Showing papers by "American Association for the Advancement of Science published in 2002"

How well do middle school science programs measure up? Findings from Project 2061's curriculum review

Abstract: The purposes of this study were to examine how well middle school programs support the attainment of key scientific ideas specified in national science standards, and to identify typical strengths and weaknesses of these programs using research-based criteria. Nine widely used programs were examined by teams of teachers and specialists in research on teaching and learning. Reviewers found that whereas key ideas were generally present in the programs, they were typically buried between detailed or even unrelated ideas. Programs only rarely provided students with a sense of purpose for the units of study, took account of student beliefs that interfere with learning, engaged students with relevant phenomena to make abstract scientific ideas plausible, modeled the use of scientific knowledge so that students could apply what they learned in everyday situations, or scaffolded student efforts to make meaning of key phenomena and ideas presented in the programs. New middle school science programs that reflect findings from learning research are needed to support teachers better in helping students learn key ideas in science. The criteria and findings from this study on the inadequacies in existing programs could serve as guidelines in new curriculum development. 2002 Wiley Periodicals, Inc. J Res Sci Teach 39: 522-549, 2002 Whereas curriculum materials (and in particular textbooks and their accompanying teacher's guides) are but one of the resources available to teachers, they have a major role in teaching and learning. Many teachers rely on them to provide some or all of their content and pedagogical content knowledge, and this is especially so when the teacher is a novice or is teaching outside his or her area of expertise (Ball & Feiman-Nemser, 1988; National Educational Goals Panel, 1994). Acknowledging their role in teaching and learning, both science education researchers and policy makers have called for systematic, research-based reviews of science curriculum materials as a means for improving their quality, influencing teacher practice, and supporting science education reform (Good, 1993; National Research Council (NRC), 1999, 2000b).

Mitf and Tfe3, two members of the Mitf-Tfe family of bHLH-Zip transcription factors, have important but functionally redundant roles in osteoclast development

Abstract: The Mitf-Tfe family of basic helix–loop–helix-leucine zipper (bHLH-Zip) transcription factors encodes four family members: Mitf, Tfe3, Tfeb, and Tfec. In vitro, each protein in the family can bind DNA as a homo- or heterodimer with other family members. Mutational studies in mice have shown that Mitf is essential for melanocyte and eye development, whereas Tfeb is required for placental vascularization. Here, we uncover a role for Tfe3 in osteoclast development, a role that is functionally redundant with Mitf. Although osteoclasts seem normal in Mitf or Tfe3 null mice, the combined loss of the two genes results in severe osteopetrosis. We also show that Tfec mutant mice are phenotypically normal, and that the Tfec mutation does not alter the phenotype of Mitf, Tfeb, or Tfe3 mutant mice. Surprisingly, our studies failed to identify any phenotypic overlap between the different Mitf–Tfe mutations. These results suggest that heterodimeric interactions are not essential for Mitf-Tfe function in contrast to other bHLH-Zip families like Myc/Max/Mad, where heterodimeric interactions seem to be essential.

Views to a Kill: Exploring the Implications of Source Selection in the Case of Guatemalan State Terror, 1977-1995

Abstract: To investigate the implications of source selection, three different sources regarding Guatemalan state terror are compared: newspapers, human rights documents, and interviews with eyewitnesses. Results show that each source pays attention to diverse types and aspects of repression in line with the objectives of the observer, the characteristics of the repressive events, and the overall political context within which events take place. Who is consulted influences what is observed/recorded. Suggestions are presented for understanding sociopolitical behavior through diverse data sources, especially behavior related to contentious activity and/or occurring within contexts that are not easily penetrable.

Analysis of students' assessments in middle school curriculum materials: Aiming precisely at benchmarks and standards

Abstract: Assessment influences every level of the education system and is one of the most crucial catalysts for reform in science curriculum and instruction. Teachers, administrators, and others who choose, assemble, or develop assessments face the difficulty of judging whether tasks are truly aligned with national or state standards and whether they are effective in revealing what students actually know. Project 2061 of the American Association for the Advancement of Science has developed and field-tested a procedure for analyzing curriculum materials, including their assessments, in terms of how well they are likely to contribute to the attainment of benchmarks and standards. With respect to assessment in curriculum materials, this procedure evaluates whether this assessment has the potential to reveal whether students have attained specific ideas in benchmarks and standards and whether information gained from students' responses can be used to inform subsequent instruction. Using this procedure, Project 2061 had produced a database of analytical reports on nine widely used science middle school curriculum materials. The analysis of assessments included in these materials shows that whereas currently available materials devote significant sections in their instruction to ideas included in national standards documents, students are typically not assessed on these ideas. The analysis results described in the report point to strengths and limitations of these widely used assessments and identify a range of good and poor assessment tasks that can shed light on important characteristics of good assessment. © 2002 Wiley Periodicals, Inc. J Res Sci Teach 39: 889–910, 2002

Performance Measurement Redux

Abstract: Recent developments in the United States in the use of performance measurement in science policy and higher education are used to comment further on the Perrin–Bernstein–Winston debate about the effective use and misuse of performance measurement. Particular attention is given to the influence of political/organizational factors and the production processes of agencies on how performance measures are constructed and used. The analysis points to further limitations in the use of performance measurement. In both cases, long-gestating, probabilistic linkages between outputs and outcomes limit the usefulness of mainstream indicators as a measure of current agency performance and as a guide to major, discontinuous resource allocation decisions. Conspicuously absent from many performance measurement undertakings are provisions for evaluating the impact of the undertakings themselves. An updated account of the status of the Government Performance and Results Act (GPRA) indicates that the Act has not had the impacts predicted for it.

