bluuebunny/crossref_metadata_2025 huggingface dataset:
Global Asset Pricing
Authors: Lewis Karen K.
Published: March 2011

Financial markets have become increasingly global in recent decades, yet the pricing of internationally traded assets continues to depend strongly upon local risk factors, leading to several observations that are difficult to explain with standard frameworks. Equity returns depend upon both domestic and global risk factors. Further, local investors tend to overweight their asset portfolios in local equity. The stock prices of firms that begin to trade across borders increase in response to this information. Foreign exchange markets also display anomalous relationships. The forward rate predicts the wrong sign of future movements in the exchange rate, implying that traders can make profits by borrowing at lower interest rate currencies and investing in higher interest rate currencies. Furthermore, the sign of the foreign exchange premium changes over time, a fact difficult to reconcile with consumption variability. In this review, I describe the implications of the current body of research for addressing these and other global asset pricing challenges.
Momentum
Authors: Jegadeesh Narasimhan , Titman Sheridan
Published: March 2011

There is substantial evidence that indicates that stocks that perform the best (worst) over a three- to 12-month period tend to continue to perform well (poorly) over the subsequent three to 12 months. Until recently, trading strategies that exploit this phenomenon were consistently profitable in the United States and in most developed markets. Similarly, stocks with high earnings momentum outperform stocks with low earnings momentum. This article reviews the momentum literature and discusses some of the explanations for this phenomenon.
Money Markets
Authors: Goodfriend Marvin
Published: March 2011

Money markets offer monetary services and short-term finance in the capital market with the credit support of institutional sponsors. Investors finance money market instruments at low interest because their salability on short notice confers an implicit monetary services yield. Low interest attracts borrowers to money markets. The fragile equilibrium depends on collective confidence in the credit quality of instruments supplied to the market. Federal Reserve monetary and credit policies have influenced interest rates and credit intermediated in the money market, especially during the credit turmoil. Permissive regulatory rulings have allowed borrowers to take increasing advantage of low interest funding in money markets via securitization and structured finance—vastly increasing maturity, credit, and liquidity transformation through asset-backed commercial paper, repurchase agreements, and money market mutual funds. Funding in such instruments and runs on these instruments helped to create the credit cycle that culminated in the turmoil of 2007–2009.
My Life in Finance
Authors: Fama Eugene F.
Published: March 2011

I was invited by the editors to contribute a professional autobiography to the Annual Review of Financial Economics. I focus on what I think is my best stuff. Readers interested in the rest can download my vita from the Web site of the University of Chicago, Booth School of Business. I only briefly discuss ideas and their origins to give the flavor of context and motivation. I do not attempt to review the contributions of others, which is likely to raise feathers. Mea culpa in advance.

Finance is the most successful branch of economics in terms of theory and empirical work, the interplay between the two, and the penetration of financial research into other areas of economics and real-world applications. I have been doing research in finance almost since its start, when Markowitz (1952 , 1959) and Modigliani & Miller (1958) set the field on the path to becoming a serious scientific discipline. It has been fun to see it all, to contribute, and to be a friend and colleague to the giants who created the field.
The Origins and Evolution of the Market for Mortgage-Backed Securities
Authors: McConnell John J. , Buser Stephen A.
Published: March 2011

The first mortgage-backed security (MBS) was issued in 1968. Thereafter, the MBS market grew rapidly with outstanding issuances exceeding $9 trillion by 2010. The growth in the MBS market was accompanied by numerous innovations such as collateralized mortgage obligations (CMOs) and the emergence of private label alternatives to MBS issued by government-sponsored entities. We trace the evolution of the MBS market and we review debates surrounding such questions as whether the MBS market has reduced the cost of housing finance, whether the MBS market is a market for lemons, and what role, if any, MBS played in the run-up and subsequent decline of home prices during the decade of the 2000s. We also detail the evolution of models for MBS valuation as developed by academics and practitioners.
Microfinance and Social Investment
Authors: Conning Jonathan , Morduch Jonathan
Published: March 2011

