Inaugural Article Research Articles

Profile of Tom A. Rapoport

Inside any cell, errant, misfolded proteins must be confiscated and destroyed. This process does not occur inside the endoplasmic reticulum, where secretory proteins are folded and packaged for export; instead, misfolded proteins must retrotranslocate—cross the endoplasmic reticulum membrane back into the cytosol. Biochemist Tom A. Rapoport, elected to the National Academy of Sciences in 2005, has spent much of his career studying the membrane channel Derlin-1, which exports proteins from the cytosol. In the last five years, he has studied the reverse protein movement process of retrotranslocation. In his Inaugural Article in this issue of PNAS, Rapoport identifies a class of proteins associated with the retrotranslocation complex (1).

Biography of Kathryn V. Anderson

T he metamorphosis of a fertilized egg into an adult organism requires a complex web of gene and protein interactions that scientists have attempted to elucidate for decades. Developmental biologist Kathryn V. Anderson has discovered many of the molecules that lay the groundwork for body plan differentiation, specifically those controlling the dorsal-ventral patterning in the fruit fly Drosophila melanogaster . Such patterning is required for specification of the nervous system, muscles, and other mesodermal cells. These signaling pathways are conserved in higher organisms and, in humans and mice, are critical for the activity of the innate immune system. Over the past several years, Anderson has used the genetic approaches she helped pioneer in Drosophila and applied them to vertebrate development. In her Inaugural Article in this issue of PNAS (1), Anderson provides a progress report on her ongoing strategy to phenotypically identify genes that control early neural development and mesoderm formation in the mouse embryo. Anderson's interest in developmental biology was first piqued during a high school science fair project as she peered through a microscope at the “mermaid's wine glass.” She marveled at these single-celled algae, formally known as Acetabularia crenulata , with their slender stalks and umbrella-shaped caps, but most intriguing were the compartments within the cell. “I thought this was great that the different parts of the cell had different roles,” she says. Born in La Jolla, CA, in 1952, Anderson's interest in development was nurtured by her schooling and her supportive parents. At San Diego's Point Loma High School, a “great biology teacher,” Michael Lorch, fostered her interest in life sciences. Moving north to attend college at University of California, Berkeley, Anderson decided to pursue biochemistry. “I was pretty much a reductionist biologist, and biochemistry seemed the hardest of the biological sciences and the most objective,” …

Biography of George W. Flynn

When molecules collide, energy is thrown into flux, shifting modes, converting types, or becoming excited enough to rupture the strongest of chemical bonds. Current knowledge of energy transfer in molecules has been revolutionized by the study of such quantum state kinetics, and physical chemist George W. Flynn has contributed greatly to this area with his inquiries into vibrational energy modes. Flynn, Eugene Higgins Professor of Chemistry at Columbia University (New York, NY) and a member of the National Academy of Sciences since 2001, examines the molecular dynamics and assembly of halogens in his Inaugural Article in this issue of PNAS (1). Flynn and his coworkers show that the self-assembly of haloethane arrays is controlled by the nature of the halogen attached, which in turn changes the van der Waal's forces between molecules, as well as the forces between molecules and surface. For more than a decade, Flynn has used scanning tunneling microscopy to spy on molecules, learning how they spontaneously arrange themselves into highly ordered patterns, and, throughout his career, he has systematically followed the kinetic properties of energy flow within individual molecules.

Genomics, genetic epidemiology, and genomic medicine

Medical science is on the threshold of unparalleled progress as a result of the advent of genomics and related disciplines. Human genomics, the study of structure, function, and interactions of all genes in the human genome, promises to improve the diagnosis, treatment, and prevention of disease. This opportunity is the result of the recent completion of the Human Genome Project. It is anticipated that genomics will bring to physicians a powerful means to discover hereditary elements that interact with environmental factors leading to disease. However, the expected transformation toward genomics-based medicine will occur over decades. It will require efforts of many scientists and physicians to begin now to sort out the vast amounts of information in the human genome and translate it to meaningful applications in clinical practice. Meanwhile, practicing physicians and health professionals need to be trained in the principles, applications, and limitations of genomics and genomic medicine. Only then will we be in a position to benefit patients, which is the ultimate goal of accelerating scientific progress in medicine. In this inaugural article, we introduce and discuss concepts, facts, and methods of genomics and genetic epidemiology that will be drawn on in the forthcoming topics of the clinical genomics series.