The Case of Carla: Dilemmas of Helping All Students to Understand Science

Abstract: This paper tells the story of four sixth-grade students, of mixed race and social class, who worked together in a small group. All four students were intrigued as they experimented with colored solutions of different densities. They all wanted to share ideas about the techniques they had used, the observations they had made, and the patterns they had seen. They all wanted to understand why the colored solutions acted as they did. In spite of these common interests, they often failed to achieve intersubjective communication about the colored solutions or about the process of planning and making a poster to report their findings. We explain these failures using the sociolinguistic concepts of polysemy, privileging, and holding the floor. In particular, Carla (an African American girl) was unable to hold the floor within the group, so her opportunities for science learning were diminished. The four students were not overtly prejudiced in their speech or actions. Yet the expectations they brought with them about how and when people should talk, how work should be done, and what standards of quality they should aspire to led them to reconstruct among themselves some of the most troubling inequities of our society as a whole. This story is about important connections. In particular it is about how the actions of children are connected to the histories of their families, and how the privileging of ideas is connected to that of people, and how the practice of science is connected to that of discrimination. Science education reformers may underestimate the difficulty of separating conceptual conflict about ideas from interpersonal conflict about privilege and status. © 2002 Wiley Periodicals, Inc. Sci Ed86:287–313, 2002; Published online in Wiley Interscience (www.interscience.wiley.com). DOI 10.1002/sce.10009

Patents and Innovation in Cancer Therapeutics: Lessons from CellPro

Abstract: How scientific knowledge is translated into diagnostic and therapeutic tools is important to patients with dread diseases as well as to regulators and policymakers. Patents play a crucial role in that process. Indeed, concern that the fruits of federally funded research would languish without commercial application led to the passage of the Bayh-Dole Act (PL 96-517), which reinforced incentives to patent the results of inventions arising from federally funded research (Eisenberg 1996). Subsequently, rates of patenting among U.S. academic institutions have increased (Henderson, Jaffe, and Trajtenberg 1988). A recent survey by the Association of University Technology Managers counted 20,968 licenses and options from 175 academic institutions and 6,375 patent applications filed in fiscal year 2000 (Pressman 2002). Analysis suggests that the number of academic patents was already rising when the Bayh-Dole Act was passed in 1980 (Mowery et al. 2001), but it is clear that the act reinforced the patenting norm in research universities and mandated a technology transfer infrastructure at those universities that had not yet established a technology licensing office. Several concerns were raised when the Bayh-Dole Act was debated. First, patents have a potential danger, as they can be used to block products from the market and protect monopolies. Indeed, establishing a limited monopoly is the very purpose of patenting. The Bayh-Dole Act thus includes a provision intended to limit monopoly rights when they might undermine public health. Under certain circumstances, government agencies can “march in” to protect the public interest. The second concern refers to the impact of patenting on open science and academic norms. This was not heavily debated before Bayh-Dole passed, in part because the act's central focus was on small businesses and nonprofits rather than academic institutions. Now, however, the possible untoward effects of academic research institutions pursuing their business interests while hindering access to research tools and reducing open publication are receiving attention (R.R. Nelson, personal communication, January 2002). We present in this article a case study of intellectual property that affected cancer treatment. The case concerns the rise and demise of CellPro, which developed cell separation devices for making stem cell suspensions for bone marrow transplantation. CellPro was a Seattle-area start-up firm founded to develop the technology. The firm was the first to market and secure the approval of the U.S. Food and Drug Administration (FDA) of a cell separation device, but it ultimately went bankrupt and sold its technology assets after losing a patent battle with Johns Hopkins University, Baxter Healthcare Corporation, and Becton-Dickinson & Company. We address how patent law and science claimed this discovery in different ways and for different purposes. The CellPro case was the first time that any federal agency—in this case, the National Institutes of Health (NIH)—was petitioned to “march in” to compel licensing under Bayh-Dole. The relevant patents were owned by Johns Hopkins and exclusively licensed (and sublicensed) to large medical device firms. The case shows the Bayh-Dole statute in action and illustrates the role of patents, particularly the importance of patent licensing practices. We begin by describing the events according to the accounts of different stakeholders, then turn to observations about the policy decisions made during this process, and conclude with options for policy change. The story starts with the personal involvement of CellPro's former CEO, Rick Murdock, whose mantle cell lymphoma was treated clinically with CellPro's Ceprate instrument. The account continues through two federal district court trials in Delaware, presided over by Judge Roderick McKelvie, followed by the review of those decisions by the Court of Appeals for the Federal Circuit, which hears appeals for all patent cases in the United States. While the second trial was under way, CellPro petitioned the federal government to “march in” and compel the licensing of the Hopkins patents. We then look at the role of Johns Hopkins and make some observations about licensing and the role of federally funded research under the Bayh-Dole statute. Patents are important, and for Johns Hopkins University, they were a source of revenue. For the large device firms, particularly Baxter, patents protected them from competition and fostered investment in developing a cell separation device. For CellPro, however, the Hopkins patents spelled doom. Indeed, patents, particularly for pharmaceuticals, are coming under increased scrutiny throughout the world. Our purpose here is not to prove that patents are either good or bad but to show how patents encourage investment in research and development and can also hinder innovation. Their net impact on social welfare is uncertain. This article examines three features of patents: (1) the breadth of patent claims; (2) the way that patents are licensed and sublicensed, which is influenced by owners and licensees; and (3) the secrecy that limits accountability to the public, even when inventions result in part from federal funding and are conducted at academic institutions whose core values are open discourse and the creation and dissemination of knowledge. For two decades, under the Bayh-Dole statute, universities have drifted into practices that can pit their business interests against their academic values. The CellPro story raises difficult questions about the use of federally funded research and university-based intellectual property. It also shows how patent law may or may not play out differently in medical fields than it has in other high-tech economic sectors. Enhancing or obstructing computer technology or automobile manufacture is different from quashing a firm producing a life-saving cancer drug or device. Cancer therapeutics are subject to an additional layer of moral (and political) analysis. Although the principles of traditional patent law still apply, they collide with norms of fairness more often, and sometimes with greater effect, than they have done in other high-tech fields. Our story starts from Claim 1 of U.S. patent 4,965,204, issued and assigned to Johns Hopkins University on October 23, 1990: “A monoclonal antibody which specifically binds to an antigen on non-malignant, immature human marrow cells, wherein said antigen is stage specific and not lineage dependent, and said antigen is also specifically bound by the antibody produced by the hybridoma deposited under ATCC Accession No. HB-8483.”1 The syntax and circumlocution are typical of patent claims, which are constructed as factual assertions linked by verbs that may sound like standard English but often have a specific legal meaning. (For example, a DNA sequence “comprising” ACTG refers to any sequence that includes that sequence within it, whereas “consisting of” ACTG means exactly and only ACTG. That is, “comprising” has a much broader scope than “consisting of” does.) Awkward sentences like these can be worth billions of dollars. Claims define the boundaries of the intellectual property that its inventor controls. Patents cost tens of thousands of dollars to obtain (and many times that amount for worldwide rights) and can cost millions to defend in litigation. For example, the legal fight over patents on recombinant insulin cost around $30 million (Marshall 1997). In our story, Claim 1 killed CellPro and thereby eliminated Baxter's competitor, increased the price (and presumably Baxter's profits), and suppressed an alternative technological approach to cell separation devices. CellPro's technology now belongs to its nemesis, Baxter.