This review puts a corporate finance lens on microfinance. Microfinance aims to democratize global financial markets through new contracts, organizations, and technology. We explain the roles that government agencies and socially minded investors play in supporting the entry and expansion of private intermediaries in the sector, and we disentangle debates about competing social and commercial firm goals. We frame the analysis with theory that explains why microfinance institutions serving lower-income communities charge high interest rates, face high costs, monitor customers relatively intensively, and have limited ability to lever assets. The analysis blurs traditional dividing lines between nonprofits and for-profits and places focus on the relationship between target market, ownership rights, and access to external capital.
Carry Trade and Momentum in Currency Markets
Authors: Burnside Craig , Eichenbaum Martin , Rebelo Sergio
Published: March 2011

We examine the empirical properties of the payoffs to two popular currency speculation strategies: the carry trade and momentum. We review three possible explanations for the apparent profitability of these strategies. The first is that speculators are being compensated for bearing risk. The second is that these strategies are vulnerable to rare disasters or peso problems. The third is that there is price pressure in currency markets.
The Economics of Credit Default Swaps
Authors: Jarrow Robert A.
Published: March 2011

Credit default swaps (CDSs) are term insurance contracts written on traded bonds. This review studies the economics of CDSs using the economics of insurance literature as a basis for analysis. It is alleged that trading in CDSs caused the 2007 credit crisis, and therefore trading CDSs is an evil that needs to be eliminated or controlled. In contrast, I argue that the trading of CDSs is welfare increasing because it facilitates a more optimal allocation of risks in the economy. To perform this function, however, the risk of the CDS seller's failure needs to be minimized. In this regard, government regulation imposing stricter collateral requirements and higher equity capital for CDS traders needs to be introduced.
Government Policy and the Fixed-Rate Mortgage
Authors: Lea Michael , Sanders Anthony B.
Published: March 2011

A central argument in the ongoing discussion about the fates of Fannie Mae and Freddie Mac is the importance of the 30-year, fixed-rate, prepayable mortgage (FRM). The FRM has been held up as the gold standard in mortgage instrument design and as an essential element of the U.S. housing-finance system. Supporters of Fannie Mae and Freddie Mac argue that a government guarantee eliminating credit risk is essential to ensuring the FRM remains the main instrument for housing finance. The FRM has benefits for the consumer through payment stability and the right to prepay the mortgage without penalty. But these benefits come at significant cost. The interest rate and prepayment risk in the FRM are costly and difficult for investors to manage. There is a premium for both the long term and the prepayment options that are paid by all users of the mortgage. The FRM causes instability in the mortgage market through periodic refinancing waves. The FRM can create negative equity in an environment of falling house prices. And the taxpayers are on the hook for hundreds of billions of dollars in losses backing the credit risk guarantees provided by Fannie Mae and Freddie Mac to support securities backed by the FRM. International experience suggests that mortgage markets work fine without an FRM (only Denmark has an equivalent instrument). Borrowers rarely stay with the same mortgage for 15–30 years. Shorter-term fixed-rate mortgages would be less expensive than the FRM in most interest rate environments, particularly if lenders were allowed to charge prepayment penalties. The taxpayer is exposed to too much risk in supporting Fannie Mae and Freddie Mac to justify continued government support for a product for which the costs outweigh the benefits.
Aeroacoustics of Musical Instruments
Authors: Fabre Benoit , Gilbert Joël , Hirschberg Avraham , Pelorson Xavier
Published: March 2011

We are interested in the quality of sound produced by musical instruments and their playability. In wind instruments, a hydrodynamic source of sound is coupled to an acoustic resonator. Linear acoustics can predict the pitch of an instrument. This can significantly reduce the trial-and-error process in the design of a new instrument. We consider deviations from the linear acoustic behavior and the fluid mechanics of the sound production. Real-time numerical solution of the nonlinear physical models is used for sound synthesis in so-called virtual instruments. Although reasonable analytical models are available for reeds, lips, and vocal folds, the complex behavior of flue instruments escapes a simple universal description. Furthermore, to predict the playability of real instruments and help phoneticians or surgeons analyze voice quality, we need more complex models.
Flow and Transport in Regions with Aquatic Vegetation
Authors: Nepf Heidi M.
Published: March 2011

