permits millions of individual probe molecules to be counted and sorted using colour codes, it is particularly amenable for the analysis of rare somatic mutations. RCA also shows promise for the detection of padlock probes bound to single-copy genes in cytological preparations.

Equality of Opportunity

Abstract: The modern formulation of equality of opportunity emerges from discussions in political philosophy from the second half of the twentieth century beginning with Rawls (1971) and Dworkin, 1981a , Dworkin, 1981b . Equality of opportunity exists when policies compensate individuals with disadvantageous circumstances so that outcomes experienced by a population depend only on factors for which persons can be considered to be responsible. Importantly, inequality of opportunity for income exists when individuals’ incomes are in some important part determined by the educational achievement and income of the families that raised them. We review the philosophical debates referred to, commenting upon them from an economist's viewpoint. We propose several ways of modeling equality (or inequality) of opportunity, pointing out that an equal-opportunity ethic implies a non-welfarist way of ranking social outcomes. We propose that economic development should be conceived of as the equalization of opportunities for income in a country. We consider equalization of opportunity from a dynamic viewpoint, and we review popular attitudes with regard to distributive justice, showing that there is substantial popular support for an equal-opportunity ethic. We discuss the empirical issues that emerge in measuring inequality of opportunity and provide a review of the empirical literature that measures degrees of inequality of opportunity for the achievement of various objectives, in various countries.

Transition Metal Catalyzed Synthesis of Arylamines and Aryl Ethers from Aryl Halides and Triflates: Scope and Mechanism.

Abstract: Oxidative addition and reductive elimination are the central steps in new palladium-catalyzed chemistry that forms C–N and C–O bonds in arylamines and ethers. In the potential mechanism shown on the right the amine is formed by reductive elimination from a four-coordinate, 16-electron amido aryl complex. The use of a chelating ligand such as 1,1′-bis(diphenylphosphanyl)ferrocene (DPPF) reduces the occurrence of the competing β-hydrogen elimination. X=Br, I; R, R′=alkyl, aryl.

CD40 and CD154 in cell-mediated immunity.

Abstract: CD40-CD154-mediated contact-dependent signals between B and T cells are required for the generation of thymus dependent (TD) humoral immune responses. CD40-CD154 interactions are however also important in many other cell systems. CD40 is expressed by a large variety of cell types other than B cells, and these include dendritic cells, follicular dendritic cells, monocytes, macrophages, mast cells, fibroblasts, and endothelial cells. CD40- and CD154-knockout mice and antibodies to CD40 and CD154 have helped to elucidate the role of the CD40-CD154 system in immune responses. Recently published studies indicate that CD40-CD154 interactions can influence T cell priming and T cell-mediated effector functions; they can also upregulate costimulatory molecules and activate macrophages, NK cells, and endothelia as well as participate in organ-specific autoimmune disease, graft rejection, and even atherosclerosis. This review focuses on the role of the CD40-CD154 system in the regulation of many newly discovered functions important in inflammation and cell-mediated immunity.

Biological Action of Leptin as an Angiogenic Factor

Abstract: Leptin is a hormone that regulates food intake, and its receptor (OB-Rb) is expressed primarily in the hypothalamus. Here, it is shown that OB-Rb is also expressed in human vasculature and in primary cultures of human endothelial cells. In vitro and in vivo assays revealed that leptin has angiogenic activity. In vivo, leptin induced neovascularization in corneas from normal rats but not in corneas from fa/fa Zucker rats, which lack functional leptin receptors. These observations indicate that the vascular endothelium is a target for leptin and suggest a physiological mechanism whereby leptin-induced angiogenesis may facilitate increased energy expenditure.

International Momentum Strategies

Abstract: International equity markets exhibit mediumn-term return continuation. Between 1980 and 1995 an internationally diversified portfolio of past medium-term Winners outperforms a portfolio of medium-term Losers after correcting for risk by more than 1 percent per month. Return continuation is present in al:l twelve sample countries and lasts on average for about one year. Return continuation is negatively related to firm size, but is not limited to small firms. The international momentum returns are correlated with those of the United States which suggests that exposure to a common factor may drive the profitability of momentum strategies. MANY PAPERS HAVIE DOCUMENTED that average stock returns are related to past performance. Jegadeesh and Titman (1993) document that over mediumterm horizons performance persists: firms with high returns over the past three months to one year continue to outperform firms with low past returns over the same period. By contrast, DeBondt and Thaler (1985, 1987) document return reversals over longer horizons. Firms with poor three- to fiveyear past performance earn higher average returns than firms that performed well in the past. There has been an extensive literature on whether these return patterns reflect an improper response by markets to information, or whether they can be explained by market microstructure biases or by properly accounting for risk.' Fama and French (1996) show that long-term reversals can be consistent with a multifactor model of returns, but their model fails to explain medium-term performance continuation. Chan, Jegadeesh, and Lakonishok (1996) find that medium-term return continuation can be explained in part by underreaction to earnings information, but price momentum is not subsumed by earnings momentum. Return reversal and continuation are only two of many pat;terns that empirical researchers have uncovered using substantially the same database of U.S. stocks. It can therefore not be ruled out that these apparent anomalies are simply the outcome of an elaborate data snooping process. This paper is