Biography of Edward Irving

The latitude lines plastered across atlases and globes are not the rigid demarcations they appear to be. Over millions of years, continents have moved relative to the Earth's magnetic field, a phenomenon recorded by the magnetization of rocks. Edward Irving, a geologist and emeritus scientist with the Geological Survey of Canada, has been reading the history of latitude variations for more than 50 years. His studies of paleomagnetism provided the first physical evidence of the theory of continental drift (1). In his Inaugural Article (2), published on page 1821 of this issue of PNAS, Irving reviews the areas of research that have informed our knowledge of Earth's history and how the planet's mountain belts, climate, and life have evolved.

Biography of J. Clark Lagarias

In plants, light enables more than energy production—it also jumpstarts physiological responses, such as stem elongation or seed germination. Phytochromes are key players in the photoreception component of regulatory plant responses to light. A plant's phytochromes act as protein switches controlled by different wavelengths of light. J. Clark Lagarias, elected to the National Academy of Sciences in 2001, has investigated the biochemistry of these switches for over 20 years. In his Inaugural Article (1) on page 17334 in this issue of PNAS, Lagarias chips away at the fundamental question of how light energy structurally transforms the phytochrome protein. The work details a molecular genetic screen that pinpoints phytochrome's rapid response in photochemical activity and spectral tuning to a single amino acid residue.

Biography of E. P. Greenberg

For the bacterium Pseudomonas aeruginosa, communication is a powerful tool. Twenty years ago, the idea that bacteria communicate with each other was not widely accepted. Today, bacterial communication is on the forefront of understanding devastating infections, such as those that plague cystic fibrosis patients or burn victims. E. Peter Greenberg, elected to the National Academy of Sciences in 2004, first introduced the term “quorum sensing” in 1994 to describe the regulation of bacterial gene expression by means of population sensing (1). Today, quorum sensing is proving more and more complicated. In his Inaugural Article on page 15833 in this issue of PNAS (2), Greenberg presents new research that questions the traditional paradigms of promoter recognition by the transcription factors involved in quorum sensing.

Biography of Arthur L. Horwich.

Inside cells, crucial helpers latch onto nonnative proteins, preventing them from misfolding. These chaperonins trap unfolded proteins inside molecular cages and facilitate folding to the final native form. Arthur L. Horwich, professor at Yale University School of Medicine (New Haven, CT), uncovered chaperonin action in 1989 (1). More than 15 years later, chaperonins remain the major focus of Horwich's research. In his Inaugural Article in this issue of PNAS (2), Horwich, who was elected to the National Academy of Sciences in 2003, probes the behavior of the bacterial chaperonin GroEL, showing that the unfolded substrate polypeptide is not a passive bystander but has an effect on the activation mechanism.

Biography of Zdenek P. Bazant.

Engineer Zdeněk P. Bažant is best known as a world leader in scaling research in solid mechanics (1–6). His research focuses on the effect of structure size on structural strength as it relates to the failure behavior of the structure. He also has made outstanding advances in structural stability (7), fracture mechanics (8), the micromechanics of material damage (8–10), concrete creep (11–13), and probabilistic mechanics (6, 8, 14). He was elected to the National Academy of Engineering in 1996 and to the National Academy of Sciences in 2002, 1 of only 153 members with such a dual appointment. In his Inaugural Article (1), published in this issue of PNAS, Bažant presents a simple justification of the scaling laws for the fracture of quasibrittle materials such as concrete, rock, fiber composites, and sea ice.

Biography of Alejandro Portes.