This review describes mean and turbulent flow and mass transport in the presence of aquatic vegetation. Within emergent canopies, the turbulent length scales are set by the stem diameter and spacing, and the mean flow is determined by the distribution of the canopy frontal area. Near sparse submerged canopies, the bed roughness and near-bed turbulence are enhanced, but the velocity profile remains logarithmic. For dense submerged canopies, the drag discontinuity at the top of the canopy generates a shear layer, which contains canopy-scale vortices that control the exchange of mass and momentum between the canopy and the overflow. The canopy-scale vortices penetrate a finite distance into the canopy, δe, set by the canopy drag. This length scale segregates the canopy into two regions: The upper canopy experiences energetic turbulent transport, controlled by canopy-scale vortices, whereas the lower canopy experiences diminished transport, associated with the smaller stem-scale turbulence. The canopy-scale vortices induce a waving motion in flexible blades, called a monami.
The Fluid Mechanics of Cancer and Its Therapy
Authors: Koumoutsakos Petros , Pivkin Igor , Milde Florian
Published: March 2011

Fluid mechanics is involved in the growth, progression, metastasis, and therapy of cancer. Blood vessels transport oxygen and nutrients to cancerous tissues, provide a route for metastasizing cancer cells to distant organs, and deliver drugs to tumors. The irregular and leaky tumor vasculature is responsible for increased interstitial pressure in the tumor microenvironment, whereas multiscale flow-structure interaction processes control tumor growth, metastasis, and nanoparticle-mediated drug delivery. We outline these flow-mediated processes, along with related experimental and computational methods for the diagnosis, predictive modeling, and therapy of cancer.
Hans W. Liepmann, 1914–2009
Authors: Narasimha Roddam , Roshko Anatol , Gharib Morteza
Published: March 2011

This article presents a brief account of the life and work of Hans W. Liepmann, a distinguished fluid dynamicist, an outstanding teacher and leader, and the third Director of the Graduate Aeronautical Laboratories, California Institute of Technology.
Multidisciplinary Optimization with Applications to Sonic-Boom Minimization
Authors: Alonso Juan J. , Colonno Michael R.
Published: March 2011

This article presents a review of key historical contributions, the current status, and future research avenues in support of the development of supersonic aircraft that are sufficiently quiet so that they can be allowed to fly supersonically over land. For this goal to be achievable, in addition to overcoming many other challenges in aerodynamics, structures, propulsion, acoustics, and aeroservoelasticity, the pressure signature created by the aircraft must be such that, when it reaches the ground, (a) it can barely be perceived by the human ear, and (b) it results in disturbances to man-made structures that do not exceed the threshold of annoyance for a significant percentage of the population. In other words, the ground-boom signature must meet a number of key constraints that can be appropriately quantified. In designing aircraft with low sonic booms, it is important to understand (a) how pressure disturbances are generated and how they propagate through the atmosphere, (b) under which conditions will the pressure signature created by an aircraft evolve to generate an acceptable low-boom signature at the ground, and (c) what multidisciplinary trade-offs need to be made to realize low-boom aircraft that are also economically and environmentally compliant. This article discusses each of these areas separately, assesses the accomplishments in each topic, identifies significant shortcomings, and suggests future research efforts (some already ongoing) that have the potential to yield solutions to all these issues.
Fluid Mechanics of Planktonic Microorganisms
Authors: Guasto Jeffrey S. , Rusconi Roberto , Stocker Roman
Published: March 2011

The diversity of the morphologies, propulsion mechanisms, flow environments, and behaviors of planktonic microorganisms has long provided inspiration for fluid physicists, with further intrigue provided by the counterintuitive hydrodynamics of their viscous world. Motivation for studying the fluid dynamics of microplankton abounds, as microorganisms support the food web and control the biogeochemistry of most aquatic environments, particularly the oceans. In this review, we discuss the fluid physics governing the locomotion and feeding of individual planktonic microorganisms (⩽1mm). In the past few years, the field has witnessed an increasing number of exciting discoveries, from the visualization of the flow field around individual swimmers to linkages between microhydrodynamic processes and ecosystem dynamics. In other areas, chiefly the ability of microorganisms to take up nutrients and sense hydromechanical signals, our understanding will benefit from reinvigorated interest, and ample opportunities for breakthroughs exist. When it comes to the fluid mechanics of living organisms, there is plenty of room at the bottom.
Particle Image Velocimetry for Complex and Turbulent Flows
Authors: Westerweel Jerry , Elsinga Gerrit E. , Adrian Ronald J.
Published: March 2011