Contact‐dependent demyelination by mycobacterium leprae in the absence of immune cells

Abstract: Demyelination results in severe disability in many neurodegenerative diseases and nervous system infections, and it is typically mediated by inflammatory responses. Mycobacterium leprae, the causative organism of leprosy, induced rapid demyelination by a contact-dependent mechanism in the absence of immune cells in an in vitro nerve tissue culture model and in Rag1-knockout (Rag1(−/−)) mice, which tack mature B and T lymphocytes. Myelinated Schwann cells were resistant to M. leprae invasion but undergo demyelination upon bacterial attachment, whereas nonmyelinated Schwann cells harbor intracellular M. leprae in large numbers. During M. leprae-induced demyelination, Schwann cells proliferate significantly both in vitro and in vivo and generate a more nonmyelinated phenotype, thereby securing the intracellular niche for M. leprae.

Confronting Demographic Denial

Abstract: (2002). Confronting Demographic Denial. Journal of Museum Education: Vol. 27, With, Not For: Redefining Community Relationships, pp. 3-6.

Mapping cellular signaling.

Abstract: Cellular signaling is an area of extensive and active research. It is also a complex topic, with information from many different cell types and organisms all contributing to the plethora of data available in this multidisciplinary field. In this issue, "Mapping Cellular Signaling," Science ( ) and STKE bring you a series of roadmaps to some signaling processes important in many cell types, signaling specific to immune cells, signaling in development and neural differentiation, and signaling in plants. The Viewpoints in Science provide both a broad overview of exciting developments in the field and new insights into the biological relevance, whereas the associated Connections Maps provide details about the molecular components involved in these pathways. The Connections Map database is intended to provide a mechanism by which potentially overwhelming amounts of information on signal transduction can be organized by experts in the field in way that is accessible to a broad audience of both experts and novices. [The Connections Maps][1] are dynamic interactive entry points for the information that is contained in the underlying database. This information represents a compendium of expert knowledge about the components involved in receiving, processing, and transmitting cellular signaling events and the relations between these components. The components are organized into pathways, allowing the interactions between components to be illustrated and allowing a convenient visual tool for beginning to understand the complexity of cellular signaling systems. The pathways are more simplified than what actually occurs within any given cell, but they help to place components into a context for understanding cellular functions. Experts in the field, whom we call Pathway Authorities, supply the data about the components, their relations, and the pathways in which they occur. This information is updated as often as is deemed necessary by the authority. New information in the database is immediately available through the Connections Maps because of the dynamic interface between the database and the Connections Maps as viewed at STKE. In order to understand the presentation of the information through the Connections Maps, it is helpful to understand the underlying structure for the information in the database. The information in the Connections Maps is organized into categories we call "canonical" and "specific." Canonical information is based on consensus knowledge from many cell types in many organisms. Specific information represents the details about a specific component as it exists in a particular cell at a particular developmental stage in a particular organism. The basic element in the Connections Map database is a component, which can be either canonical or specific, and which represents the basic attributes of that signaling entity. Components are pathway-independent in that they are found in nature (and in the Connections Maps) incorporated into multiple pathways. Once a component is incorporated into a pathway by an authority, we create a new data record to store information that is relevant to the function of that component in the context of the particular pathway. Thus, the component now has two associated records: (i) the general or pathway-independent information and (ii) pathway-dependent information that pertains to its occurrence in a particular pathway, but may not be generalizable to that component's roles in other pathways. In addition to information about the components, the database contains information about the interactions among components. The information about the components and the relations between components is elucidated with a combination of natural language descriptions, attributes defined by terms in controlled vocabularies, selected references, and links to external databases, such as the Entrez database of gene and protein sequences and FlyBase. The pathways presently in the Connections Maps represent a small fraction of the total we expect to amass. These pathways were started by scientists willing to be pioneers in this novel method for systematizing information and in this new form of authorship. Authorities are at work on many more pathways, including mitogen-activated protein kinase pathways, specific G protein-coupled receptor pathways, intrinsic apoptosis pathways, and many others. The editors and Authorities invite you to explore the pathways. Although each of the pathways highlighted in this week's focus issue has been reviewed by scientists in the field, the community is encouraged to send in feedback that will help validate and authenticate the information in the database, and thus to join us in the process of building what promises to be an incredible resource for scientists, educators, students, or anyone interested in cellular regulation. [1]: http://stke.sciencemag.org/cm/

Moving the Earth

Abstract: Galileo’s discoveries about motion formed a major part of a much larger development across all of the sciences, a development now known as the Scientific Revolution. In the study of the physical world, the science of motion, or mechanics, joined with the science of astronomy to form the basic approach to modern physics. Paralleling the revolution in mechanics, the revolution in astronomy involved an extremely difficult transition for most people from the common-sense view of the Universe in which the Earth is stationary at the center of the Universe to our current, more abstract, view that the Earth is actually spinning on its axis as it orbits around a star, our Sun, as the third planet. Since the Earth was now seen as a moving object, the revolution in mechanics helped to encourage the revolution in astronomy, and vice versa. This chapter looks at the parallel developments in astronomy, before turning to the causes of motion in the next chapter.