Network Forms of Organization

Abstract: Initial sociological interest in network forms was motivated in part by a critique of economic views of organization. Sociologists sought to highlight the prevalence and functionality of organizational forms that could not be classified as markets or hierarchies. As a result of this work, we now know that network forms of organization foster learning, represent a mechanism for the attainment of status or legitimacy, provide a variety of economic benefits, facilitate the management of resource dependencies, and provide considerable autonomy for employees. However, as sociologists move away from critiquing what are now somewhat outdated economic views, they need to balance the exclusive focus on prevalence and functionality with attention to constraint and dysfunctionality. The authors review work that has laid a foundation for this broader focus and suggest analytical concerns that should guide this literature as it moves forward.

Efficient region tracking with parametric models of geometry and illumination

Abstract: As an object moves through the field of view of a camera, the images of the object may change dramatically. This is not simply due to the translation of the object across the image plane; complications arise due to the fact that the object undergoes changes in pose relative to the viewing camera, in illumination relative to light sources, and may even become partially or fully occluded. We develop an efficient general framework for object tracking, which addresses each of these complications. We first develop a computationally efficient method for handling the geometric distortions produced by changes in pose. We then combine geometry and illumination into an algorithm that tracks large image regions using no more computation than would be required to track with no accommodation for illumination changes. Finally, we augment these methods with techniques from robust statistics and treat occluded regions on the object as statistical outliers. Experimental results are given to demonstrate the effectiveness of our methods.

Acetylcholine receptors containing the β2 subunit are involved in the reinforcing properties of nicotine

Abstract: Release of the neurotransmitter dopamine in the mesolimbic system of the brain mediates the reinforcing properties of several drugs of abuse, including nicotine1. Here we investigate the contribution of the high-affinity neuronal nicotinic acetylcholine receptor2 to the effects of nicotine on the mesolimbic dopamine system in mice lacking the β2 subunit of this receptor3. We found that nicotine stimulates dopamine release in the ventral striatum of wild-type mice but not in the ventral striatum of β2-mutant mice. Using patch-clamp recording, we show that mesencephalic dopaminergic neurons from mice without the β2 subunit no longer respond to nicotine, and that self-administration of nicotine is attenuated in these mutant mice. Our results strongly support the idea that the β2-containing neuronal nicotinic acetylcholine receptor is involved in mediating the reinforcing properties of nicotine.

Phylogeny and PCR–based classification of Wolbachia strains using wsp gene sequences

Abstract: Wolbachia are a group of intracellular inherited bacteria that infect a wide range of arthropods. They are associated with a number of different reproductive phenotypes in their hosts, such as cytoplasmic incompatibility, parthenogenesis and feminization. While it is known that the bacterial strains responsible for these different host phenotypes form a single clade within the α–Proteobacteria, until now it has not been possible to resolve the evolutionary relationships between different Wolbachia strains. To address this issue we have cloned and sequenced a gene encoding a surface protein of Wolbachia ( wsp ) from a representative sample of 28 Wolbachia strains. The sequences from this gene were highly variable and could be used to resolve the phylogenetic relationships of different Wolbachia strains. Based on the sequence of the wsp gene from different Wolbachia isolates we propose that the Wolbachia pipientis clade be initially divided into 12 groups. As more sequence information becomes available we expect the number of such groups to increase. In addition, we present a method of Wolbachia classification based on the use of group–specific wsp PCR primers which will allow Wolbachia isolates to be typed without the need to clone and sequence individual Wolbachia genes. This system should facilitate future studies investigating the distribution and biology of Wolbachia strains from large samples of different host species.

The minimum description length principle in coding and modeling

Abstract: We review the principles of minimum description length and stochastic complexity as used in data compression and statistical modeling. Stochastic complexity is formulated as the solution to optimum universal coding problems extending Shannon's basic source coding theorem. The normalized maximized likelihood, mixture, and predictive codings are each shown to achieve the stochastic complexity to within asymptotically vanishing terms. We assess the performance of the minimum description length criterion both from the vantage point of quality of data compression and accuracy of statistical inference. Context tree modeling, density estimation, and model selection in Gaussian linear regression serve as examples.