Particle image velocimetry (PIV) has evolved to be the dominant method for velocimetry in experimental fluid mechanics and has contributed to many advances in our understanding of turbulent and complex flows. In this article we review the achievements of PIV and its latest implementations: time-resolved PIV for the rapid capture of sequences of vector fields; tomographic PIV for the capture of fully resolved volumetric data; and statistical PIV, designed to optimize measurements of mean statistical quantities rather than instantaneous fields. In each implementation, the accuracy and spatial resolution are limited. To advance the method to the next level, we need a completely new approach. We consider the fundamental limitations of two-pulse PIV in terms of its dynamic ranges. We then discuss new paths and developments that hold the promise of achieving a fundamental reduction in uncertainty.
Direct Numerical Simulation on the Receptivity, Instability, and Transition of Hypersonic Boundary Layers
Authors: Zhong Xiaolin , Wang Xiaowen
Published: March 2011

The prediction of the laminar-turbulent transition of boundary layers is critically important to the development of hypersonic vehicles because the transition has a first-order impact on aerodynamic heating, drag, and vehicle operation. The success of transition prediction relies on a fundamental understanding of the relevant physical mechanisms. In the 20 years since the review by Kleiser & Zang (1991) on the direct numerical simulation (DNS) of the boundary-layer transition, significant progress has been made on DNS in the hypersonic flow regime and in the spatial DNS approach. Many high-order shock-capturing and shock-fitting finite-difference methods have been developed and extensively applied to numerical simulations of the hypersonic boundary-layer transition. DNS has become a powerful research tool and has led to discoveries of new transition mechanisms. This article reviews the recent progress of DNS on hypersonic boundary-layer receptivity, instability, and transition. The current status and future directions are also presented.
Smoothed Particle Hydrodynamics and Its Diverse Applications
Authors: Monaghan J.J.
Published: March 2011

This review focuses on the applications of smoothed particle hydrodynamics (SPH) to incompressible or nearly incompressible flow. In the past 17 years, the range of applications has increased as researchers have realized the ability of SPH algorithms to handle complex physical problems. These include the disruption of free surfaces when a wave hits a rocky beach, multifluid problems that may involve the motion of rigid and elastic bodies, non-Newtonian fluids, virtual surgery, and chemical precipitation from fluids moving through fractured media. SPH provides a fascinating tool that has some of the properties of molecular dynamics while retaining the attributes of the macroscopic equations of continuum mechanics.
The Significance of Simple Invariant Solutions in Turbulent Flows
Authors: Kawahara Genta , Uhlmann Markus , van Veen Lennaert
Published: March 2011

Recent remarkable progress in computing power and numerical analysis is enabling us to fill a gap in the dynamical systems approach to turbulence. A significant advance in this respect has been the numerical discovery of simple invariant sets, such as nonlinear equilibria and periodic solutions, in well-resolved Navier-Stokes flows. This review describes some fundamental and practical aspects of dynamical systems theory for the investigation of turbulence, focusing on recently found invariant solutions and their significance for the dynamical and statistical characterization of low-Reynolds-number turbulent flows. It is shown that the near-wall regeneration cycle of coherent structures can be reproduced by such solutions. The typical similarity laws of turbulence, i.e., the Prandtl wall law and the Kolmogorov law for the viscous range, as well as the pattern and intensity of turbulence-driven secondary flow in a square duct can also be represented by these simple invariant solutions.
Human Copy Number Variation and Complex Genetic Disease
Authors: Girirajan Santhosh , Campbell Catarina D. , Eichler Evan E.
Published: March 2011

Copy number variants (CNVs) play an important role in human disease and population diversity. Advancements in technology have allowed for the analysis of CNVs in thousands of individuals with disease in addition to thousands of controls. These studies have identified rare CNVs associated with neuropsychiatric diseases such as autism, schizophrenia, and intellectual disability. In addition, copy number polymorphisms (CNPs) are present at higher frequencies in the population, show high diversity in copy number, sequence, and structure, and have been associated with multiple phenotypes, primarily related to immune or environmental response. However, the landscape of copy number variation still remains largely unexplored, especially for smaller CNVs and those embedded within complex regions of the human genome. An integrated approach including characterization of single nucleotide variants and CNVs in a large number of individuals with disease and normal genomes holds the promise of thoroughly elucidating the genetic basis of human disease and diversity.
Toxin-Antitoxin Systems in Bacteria and Archaea
Authors: Yamaguchi Yoshihiro , Park Jung-Ho , Inouye Masayori
Published: March 2011