The Puzzle of Complex Disease: The Signaling Piece

Abstract: Humans are complicated biological systems with a natural tendency to try to maintain a healthy and "normal" physiological state. A diseased condition can arise from a multitude of perturbations of this homeostatic scenario. These perturbations can be the result of genetic, environmental, or behavioral factors, or a combination of these. Discussed in this week's issue of Science The Puzzle of Complex Diseases ( ) is the tremendous challenge to understanding how complex "multifactorial" diseases, such as heart disease, diabetes, and cancer, evolve and how they can be effectively treated. How do clinical advances occur and where does signal transduction knowledge fit in? According to the Science Viewpoint by Rees ( ), there is no simple correspondence between genotype and phenotype in a complex disease situation. Observing patient responses to treatments and paying attention to potential side effects of treatments can even provide unexpected insights into the progression of other complex diseases. For example, retinoids, now widely used to treat skin disorders, were initially used in the clinic for a different application. Whereas the clinic provides the opportunity to observe patient responses to therapeutic interventions and discover physiological connections, bench research can provide comprehensive information on genes, proteins, and signaling networks relevant to disease pathology. This mechanistic insight into complex disease development can lead to strategies for the design of specific drugs. In a STKE Perspective, Liebman ( ) explains an approach that integrates both clinical data with experimental findings, and the challenges to such an attempt. Many examples now exist where the underlying genetic defects for a disorder or cellular regulatory processes affected during disease progression have been uncovered. One example described by Courtois and Israel ( ) in a Perspective from the STKE Archive is the nature of the epidermal disorder called incontinentia pigmenti, which has been gleaned from understanding the regulation of the transcription factor NF-κB. Other examples where understanding the cellular signaling network may assist in therapeutic intervention are the hypermetabolic disease cachexia, and type II diabetes. In the STKE Perspective, Tracey ( ) describes a number of signaling molecules (including tumor necrosis factor and interferon gamma) that are implicated in cachexia and that may be a guide to future therapeutic strategies. In the STKE Archive, a Perspective by Rangwala and Lazar ( ) describes new therapuetic agents that affect the nuclear hormone receptor peroxisome proliferator-activated receptor γ, which is the target for anitdiabetic drugs used to treat type II diabetes. In a Science Viewpoint, Strohman ( ) discusses how the application of a systems approach to understanding biological processes, such as metabolism, may aid in making useful predictions about complex diseases. Systems approaches to cellular signaling networks on a more basic level is the topic of the Perspectives by Lok ( ) and Ashman et al . ( ) in the STKE Archive. Complex diseases include psychiatric disorders, heart disease, and cancer. The descriptive profile of the psychiatric disorder schizophrenia now includes signaling through the N -methyl-D-aspartate (NMDA)-subtype of glutamate receptors, described in the Review by Sawa and Snyder ( ) in Science . This complex disease puzzle may also include modulators of NMDA receptors, such as the neurosteroids described by Gibbs and Farb ( ) and by Tasker ( ) in Perspectives available in the STKE archive. The complexities of some heart conditions are now beginning to be understood at cellular and molecular levels. A Perspective by Fozzard and Kyle ( ) describes how alteration of ion channel glycosylation underlies abnormalities characteristic of cardiac arrhythmias, and a Review in the STKE archive by Xiao ( ) describes the role of β-adrenergic receptor signaling in chronic heart failure. Cancer presents one of the most complex disease progressions from initial cellular transformation to metastasis and colonization of new tumor sites. A Protocol by Dong and Cmarik ( ) describes how cells can be isolated for analysis to study the molecular and biochemical events associated with cellular transformation. In the STKE archive, the Review by Mastumoto and Claesson-Welch ( ) describes the molecular pathways leading to angiogenesis, the inhibition of which is a major avenue being pursued for cancer treatments. No single discipline or approach alone will likely solve the puzzle of complex diseases. Insights into signaling mechanisms have surely provided many essential pieces and, hopefully, will help in the synthesis of more effective diagnoses and treatments in the future. Featured in This Focus Issue on The Puzzle of Complex Diseases Related Resources at STKE

The Electric Age

Abstract: In Chapter 6, we discussed the development of steam engines during the eighteenth and nineteenth centuries. These engines enabled industrialization by making available the vast stores of energy contained in coal, wood, and oil. By burning fuel, chemical energy is converted into heat energy, which in turn can be used to boil water to produce steam. By letting the steam expand against a piston or a turbine blade, heat energy can be converted to mechanical energy. In this way, a steam engine can power machinery.

Mapping the Steps toward Basic Understanding of Scientific Inquiry

Abstract: Benchmarks for Science Literacy (AAAS 1993) lists for four gradelevels the steps by which students might achieve science literacy before leaving high school. These steps and the conceptual connections among them are now being “mapped” to suggest where anyone idea or skill comes from, what it is connected to, and where it leads. A set of 49 such “strand maps” appears in Atlas of Science Literacy (AAAS 2001). This paperdescribes strand maps in general and examinesthree draft maps titled Evidence and Reasoning, Scientific Investigations, and Scientific Theories, which together represent one section of Benchmarks Chapter 1, on scientific inquiry. The maps do not prescribe any particular curriculum, but can aid in planning a variety of curricula, analyzing instructional materials, assessing student understanding, and can be used in professional development for teachers.

Probing the Atom

Abstract: It has been hypothesized for millennia that all matter is made of tiny, indivisible, smallest bits of matter called atoms. Great progress had been made during the nineteenth century in attributing the thermodynamic laws and some of the properties of matter, especially gases, to the kinetic-molecular theory (Chapter 7). In addition, it was known for centuries that there are different types of so-called fundamental “elements” in nature—gold, silver, copper, sodium, etc. There are the smallest units into which substances can be divided by chemical means. Eventually it was found useful to give the elements special symbols, for example, “C” for carbon, “O” for oxygen, “H” for hydrogen, and so on.

Tracking sequestered carbon in the timber trade

Abstract: The most recent meeting discussing the Kyoto Protocol focused on market-based mechanisms to reduce greenhouse gases. This could pave the way for initiatives that allow polluters to offset their emissions if they buy carbon sequestered through reforestation (Sandalow & Bowles 2001). But rather than lose credit when the trees are harvested, investors must continue to track the sequestered carbon once trees become timber. I examined trade statistics for the best-tracked timber species, namely mahogany, Swietenia macrophylla King (Meliaceae). Although mahogany is regulated by one of the most restrictive trade agreements, the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES), I found discrepancies in USA trade statistics of c. 30%, representing c. US$ 100 million over the last 4 years. For comparison, I also calculated differences in trade data for all sawnwood, according to the United Nations Food and Agricultural Organization (FAO); discrepancies between USA and exporter reports were c. 38%. Large accounting problems must be solved before sequestered carbon should become a globally traded commodity.