Alejandro Portes is a premier sociologist who has shaped the study of immigration and urbanization for 30 years. He is chair of the department of sociology at Princeton University (Princeton, NJ) as well as co-founder and director of Princeton's Center for Migration and Development. In 1998, Portes became a fellow of the American Academy of Arts and Sciences, and he was elected to the National Academy of Sciences in 2001. From 1998 to 1999, Portes served as president of the American Sociological Association. He has authored and edited numerous books and has published articles on a range of policy issues, including immigrant assimilation, Latin American politics, and United States/Cuba relations (1–4). A Cuban exile himself, Portes has spent his career tracking the lives of different immigrant nationalities in the United States. He has chronicled the causes and consequences of immigration to the United States, with an emphasis on informal economies, transnational communities, and ethnic enclaves (5–8). In Portes's Inaugural Article (9), published in this issue of PNAS, he and Hao study the children of immigrants and the factors that determine their successful adaptation to life in the United States, such as family support and school socioeconomic status (SES). ### A Need to Understand the Past Portes was born in Havana, Cuba, on October 13, 1944. He began his under-graduate studies at the University of Havana in 1959 but left after just one year. At the time, Cuba was in the midst of a revolution, as dictator Fulgencio Batista was overthrown and a new regime was established under the leadership of Fidel Castro. “I left in 1960 because of opposition to the regime and became a political exile,” he says. In 1963, Portes resumed his studies at the Catholic University of Argentina in Buenos Aires. He completed his B.A. in sociology in 1965 …

Scaling theory for quasibrittle structural failure.

This inaugural article has a twofold purpose: (i) to present a simpler and more general justification of the fundamental scaling laws of quasibrittle fracture, bridging the asymptotic behaviors of plasticity, linear elastic fracture mechanics, and Weibull statistical theory of brittle failure, and (ii) to give a broad but succinct overview of various applications and ramifications covering many fields, many kinds of quasibrittle materials, and many scales (from 10(-8) to 10(6) m). The justification rests on developing a method to combine dimensional analysis of cohesive fracture with second-order accurate asymptotic matching. This method exploits the recently established general asymptotic properties of the cohesive crack model and nonlocal Weibull statistical model. The key idea is to select the dimensionless variables in such a way that, in each asymptotic case, all of them vanish except one. The minimal nature of the hypotheses made explains the surprisingly broad applicability of the scaling laws.

Biography of David Tilman.

David Tilman describes himself as both a theoretical and an experimental ecologist. Currently the McKnight Presidential Chair in Ecology and Regents Professor at the University of Minnesota (St. Paul), Tilman has spent his career developing theories of biodiversity and species composition that he has tested in carefully designed and controlled experiments. His work on resource competition in both algal and grassland ecosystems has helped shape ecology into a more predictive and quantitative science. For this and numerous other contributions, Tilman was elected to the National Academy of Sciences in 2002. In his Inaugural Article, featured in this issue of PNAS (1), Tilman presents a new theory of species diversity and abundance within ecosystems. The theory was inspired, in part, by data he gathered over the past two decades at the Cedar Creek Natural History Area (Bethel, MN), where he currently serves as director. Through his new stochastic niche theory, Tilman offers an explanation for the patterns seen during the assembly of species into ecosystems, including what controls the number of species and their abundances, and why some ecosystems are more readily invaded by exotic species than others. The article suggests that stochastic niche theory offers a resolution to the controversy between whether it is “neutral” or “niche” processes that determine the diversity and composition of ecosystems.

Cultural traffic in the medieval Romance world

This article introduces the issue by discussing ‘Romance Studies’ as an ideological construct and suggesting ways in which this might inform our understanding of cultural exchanges in the parts of medieval Europe where Romance languages were spoken. Through an examination of programmatic inaugural articles in two major academic journals in the field (Romania, established in 1872, and Cultura Neolatina, published in 1941), the authors show that any idea of a ‘Romance world’, of its value and of its boundaries (both internal and external) is contingent on historical and ideological factors, which in turn means that modern ideas about what may have constituted the ‘Romance world’ in the past are often inflected by modern political, cultural and ideological concerns. A further example is the ‘discovery’ of the kharjas of medieval Iberia in 1949.