Almost all bacteria and many archaea contain genes whose expression inhibits cell growth and may lead to cell death when overproduced, reminiscent of apoptotic genes in higher systems. The cellular targets of these toxins are quite diverse and include DNA replication, mRNA stability, protein synthesis, cell-wall biosynthesis, and ATP synthesis. These toxins are co-expressed and neutralized with their cognate antitoxins from a TA (toxin-antitoxin) operon in normally growing cells. Antitoxins are more labile than toxins and are readily degraded under stress conditions, allowing the toxins to exert their toxic effect. Presence of at least 33 TA systems in Escherichia coli and more than 60 TA systems in Mycobacterium tuberculosis suggests that the TA systems are involved not only in normal bacterial physiology but also in pathogenicity of bacteria. The elucidation of their cellular function and regulation is thus crucial for our understanding of bacterial physiology under various stress conditions.
Comparative Genetics and Genomics of Nematodes: Genome Structure, Development, and Lifestyle
Authors: Sommer Ralf J. , Streit Adrian
Published: March 2011

Nematodes are found in virtually all habitats on earth. Many of them are parasites of plants and animals, including humans. The free-living nematode, Caenorhabditis elegans, is one of the genetically best-studied model organisms and was the first metazoan whose genome was fully sequenced. In recent years, the draft genome sequences of another six nematodes representing four of the five major clades of nematodes were published. Compared to mammalian genomes, all these genomes are very small. Nevertheless, they contain almost the same number of genes as the human genome. Nematodes are therefore a very attractive system for comparative genetic and genomic studies, with C. elegans as an excellent baseline. Here, we review the efforts that were made to extend genetic analysis to nematodes other than C. elegans, and we compare the seven available nematode genomes. One of the most striking findings is the unexpectedly high incidence of gene acquisition through horizontal gene transfer (HGT).
Double-Strand Break End Resection and Repair Pathway Choice
Authors: Symington Lorraine S. , Gautier Jean
Published: March 2011

DNA double-strand breaks (DSBs) are cytotoxic lesions that can result in mutagenic events or cell death if left unrepaired or repaired inappropriately. Cells use two major pathways for DSB repair: nonhomologous end joining (NHEJ) and homologous recombination (HR). The choice between these pathways depends on the phase of the cell cycle and the nature of the DSB ends. A critical determinant of repair pathway choice is the initiation of 5′-3′ resection of DNA ends, which commits cells to homology-dependent repair, and prevents repair by classical NHEJ. Here, we review the components of the end resection machinery, the role of end structure, and the cell-cycle phase on resection and the interplay of end processing with NHEJ.
Maternal and Zygotic Control of Zebrafish Dorsoventral Axial Patterning
Authors: Langdon Yvette G. , Mullins Mary C.
Published: March 2011

Vertebrate development begins with precise molecular, cellular, and morphogenetic controls to establish the basic body plan of the embryo. In zebrafish, these tightly regulated processes begin during oogenesis and proceed through gastrulation to establish and pattern the axes of the embryo. During oogenesis a maternal factor is localized to the vegetal pole of the oocyte that is a determinant of dorsal tissues. Following fertilization this vegetally localized dorsal determinant is asymmetrically translocated in the egg and initiates formation of the dorsoventral axis. Dorsoventral axis formation and patterning is then mediated by maternal and zygotic factors acting through Wnt, BMP (bone morphogenetic protein), Nodal, and FGF (fibroblast growth factor) signaling pathways, each of which is required to establish and/or pattern the dorsoventral axis. This review addresses recent advances in our understanding of the molecular factors and mechanisms that establish and pattern the dorsoventral axis of the zebrafish embryo, including establishment of the animal-vegetal axis as it relates to formation of the dorsoventral axis.
Fusion and Fission: Interlinked Processes Critical for Mitochondrial Health
Authors: Chan David C.
Published: March 2011