Reflections on Self: Self-Serving Signals

Abstract: This week's issue of Science presents a special section on the concept of self-descrimination entitled Reflections on Self: Immunity and Beyond. At a general level, the concept of "self" can be viewed in many diverse ways, ranging from the philosophical self [me, myself, and I; see the Viewpoint by Churchland ( )], the sociological self [identity within a community; see the Viewpoint by Queller and Strassmann ( )], and the ethical self [as it pertains to scientific issues, such as cloning; see the Viewpoint by Brock ( )], to the immunological self and the many fundamental processes of the immune system that are constantly surveying for signs of nonself that might signal and infection [see Viewpoints by Medzhitov and Janeway ( ) and by Matzinger ( )]. What is surprisingly common to some of these areas is that the concept of self has co-evolved with experimental discoveries that have offered breakthroughs in cell signaling. New hypotheses regarding higher biological functions in the context of self and nonself have arisen from new knowledge of signaling pathways and networks, in disciplines from brain and behavioral neuroscience to immunology. The immune system is the quintessential self and nonself recognition system in biology. In fact, Medzhitov and Janeway explain that the innate immune system of vertebrates can handle foreignness through multiple strategies. These include recognition of nonself or pathogen-associated molecules by specialized cells, recognition of what the authors call "missing self" or removal of cells that don't display proper a self signal, and recognition of "induced self" such as markers of transformed or apoptotic cells. Many of these signaling cascades have been well characterized, and Reviews by O'Neill ( ) and McVicar and Burshtyn ( ) in the STKE Archive describe the evolutionarily conserved Toll-like receptors that function in host defense and the intricate receptor system of the executioner natural killer cells, respectively. A Perspective by Richter and Duckett ( ) in the STKE Archive also discusses IAPs (inhibitors of apoptosis), molecules first identified in viruses able to subvert apoptosis in infected cells. In the Science Viewpoint, Matzinger suggests that the model of tolerating self and attacking nonself is too simplistic today, and proposes that understanding the many layers of immune cells and signals that are called upon from both the adaptive and innate immune systems requires a more network-based model. Indeed, orchestrating such a network requires recruiting the appropriate lymphocytes to locations harboring foreign or modified self-antigens, and in the STKE Review, Bismuth and Boumsell ( ) comment on how semaphorin molecules of the immune system may be critical guidance controls for such encounters. Zell and Jenkins ( ) offer a technique to study T cell receptor-mediated signal transduction ex vivo under conditions that more accurately reflect a T cell's encounter with an antigen-presenting cell. Finally, a Perspective by Rudd et al . ( ) discusses how the T cell co-receptor CTLA-4 may regulate the presence of lipid rafts on the cell surface, thereby controlling T cell activation. Membrane microdomains, such as lipid rafts, are thought to localize signaling molecules that are activated by the T cell receptor. Interestingly, CTLA-4 is also thought to localize at the immunological synapse, the interaface between a T cell and an antigen-presenting cell. More information on lipid rafts, the immunological synapse, and T cell receptor signaling can be found in the STKE Archive of Perspectives, Reviews, and Protocols (see below). You can also explore detailed signaling pathway information at the Connections Maps on T cell signaling by Koretzky and Singer ([http://stke.sciencemag.org/cgi/cm/CMP_7019][1]), B cell signaling by Gauld et al . ([http://stke.sciencemag.org/cgi/cm/CMP_6909][1]), tumor necrosis factor (TNF) signaling by Chen and Goeddel ([http://stke.sciencemag.org/cgi/cm/CMP_7107][1]), and the Jak-STAT pathways by Aaronson and Horvath [Jak-STAT canonical pathway ([http://stke.sciencemag.org/cgi/cm/CMP_8301][1]), Type I interferon pathway ([http://stke.sciencemag.org/cgi/cm/CMP_8390][1]), STAT3 pathway ([http://stke.sciencemag.org/cgi/cm/CMP_9229][1]), and Interferon gamma pathway ([http://stke.sciencemag.org/cgi/cm/CMP_9590][1])]. Featured in This Focus Issue on Self and Nonself Related Resources at STKE [1]: pending:yes