A Behavioral Approach to Law and Economics

Abstract: Economic analysis of law usually proceeds under the assumptions of neoclassical economics. But empirical evidence gives much reason to doubt these assumptions; people exhibit bounded rationality, bounded self-interest, and bounded willpower. This article offers a broad vision of how law and economics analysis may be improved by increased attention to insights about actual human behavior. It considers specific topics in the economic analysis of law and proposes new models and approaches for addressing these topics. The analysis of the article is organized into three categories: positive, prescriptive, and normative. Positive analysis of law concerns how agents behave in response to legal rules and how legal rules are shaped. Prescriptive analysis concerns what rules should be adopted to advance specified ends. Normative analysis attempts to assess more broadly the ends of the legal system: Should the system always respect people's choices? By drawing attention to cognitive and motivational problems of both citizens and government, behavioral law and economics offers answers distinct from those offered by the standard analysis.

Attitude change: Multiple roles for persuasion variables.

Abstract: OVERVIEW The O.J. Simpson " trial of the century " in the mid-1990s captured the attention of the American populace more than any other public spectacle since the kidnaping of the Lindberg baby in the 1920s. A prominent football player and popular sportscaster was charged with a gruesome double homicide. The attorneys for the prosecution and defense were of various races and genders. The evidence presented on each side was at times amazingly simple, visual, and emotional, and at times was verbal, abstract, and probably incomprehensible to jurors. The witnesses included individuals of diverse styles, demeanors, and credibility. The jurors, the recipients of the messages from these various sources, were themselves a mixed group of people of diverse backgrounds, beliefs, and personal experiences who had to sift through the trial material and arrive at a decision as to whether the defendant had been proven guilty or not. The context in which all of this took place was at times tense and sad, and at times filled with humor and positive feelings. Not surprisingly, no experiment has ever captured the extraordinary complexity inherent in this situation, yet almost all of the variables present in this trial (and many not present) have been examined in the social psychological literature on attitude formation and change. This chapter provides an overview of research on these diverse variables and addresses the processes by which these variables are thought to result in influence. Although it has become a cliché to say that the attitude construct is the most indispensable concept in contemporary social psychology, this statement appears as true today as when Allport (1935) initially wrote it in reviews of the attitude concept). Attitudes remain important as we enter the 21st century because of the fundamental role that individuals' attitudes, both explicit and implicit (Greenwald & Banaji, 1995), play in the critical choices people make regarding their own health and security as well as those of their families, friends, and nations. From purchase decisions provoked by liking for a product to wars spurned by ethnic prejudices, attitudes help to determine a wide variety of potentially consequential outcomes. Before turning to the relevant studies, it is useful to address some definitional issues. The term attitude is used to refer to a person's overall evaluation of persons (including oneself), objects, and issues. Thus, one's attitude refers to how favorably or unfavorably or how positively or negatively in general …

Temporal Cortex Activation in Humans Viewing Eye and Mouth Movements

Abstract: We sought to determine whether regions of extrastriate visual cortex could be activated in subjects viewing eye and mouth movements that occurred within a stationary face. Eleven subjects participated in three to five functional magnetic resonance imaging sessions in which they viewed moving eyes, moving mouths, or movements of check patterns that occurred in the same spatial location as the eyes or mouth. In each task, the stimuli were superimposed on a radial background pattern that continually moved inward to control for the effect of movement per se. Activation evoked by the radial background was assessed in a separate control task. Moving eyes and mouths activated a bilateral region centered in the posterior superior temporal sulcus (STS). The moving check patterns did not appreciably activate the STS or surrounding regions. The activation by moving eyes and mouths was distinct from that elicited by the moving radial background, which primarily activated the posterior-temporal-occipital fossa and the lateral occipital sulcus—a region corresponding to area MT/V5. Area MT/V5 was also strongly activated by moving eyes and to a lesser extent by other moving stimuli. These results suggest that a superior temporal region centered in the STS is preferentially involved in the perception of gaze direction and mouth movements. This region of the STS may be functionally related to nearby superior temporal regions thought to be involved in lip-reading and in the perception of hand and body movement.

Mechanisms of mhc class i-restricted antigen processing

Abstract: ▪ Abstract Classical class I molecules assemble in the endoplasmic reticulum (ER) with peptides mostly generated from cytosolic proteins by the proteasome. The activity of the proteasome can be modulated by a variety of accessory protein complexes. A subset of the proteasome β-subunits (LMP2, LMP7, and MECL-1) and one of the accessory complexes, PA28, are upregulated by γ-interferon and affect the generation of peptides to promote more efficient antigen recognition. The peptides are translocated into the ER by the transporter associated with antigen processing (TAP). A transient complex containing a class I heavy chain–β2 microglobulin (β2m) dimer is assembled onto the TAP molecule by successive interactions with the ER chaperones calnexin and calreticulin and a specialized molecule, tapasin. Peptide binding releases the class I–β2m dimer for transport to the cell surface, while lack of binding results in proteasome-mediated degradation. The products of certain nonclassical MHC-linked class I genes bind p...