Mitochondria are dynamic organelles that continually undergo fusion and fission. These opposing processes work in concert to maintain the shape, size, and number of mitochondria and their physiological function. Some of the major molecules mediating mitochondrial fusion and fission in mammals have been discovered, but the underlying molecular mechanisms are only partially unraveled. In particular, the cast of characters involved in mitochondrial fission needs to be clarified. By enabling content mixing between mitochondria, fusion and fission serve to maintain a homogeneous and healthy mitochondrial population. Mitochondrial dynamics has been linked to multiple mitochondrial functions, including mitochondrial DNA stability, respiratory capacity, apoptosis, response to cellular stress, and mitophagy. Because of these important functions, mitochondrial fusion and fission are essential in mammals, and even mild defects in mitochondrial dynamics are associated with disease. A better understanding of these processes likely will ultimately lead to improvements in human health.
Uniting Germline and Stem Cells: The Function of Piwi Proteins and the piRNA Pathway in Diverse Organisms
Authors: Juliano Celina , Wang Jianquan , Lin Haifan
Published: March 2011

The topipotency of the germline is the full manifestation of the pluri- and multipotency of embryonic and adult stem cells, thus the germline and stem cells must share common mechanisms that guarantee their multipotentials in development. One of the few such known shared mechanisms is represented by Piwi proteins, which constitute one of the two subfamilies of the Argonaute protein family. Piwi proteins bind to Piwi-interacting RNAs (piRNAs) that are generally 26 to 31 nucleotides in length. Both Piwi proteins and piRNAs are most abundantly expressed in the germline. Moreover, Piwi proteins are expressed broadly in certain types of somatic stem/progenitor cells and other somatic cells across animal phylogeny. Recent studies indicate that the Piwi-piRNA pathway mediates epigenetic programming and posttranscriptional regulation, which may be responsible for its function in germline specification, gametogenesis, stem cell maintenance, transposon silencing, and genome integrity in diverse organisms.
The Biosynthetic Capacities of the Plastids and Integration Between Cytoplasmic and Chloroplast Processes
Authors: Rolland Norbert , Curien Gilles , Finazzi Giovanni , Kuntz Marcel , Maréchal Eric , Matringe Michel , Ravanel Stéphane , Seigneurin-Berny Daphné
Published: March 2011

Plastids are semiautonomous organelles derived from cyanobacterial ancestors. Following endosymbiosis, plastids have evolved to optimize their functions, thereby limiting metabolic redundancy with other cell compartments. Contemporary plastids have also recruited proteins produced by the nuclear genome of the host cell. In addition, many genes acquired from the cyanobacterial ancestor evolved to code for proteins that are targeted to cell compartments other than the plastid. Consequently, metabolic pathways are now a patchwork of enzymes of diverse origins, located in various cell compartments. Because of this, a wide range of metabolites and ions traffic between the plastids and other cell compartments. In this review, we provide a comprehensive analysis of the well-known, and of the as yet uncharacterized, chloroplast/cytosol exchange processes, which can be deduced from what is currently known about compartmentation of plant-cell metabolism.
The Rules of Engagement in the Legume-Rhizobial Symbiosis
Authors: Oldroyd Giles E.D. , Murray Jeremy D. , Poole Philip S. , Downie J. Allan
Published: March 2011

Rhizobial bacteria enter a symbiotic association with leguminous plants, resulting in differentiated bacteria enclosed in intracellular compartments called symbiosomes within nodules on the root. The nodules and associated symbiosomes are structured for efficient nitrogen fixation. Although the interaction is beneficial to both partners, it comes with rigid rules that are strictly enforced by the plant. Entry into root cells requires appropriate recognition of the rhizobial Nod factor signaling molecule, and this recognition activates a series of events, including polarized root-hair tip growth, invagination associated with bacterial infection, and the promotion of cell division in the cortex leading to the nodule meristem. The plant's command of the infection process has been highlighted by its enforcement of terminal differentiation upon the bacteria within nodules of some legumes, and this can result in a loss of bacterial viability while permitting effective nitrogen fixation. Here, we review the mechanisms by which the plant allows bacterial infection and promotes the formation of the nodule, as well as the details of how this intimate association plays out inside the cells of the nodule where a complex interchange of metabolites and regulatory peptides force the bacteria into a nitrogen-fixing organelle-like state.
RNA-Mediated Epigenetic Programming of Genome Rearrangements
Authors: Nowacki Mariusz , Shetty Keerthi , Landweber Laura F.
Published: March 2011