Introduction

There has always been a great need for those involved in the laboratories of assisted reproductive technologies (ART) and reproductive endocrinology to discuss the technological advances developed in their laboratories. However, there are so many advances and so little time to learn and understand them. To fill this need, this issue of Fertility and Sterility will have its inaugural article for a new section entitled “Lessons from the Laboratory.” This section will serve as a bridge between the laboratory and clinical practice. Each article will strive to contain explanations of techniques and their power and limitations. They will provide information as to how the clinician can best interpret the results using these techniques to better inform the patients who can most benefit. The strength of this special section is that articles will be written by those in the laboratory who are experts in these techniques and who can provide experience and insight into the use of the techniques they use daily.

Message from the editor

I would like to thank the members of the oncology community for the increasingly strong support that you have been providing to Cancer. Over the past year, we have enjoyed a marked 11% increase in the total number of manuscripts submitted for evaluation. At the same time, the overall manuscript acceptance rate has been cut in half, such that currently, only 21% of all submitted manuscripts are accepted for publication. We hope that these changes result in reports that are more useful to you in your clinical practice or research. It also is gratifying to see a concomitant increase in the impact factor rating for Cancer. While Cancer does not tailor its editorial policy to affect the impact factor rating, it still is satisfying to see that work published in Cancer is reaching a broad audience, where it can have maximum utility. In addition, the majority of accepted articles are now published in print within four months of receipt of final manuscripts. This fast publication time serves the interests of our authors, our readers, and the oncology community. To further enhance the utility of accepted manuscripts, beginning with this year's July 1 issue, all manuscripts accepted for print publication in Cancer will be available online “as soon as ready.” The EarlyView system was a joint collaboration of the American Cancer Society and John Wiley & Sons, the publisher of Cancer. This web-based site will display all accepted manuscripts within 7–10 days of receipt of author-corrected page proofs. We are in the process of making another change that we hope is a positive one for Cancer. The inaugural article in a series focusing on issues in bioethics and legal oncology will be published in the July 15 issue of Cancer. Articles in this new section will focus on interdisciplinary concerns regarding the practice of oncology, as well as relevant ethical and legal issues. We anticipate that initially we will publish an article in this section at least once every 8–12 weeks, and we welcome suggestions regarding subjects of interest. Please let us know whether this new series “hits the mark.” Thank you again for your interest and participation in Cancer. I am confident that, working together with readers and authors, Cancer can continue to evolve and to meet your needs and expectations even better in the future!

Soft and hard classification by reproducing kernel Hilbert space methods.

Reproducing kernel Hilbert space (RKHS) methods provide a unified context for solving a wide variety of statistical modelling and function estimation problems. We consider two such problems: We are given a training set [yi, ti, i = 1, em leader, n], where yi is the response for the ith subject, and ti is a vector of attributes for this subject. The value of y(i) is a label that indicates which category it came from. For the first problem, we wish to build a model from the training set that assigns to each t in an attribute domain of interest an estimate of the probability pj(t) that a (future) subject with attribute vector t is in category j. The second problem is in some sense less ambitious; it is to build a model that assigns to each t a label, which classifies a future subject with that t into one of the categories or possibly "none of the above." The approach to the first of these two problems discussed here is a special case of what is known as penalized likelihood estimation. The approach to the second problem is known as the support vector machine. We also note some alternate but closely related approaches to the second problem. These approaches are all obtained as solutions to optimization problems in RKHS. Many other problems, in particular the solution of ill-posed inverse problems, can be obtained as solutions to optimization problems in RKHS and are mentioned in passing. We caution the reader that although a large literature exists in all of these topics, in this inaugural article we are selectively highlighting work of the author, former students, and other collaborators.

Clinical trials in cardiovascular medicine.