Focus Issue: The Kinome--Techniques and Methods for Analysis

Abstract: A Review in this week's issue of Science represents a landmark for the field of signal transduction. Manning et al . provide analysis of the complete set of human protein kinases--and the coining of the inevitable terminology, "the human kinome." Science , STKE, and sponsors Cell Signaling Technology, Inc., and Sugen, Inc., also mark the occasion with a pull-out poster displaying a phylogenetic tree with all 518 enzymes. Related new and archived material is also provided at STKE. One cannot be certain at this stage that each and every kinase has been uncovered, but for most intents and purposes, the full extent of this critical set of signaling regulators is now evident. This allows comparison with the related complements of enzymes from other organisms for which (relatively) complete genomic sequences are known. The authors turn up over 60 enzymes not previously described. The implications of the work are dramatic, both in terms of basic science and the application of that science to development of new therapeutics. For example, four families of functionally uncharacterized kinases are evident in the human genome, and these have orthologs in flies and worm. This presumably indicates that the proteins are conserved to serve an important function, but no biological role has yet been described. The value of detailed understanding of the protein kinases and their inhibitors could hardly be more apparent than after the phenomenal success recently achieved with the tyrosine kinase inhibitor STI571 [Gleevec(TM); imatinib mesylate] in treatment of chronic myelogenous leukemia and recent approval of the drug for use against gastrointestinal stromal tumors. Many tyrosine kinases are implicated in cancer, but scores of other disease states also reflect inappropriate regulation of these key enzymes. In the 50 years since regulation of protein activity by covalent phosphorylation was discovered, intense research efforts have been applied to characterize a broad range of kinases. Nevertheless, identification of the relevant biological substrates for any particular kinase in a particular biological role has proven to be very difficult. In a Perspective in this issue of Science's STKE , Manning and Cantley take a critical look at the techniques currently available to aid investigators in the search for the targets of their favorite kinase. These range from improvements to traditional in vitro assays to proteomic screens and a new method to create engineered kinases that specifically use modified adenosine triphosphate (ATP) analogs to label their substrates. STKE Protocols contain several of these conventional and newer methodologies for studying protein kinases and phosphorylation-dependent protein interactions (see Wooten; Steen et al .; and Shaywitz et al .). In this issue, in a Protocol by Eyckerman et al ., the Janus kinases are put to use in a modification of the yeast two-hybrid method that uses modified cytokine receptor molecules to allow detection of protein interactions in mammalian cells. In the postgenomic age, bioinformatics tools to identify new members of protein families and to search for interaction targets are powerful aids that help reveal protein functions and refine our understanding of signaling networks. Manning and Cantley discuss some of the advantages and disadvantages to these "dry" experiments. Many tools that are available on the World Wide Web are listed in at the STKE in the "ST on the Web" section, which has brief descriptions and links providing access to these resources (see Bioinformatics Resources and Protein Databases). A Perspective by Pelech and Zhang represents a new type of article for STKE, but one that may become more common as investigators present data sets from high-throughput screens. Pelech and colleagues at Kinexus Bioinformatics Corporation have assembled a panel of commercial antibodies that recognize more than 70 kinases. They agreed to share recently obtained data in which the panel of antibodies was used to examine expression of the enzymes in cell lines and various tissues from rat and monkey. The primary data are available as supplementary material to the Perspective in which the authors describe the screen and the unexpected variation they observe in abundance of the kinases in various tissues. The editors note that this contribution represents a less formal communication than an original research paper, in particular because the data provided have not been peer reviewed. STKE also features three new Connections Maps from Johnson and Lapadat describing mitogen-activated protein kinase (MAPK) signaling. The MAPKs participate in regulation of a broad range of biological activities and are among the most widely expressed enzymes in the screen described by Pelech and Zhang. Each of the three major subfamilies of MAPKs is represented with a separate Connections Map. The ERK Pathway describes regulation of the extracellular signal-regulated kinases (ERKs), which have critical roles in control of cell division. The JNK Pathway describes the c-Jun NH2-terminal kinases, an intricate web of signaling proteins that are key regulators of transcription. A third map depicts the p38 MAPK Pathway, with roles in stress responses and cytokine signaling. In a Science Viewpoint, Johnson and Lapadat describe the basic characteristics and physiological roles of these pathways. These kinase cascades provide a sense of the elaborate complexity of kinase-mediated signaling in cells as hundreds of enzymes monitor and respond to signals from the environment and the cell's interior to control decisions to grow, divide, or die. Other STKE Connections Maps contain many signaling pathways with central roles for protein and lipid kinases. Featured in This Focus Issue Related Resources at STKE

The dynamic synapse: neuronal nexus for signaling.

Abstract: There is not much that appears static in the neuronal synapse--an abundance of genetic, biochemical, pharmacological, electrophysiological, and microscopic information regarding this structure has revealed that the key to its role in mediating cell-to-cell communication in the central and peripheral nervous systems is its ever-changing nature. Yet we remain at a gross level of understanding how this complex architecture arises and how it is modulated. This week, Science presents a Special Issue that highlights recent insights in the development, organization, and plasticity of the dynamic synapse. Science's STKE delves deeper into some of the proposed molecular mechanisms that underlie synaptic plasticity. What becomes clear from this exploration is that we are at an early and exciting stage of understanding communication through this intercellular link at a detailed molecular level. Synaptic connections between neurons and target cells develop, mature, stabilize, and remodel, but the activity-dependent and -independent nature of these steps is somewhat disputed. In Science , Cohen-Cory explains how various model systems and methodologies have limited or expanded some of the contrary views on the relationships between synaptic activity, synapse development, and the plasticity that has long been implicated in learning and memory. The STKE Archive is rich in Perspectives discussing various aspects of activity-dependent changes in synaptic function. For example, Impey and Goodman discuss the mechanisms by which activity alters gene expression, Kosik and Krichevsky describe how RNA translation may be locally regulated by synaptic activity, and O'Donovan and Darnell highlight how alternative splicing can be regulated by synaptic activity. Fluorescent and real-time visualization techniques applied to hippocampal and cortical neurons have accelerated our understanding of neuron connectivity in central synapses, and Protocols by Dodt et al . and Polleux and Ghosh describing such contemporary procedures can also be found in the STKE Archive. Hippocampal neurons have provided the primary experimental paradigm for examining mammalian central synaptogenesis and function, and their manipulation has revealed that specific neurotransmitters and their cognate receptors are critical components of the synaptic signaling network. Differential expression in the mammalian brain of three different receptors for the neurotransmitter glutamate has triggered interest in determining whether their expression at the cell surface is a mechanism for regulating synaptic strength. Additional diversity in glutamate receptors is further achieved through RNA editing, which is described by in the STKE Perspective by Schmauss and Howe. The STKE Protocol by Grosshans et al . describes methods for analysis of glutamate receptor expression in organotypic hippocampal slices. The STKE Review by Contractor and Heinemann provides insight into glutamate receptor trafficking, focusing on the mobilization of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-type glutamate receptors from intracellular pools to synaptic and nonsynaptic sites in the postsynaptic neuronal membrane. A network of proteins that associate with glutamate receptors, including membrane, cytoskeletal, and PDZ domain-containing intracellular proteins, may underlie the dynamics of receptor recruitment, stabilization, and turnover in the synapse. An STKE Perspective by deSouza and Ziff discusses the recent finding that the postsynaptic density protein PSD-95 is reversibly palmitoylated, a modification that could influence AMPA signaling by restricting receptor localization to membrane lipid rafts. This follows an emerging theme of how protein lipidation and location can control the activity of signaling molecules at membranes (see also the STKE Perspective by Berthiaume). A Science Review by Sheng and Kim further delineates the protein-protein interacting network of central synapses and the multiple biochemical pathways (including the Ras to mitogen-activation protein kinase, the calcium-calmodulin kinase II, and the phosphatidylinositol 3-phosphate kinase pathways) associated with activated glutamate receptors. It is clear that a spatiotemporal understanding is now needed to elucidate how these components and pathways are integrated into dynamic synaptic circuits both in the developing and mature nervous system. Neurotransmitters that modulate synaptic activity are released to postsynaptic neurons through exocytosis of cargo-carrying synaptic vesicles from presynaptic neurons. The Science Review by Rettig and Neher explains that tremendous insights into the molecular machinery controlling this calcium-triggered event have been gleaned from studying neurosecretory cells. Synaptic vesicles are also recycled locally, and the slow and fast tracks of this process are described in a review by Galli amd Haucke. The response of neurons to neurotransmitters is also dynamic and can change during development. In their STKE Perspective, Kriegstein and Owens propose some caution when categorizing neurotransmitters as either excitatory or inhibitory as they discuss the surprising discovery that γ-aminobutyric acid (GABA) can elicit both responses in the developing mammalian brain. A growing array of synapse components and signaling pathways implicated in synapse dynamics begs the question of how these elements couple to each other and how they are linked to synaptic activity. There is likely no simple strategy behind how synaptic activity modulates synapse architecture and vice versa. These issues are not only at the forefront of neuronal synapse research, but now also confront those who study similar "synaptic" cell-cell interfaces in other biological systems (see the Science Viewpoint by Dustin and Colman that contrasts the neuronal and immunological synapses). Featured in this Focus Issue Related Resources at STKE