RNA, normally thought of as a conduit in gene expression, has a novel mode of action in ciliated protozoa. Maternal RNA templates provide both an organizing guide for DNA rearrangements and a template that can transport somatic mutations to the next generation. This opportunity for RNA-mediated genome rearrangement and DNA repair is profound in the ciliate Oxytricha, which deletes 95% of its germline genome during development in a process that severely fragments its chromosomes and then sorts and reorders the hundreds of thousands of pieces remaining. Oxytricha's somatic nuclear genome is therefore an epigenome formed through RNA templates and signals arising from the previous generation. Furthermore, this mechanism of RNA-mediated epigenetic inheritance can function across multiple generations, and the discovery of maternal template RNA molecules has revealed new biological roles for RNA and has hinted at the power of RNA molecules to sculpt genomic information in cells.
Personalized Medicine: Progress and Promise
Authors: Chan Isaac S. , Ginsburg Geoffrey S.
Published: March 2011

Personalized medicine is a broad and rapidly advancing field of health care that is informed by each person's unique clinical, genetic, genomic, and environmental information. Personalized medicine depends on multidisciplinary health care teams and integrated technologies (e.g., clinical decision support) to utilize our molecular understanding of disease in order to optimize preventive health care strategies. Human genome information now allows providers to create optimized care plans at every stage of a disease, shifting the focus from reactive to preventive health care. The further integration of personalized medicine into the clinical workflow requires overcoming several barriers in education, accessibility, regulation, and reimbursement. This review focuses on providing a comprehensive understanding of personalized medicine, from scientific discovery at the laboratory bench to integration of these novel ways of understanding human biology at the bedside.
The Tension Between Data Sharing and the Protection of Privacy in Genomics Research
Authors: Kaye Jane
Published: March 2011

Next-generation sequencing and global data sharing challenge many of the governance mechanisms currently in place to protect the privacy of research participants. These challenges will make it more difficult to guarantee anonymity for participants, provide information to satisfy the requirements of informed consent, and ensure complete withdrawal from research when requested. To move forward, we need to improve the current governance systems for research so that they are responsive to individual privacy concerns but can also be effective at a global level. We need to develop a system of e-governance that can complement existing governance systems but that places greater reliance on the use of technology to ensure compliance with ethical and legal requirements. These new governance structures must be able to address the concerns of research participants while at the same time ensuring effective data sharing that promotes public trust in genomics research.
Genomic Approaches to Deconstruct Pluripotency
Authors: Loh Yuin-Han , Yang Lin , Yang Jimmy Chen , Li Hu , Collins James J. , Daley George Q.
Published: March 2011

Embryonic stem cells (ESCs) first derived from the inner cell mass of blastocyst-stage embryos have the unique capacity of indefinite self-renewal and potential to differentiate into all somatic cell types. Similar developmental potency can be achieved by reprogramming differentiated somatic cells into induced pluripotent stem cells (iPSCs). Both types of pluripotent stem cells provide great potential for fundamental studies of tissue differentiation, and hold promise for disease modeling, drug development, and regenerative medicine. Although much has been learned about the molecular mechanisms that underlie pluripotency in such cells, our understanding remains incomplete. A comprehensive understanding of ESCs and iPSCs requires the deconstruction of complex transcription regulatory networks, epigenetic mechanisms, and biochemical interactions critical for the maintenance of self-renewal and pluripotency. In this review, we will discuss recent advances gleaned from application of global “omics” techniques to dissect the molecular mechanisms that define the pluripotent state.
Unraveling the Genetics of Cancer: Genome Sequencing and Beyond
Authors: Wong Kit Man , Hudson Thomas J. , McPherson John D.
Published: March 2011

Advances in next-generation sequencing technology are enabling the systematic analyses of whole cancer genomes, providing insights into the landscape of somatic mutations and the great genetic heterogeneity that defines the unique signature of an individual tumor. Moreover, integrated studies of the genome, epigenome, and transcriptome reveal mechanisms of tumorigenesis at multiple levels. Progress in sequencing technologies and bioinformatics will improve the costs, sensitivity, and accuracy of detecting somatic mutations, while large-scale projects are underway to coordinate cancer genome sequencing at the global level to facilitate the generation and dissemination of high-quality uniform genetic data. These developments will create opportunities for deeper studies of cancer genetics and the clinical application of genome sequencing, and will motivate further research in cancer pathogenesis.
LINE-1 Elements in Structural Variation and Disease
Authors: Beck Christine R. , Garcia-Perez José Luis , Badge Richard M. , Moran John V.
Published: March 2011