The practice of cardiology is increasingly driven by evidence-based medicine centering around the results of clinical trials.1 In this inaugural article of Clinical Cardiology: Physician Update , I will focus on the design, analysis, and interpretation of clinical trials in cardiovascular medicine. Armed with the tools described herein, clinicians will be better equipped to understand and synthesize the results of the multitude of clinical trials appearing in the cardiology literature. A major goal of this effort is to shorten the delay between the publication of trial results and the translation of their findings into clinical practice. Trials of new therapies in cardiology typically compare the new treatment to a control. The control group receives the treatment against which the test intervention is being compared. Control and test treatments must be both medically justifiable and compatible with the healthcare needs of study patients. Either treatment must be acceptable to study patients and to the physicians administering them; there must be a reasonable doubt regarding the efficacy of the test treatment; and there should be reason to believe that the benefits will outweigh the risks of treatment. When the control treatment is a placebo, the trial is referred to as a placebo-controlled trial.2 Given the burgeoning supply of new treatments in the cardiovascular armamentarium, more and more trials compare the test therapy to a standard therapy. This is referred to as an active controlled trial.3 4 Randomized controlled trials typically involve the randomization of patients to either the control or test treatment (ie, randomized concurrent control). These trials are the gold standard for evaluating new therapies, and they form the foundation for the highest level of recommendations in practice guideline documents that stress evidence-based medicine5 (Figure 1⇓). Randomization has 3 important influences that explain why it is …

Profile – Jennifer Lippincott-Schwartz

organdies, from lysosomes to the Golgi apparatus, are static entities. Most recently, she has focused on cellular sorting and recycling systems. In her inaugural article (1), LippincottSchwartz, a tenured investigator at the National Institutes of Health (NIH, Bethesda, MD), explores how the ubiquitin tag, once thought to be a 1-way ticket to the proteasome, can also, in concert with the p62 protein, efficiently ship proteins and other targets to the autophagosome. The work has implications for improving researchers' understanding of neurodegenerative diseases characterized by the accumulation of cellular debris.

Inaugural Article: Acetylcholine receptor channel structure in the resting, open, and desensitized states probed with the substituted-cysteine-accessibility method

The nicotinic acetylcholine (ACh) receptors cycle among classes of nonconducting resting states, conducting open states, and nonconducting desensitized states. We previously probed the structure of the mouse-muscle ACh receptor channel in the resting state obtained in the absence of agonist and in the open states obtained after brief exposure to ACh. We now have probed the structure in the stable desensitized state obtained after many minutes of exposure to ACh. Muscle-type receptor has the subunit composition alpha(2)betagammadelta. Each subunit has four membrane-spanning segments, M1-M4. The channel lumen in the membrane domain is lined largely by M2 and to a lesser extent by M1 from each of the subunits. We determined the rates of reaction of a small, sulfhydryl-specific, charged reagent, 2-aminoethyl methanethiosulfonate with cysteines substituted for residues in alphaM2 and the alphaM1-M2 loop in the desensitized state and compared these rates to rates previously obtained in the resting and open states. The reaction rates of the substituted cysteines are different in the three functional states of the receptor, indicating significant structural differences. By comparing the rates of reaction of extracellularly and intracellularly added 2-aminoethyl methanethiosulfonate, we previously located the closed gate in the resting state between alphaG240 and alphaT244, in the predicted M1-M2 loop at the intracellular end of M2. Now, we have located the closed gate in the stable desensitized state between alphaG240 and alphaL251. The gate in the desensitized state includes the resting state gate and an extension further into M2.

Inaugural Article: Metabolic engineering of plant alkaloid biosynthesis

Plant alkaloids, one of the largest groups of natural products, provide many pharmacologically active compounds. Several genes in the biosynthetic pathways for scopolamine, nicotine, and berberine have been cloned, making the metabolic engineering of these alkaloids possible. Expression of two branching-point enzymes was engineered: putrescine N-methyltransferase (PMT) in transgenic plants of Atropa belladonna and Nicotiana sylvestris and (S)-scoulerine 9-O-methyltransferase (SMT) in cultured cells of Coptis japonica and Eschscholzia californica. Overexpression of PMT increased the nicotine content in N. sylvestris, whereas suppression of endogenous PMT activity severely decreased the nicotine content and induced abnormal morphologies. Ectopic expression of SMT caused the accumulation of benzylisoquinoline alkaloids in E. californica. The prospects and limitations of engineering plant alkaloid metabolism are discussed.