Coding and Noncoding RNA: An Expanding RNA World

Abstract: A special section in this week's issue of Science , RNA Silencing and Noncoding RNA ( ), reveals how astonishingly abundant and versatile RNA is Noncoding RNAs are present in prokaryotes and eukaryotes and include those species that do not function as messenger RNA (mRNA), transfer RNA, or ribosomal RNA For example, small interfering RNAs are about 25 nucleotides in length and have been implicated in a process called gene silencing These short, double-stranded RNA (dsRNA) fragments complement the sequence of the silenced gene, and the precise mechanisms of RNA silencing are being rapidly revealed in protozoa, plants, fungi, and animals, as described by Zamore ( ) Growing interest in elucidating the natural roles of RNA silencing has led to the application of RNA interference to evaluate gene function, and a Protocol by Worby et al ( ) describes how treatment of cultured cells with exogenous dsRNA is now a powerful tool for dissecting cellular signaling pathways Storz ( ) indicates that mRNA stability and processing can be regulated by small nuclear RNAs and by microRNAs, the latter of which are also about 25 nucleotides long Fritz et al ( ) provide a Protocol to assess mRNA stability, an important determinant in the mRNA life cycle STKE complements the Science special issue with information about mRNA, the coding RNA Much is still being uncovered about how transcription and mRNA processing are regulated Spatial restriction is even imposed on certain mRNAs For example, Manseau ( ) describes the specific localization and possible transport mechanisms of mRNAs encoding the signaling molecules transforming growth factor-alpha and wingless in the developing Drosophila oocyte and embryo A rationale for differential trafficking of mRNA in neurons is explained by Kosik and Krichevsky ( ), in which a dynamic structure called an RNA granule delivers its cargo of specific mRNAs to regions critical for maintaining plasticity The presence of multiple splicing sites on pre-mRNA and the process of alternative splicing can yield multiple mRNAs for each gene Cooper ( ) states that approximately 60% of the human genes are alternatively spliced and provides recent insights in understanding cell-specific splicing in vertebrates in his meeting report from the Sixth Annual Meeting of the RNA Society (2001) Finkbeiner ( ) notes that this splicing may depend not only on factors that recognize exons and their flanking sequences, but possibly on similar interactions that occur in introns Growth factors, cytokines, and hormones all regulate alternative splicing, but the molecular links connecting specific signaling pathways to this process are still under investigation In neurons, almost all neurotransmitter receptor and ion channel pre-mRNAs undergo alternative splicing to generate multiple isoforms This strategy underlies specificity in receptor and channel subunit assembly, protein interactions, subcellular localization, and sensitivities to regulatory molecules O'Donovan and Darnell ( ) describe a connection made between calcium-calmodulin-dependent protein kinase (CaMK) activity in neurons and the alternative splicing of Slowpoke (Slo)/BK mRNAs that encode calcium and voltage-gated potassium channels CaMK appears to couple transcription and splicing of Slo/BK pre-mRNA, and the presence of a particular RNA element is needed to confer this responsiveness Fury et al ( ) also point out that Slo/BK channel activity is further regulated by phosphorylation of subunit-specific sites, whose presence is determined by alternative splicing Schmauss and Howe ( ) describe how certain neurotransmitter receptors undergo RNA editing, a process that facilitates single-nucleotide changes of pre-mRNA Such a modification can increase protein diversity by introducing a frame shift or a stop codon, or by altering a single residue in a functionally important region of the protein For example, a single residue switch within the pore regions of two types of glutamate receptors, the AMPA and kainate receptors, affects the permeability of these channels to calcium, an important intracellular modulator of synaptic plasticity Particular mRNA secondary strucutures are recognized by the cellular RNA editing machinery, and it is likely that once mRNA is edited, the secondary structure is resolved so that splicing can ensue A Protocol by Parekh-Olmeda et al ( ) describes how a direct change of a single nucleotide can be accomplished through a RNA-DNA hybrid in a process called targeted gene repair As Ahlquist ( ) points out, viral and cellular RNA-dependent RNA polymerases are functionally similar in that they copy mRNA templates to generate dsRNA DsRNA is an intermediate in the replication of many viruses and the Reviews by D'Acquisto and Ghosh ( ) and by Williams ( ) indicate that binding of such viral dsRNA to the serine-threonine protein kinase R inhibits viral replication Moreover, Plasterk ( ) mentions that host cells may protect their genomes from viral invasion and from transposon movement by RNA silencing mechanisms that are triggered by such dsRNA The RNA world has certainly grown beyond its interface between the genome and the proteome As Storz puts it, the boundaries of the "RNome" likely extend beyond what is presently apparent Featured in This Focus Issue on Coding and Noncoding RNA Related Resources at STKE

Einstein and Relativity Theory

Abstract: Following Newton’s triumph, work expanded not only in mechanics but also in the other branches of physics, in particular, in electricity and magnetism. This work culminated in the late nineteenth century in a new and successful theory of electricity and magnetism based upon the idea of electric and magnetic fields. The Scottish scientist James Clerk Maxwell, who formulated the new electromagnetic field theory, showed that what we observe as light can be understood as an electromagnetic wave. Newton’s physics and Maxwell’s theory account, to this day, for almost everything we observe in the everyday physical world around us. The motions of planets, cars, and projectiles, light and radio waves, colors, electric and magnetic effects, and currents all fit within the physics of Newton, Maxwell, and their contemporaries. In addition, their work made possible the many wonders of the new electric age that have spread throughout much of the world since the late nineteenth century. No wonder that by 1900 some distinguished physicists believed that physics was nearly complete, needing only a few minor adjustments. No wonder they were so astonished when, just 5 years later, an unknown Swiss patent clerk, who had graduated from the Swiss Polytechnic Institute in Zurich in 1900, presented five major research papers that touched off a major transformation in physics that is still in progress. Two of these papers provided the long-sought definitive evidence for the existence of atoms and molecules; another initiated the development of the quantum theory of light; and the fourth and fifth papers introduced the theory of relativity. The young man’s name was Albert Einstein, and this chapter introduces his theory of relativity and some of its many consequences.

Probing the Nucleus

Abstract: We saw in Chapter 14 that studies of the atom indicated that the atom consists of a very small, positively charged nucleus surrounded by negatively charged electrons. Experiments on the scattering of a particles revealed that the nucleus has dimensions of the order of 10-14 m. Since the diameter of an atom is of the order of 10-10 m, the nucleus takes up only a minute fraction of the volume of an atom. The nucleus, however, contains nearly all of the mass of the atom, as was also shown by the scattering experiments.

Newton’s Unified Theory

Abstract: Forty-five years passed between the death of Galileo in 1642 and the publication in 1687 of Newton’s greatest work, the Philosophiae Naturalis Principia Mathematica, or the Principia (Principles) for short. In those years, major changes occurred in the social organization of scientific studies. The new philosophy of experimental science, applied with enthusiasm and imagination, produced a wealth of new results. Scholars began to work together and to organize scientific societies in Italy, France, and England. One of the most famous, the Royal Society of London for Improving Natural Knowledge, was founded in 1662. Through these societies, scientific experimenters exchanged information, debated new ideas, argued against opponents of the new experimental activities, and published technical papers. Each society sought public support for its work and published studies in widely read scientific journals. Through the societies, scientific activities became well defined, strong, and international.

The Nucleus and Its Applications

Abstract: The discoveries of radioactivity and isotopes were extraordinary advances. And as usual, they also raised new questions about the structure of atoms, questions that involved the atomic nucleus. We saw in Chapter 17 that the transformation rules of radioactivity could be understood in terms of the Rutherford-Bohr model of the atom. But that model said nothing about the nucleus other than that it is small, has charge and mass, and may emit an a or a β particle. This implies that the nucleus has a structure that changes when a radioactive process occurs. The question arose: Can a theory or model of the atomic nucleus be developed that will explain the facts of radioactivity and the existence of isotopes?

STKE Focus Issue on the Bionic Human: The Molecular Signaling of Tissue Repair

Abstract: The prospect of replacing injured or diseased human cells, tissues, and organs with their normal counterparts lies at the evolving interface between two disciplines--biological science and applied engineering. The special issue in Science magazine on the Bionic Human ( and ) highlights current state-of-the-art technologies that are revolutionizing the development of prosthetic devices and engineered tissues, bringing this clinical goal ever so closer. This issue of the STKE expands on several of these topics, revealing why a fundamental understanding of cell signaling remains at the heart of many of these technological advances. Several Viewpoints in Science , including those of Hench and Polak ( ) and Griffith and Naughton ( ), point to why today's engineered biomaterials are designed to account for how various living tissues respond to the physiological loads or biochemical stimuli to which they are normally exposed. These newer materials interact with relevant cell surface proteins, such as integrins, to regulate normal cell proliferation, differentiation, and the production and organization of extracellular matrix. STKE's Perspective by Alenghat and Ingber ( ) describes how cells respond to mechanical stimulation, particularly sensory cells. Indeed, understanding sensory hair cell response to sound stimulation is integral to engineering auditory prothetics, as described in Science by Rauschecker and Shannon ( ). Engineering living tissue for implantation requires understanding how cells grow and differentiate in three dimensions. Hench and Polak raise the additional issue of how to get a blood supply to such implanted engineered tissue. The STKE Perspective by Stupack and Cheresh ( ) takes a deeper look at angiogenesis and how proangiogenic factors and remodeling of the extracellular environment by vascular endothelial cells contributes to this complex process. A Review on signaling by the proangiogenic factor vascular endothelial growth factor (VEGF) can also be found in the STKE Archive by Matsumoto and Claesson-Welsh ( ). One of the greatest clinical challenges is treatment of processes controlled by the central and peripheral nervous systems. Implantation of tailored biomaterials that sustain a controlled release of appropriate molecules that promote or inhibit neurite outgrowth may serve to stimulate nerve regeneration is the topic of the Science Viewpoint by Schwab ( ). STKE features a Review by He et al . ( ) describing axon guidance by Semaphorins. Articles in the STKE Archive, such as the Perspective about netrin signaling by Merz and Culotti ( ) and the Review on Ephrins and Eph Receptors by Boyd ( ) describe other players in controlling axon migration. Insight into processes and signaling mechanisms regulated by neurotrophins are highlighted in a Perspective on retrograde signaling by Segal ( ) and a Book Review by Roth ( ) from the STKE Archives. The regulation of synapse development is the focus of the Perspective on γ-amino butyric acid (GABA) in developing synapses by Kriegstein and Owens ( ). Finally, implanted biomaterials must have a minimal toxic response. Optimal implants are those that are inert and do not trigger an immune response. A Review in the STKE Archive by O'Neill ( ) describes some general aspects of host defense mediated by Toll-like receptors. Featured in This Focus Issue on the Bionic Human Related Resources at STKE

Conserving Matter and Motion

Abstract: Newton’s success in mechanics altered profoundly the way in which scientists viewed the Universe. The motions of the Sun and planets could now be considered as purely mechanical, that is, governed by the laws of mechanics, much like a machine. As for any machine, whether a clock or the solar system, the motions of the parts were completely determined once the system had been put together.