The completion of the human genome reference sequence ushered in a new era for the study and discovery of human transposable elements. It now is undeniable that transposable elements, historically dismissed as junk DNA, have had an instrumental role in sculpting the structure and function of our genomes. In particular, long interspersed element-1 (LINE-1 or L1) and short interspersed elements (SINEs) continue to affect our genome, and their movement can lead to sporadic cases of disease. Here, we briefly review the types of transposable elements present in the human genome and their mechanisms of mobility. We next highlight how advances in DNA sequencing and genomic technologies have enabled the discovery of novel retrotransposons in individual genomes. Finally, we discuss how L1-mediated retrotransposition events impact human genomes.
Genetics of Speech and Language Disorders
Authors: Kang Changsoo , Drayna Dennis
Published: March 2011

Vocal communication mediated by speech and language is a uniquely human trait, and has served an important evolutionary role in the development of our species. Deficits in speech and language functions can be of numerous types, including aphasia, stuttering, articulation disorders, verbal dyspraxia, and specific language impairment; language deficits are also related to dyslexia. Most communication disorders are prominent in children, where they are common. A number of these disorders have been shown to cluster in families, suggesting that genetic factors are involved, but their etiology at the molecular level is not well understood. In the past decade, genetic methods have proven to be powerful for understanding these etiologies. Linkage studies and molecular genetic analyses in a large family containing multiple individuals affected with verbal dyspraxia led to the discovery of mutations in the FOXP2 gene. This gene encodes a forkhead domain transcription factor, a finding that has led researchers to a new avenue of investigation into the substrates and mechanisms that underlie human speech development. In studies of stuttering, linkage and candidate gene approaches in consanguineous families identified mutations in the lysosomal enzyme-targeting pathway genes GNPTAB, GNPTG, and NAGPA, revealing a role for inherited defects in cell metabolism in this disorder. In specific language impairment, linkage studies have identified several loci, and candidate gene association studies are making progress in identifying causal variants at these loci. Although only a small fraction of all cases of speech and language disorders can be explained by genetic findings to date, the significant progress made thus far suggests that genetic approaches will continue to provide important avenues for research on this group of disorders.
Copy Number and SNP Arrays in Clinical Diagnostics
Authors: Schaaf Christian P. , Wiszniewska Joanna , Beaudet Arthur L.
Published: March 2011

The ability of chromosome microarray analysis (CMA) to detect submicroscopic genetic abnormalities has revolutionized the clinical diagnostic approach to individuals with intellectual disability, neurobehavioral phenotypes, and congenital malformations. The recognition of the underlying copy number variant (CNV) in respective individuals may allow not only for better counseling and anticipatory guidance but also for more specific therapeutic interventions in some cases. The use of CMA technology in prenatal diagnosis is emerging and promises higher sensitivity for several highly penetrant, clinically severe microdeletion and microduplication syndromes. Genetic counseling complements the diagnostic testing with CMA, given the presence of CNVs of uncertain clinical significance, incomplete penetrance, and variable expressivity in some cases. While oligonucleotide arrays with high-density exonic coverage remain the gold standard for the detection of CNVs, single-nucleotide polymorphism (SNP) arrays allow for detection of consanguinity and most cases of uniparental disomy and provide a higher sensitivity to detect low-level mosaic aneuploidies.
Innate Antifungal Immunity: The Key Role of Phagocytes
Authors: Brown Gordon D.
Published: March 2011

Fungal diseases have emerged as significant causes of morbidity and mortality, particularly in immune-compromised individuals, prompting greater interest in understanding the mechanisms of host resistance to these pathogens. Consequently, the past few decades have seen a tremendous increase in our knowledge of the innate and adaptive components underlying the protective (and nonprotective) mechanisms of antifungal immunity. What has emerged from these studies is that phagocytic cells are essential for protection and that defects in these cells compromise the host's ability to resist fungal infection. This review covers the functions of phagocytes in innate antifungal immunity, along with selected examples of the strategies that are used by fungal pathogens to subvert these defenses.
Prevention and Treatment of Papillomavirus-Related Cancers Through Immunization
Authors: Frazer Ian H. , Leggatt Graham R. , Mattarollo Stephen R.
Published: March 2011

Cervical and other anogenital cancers are initiated by infection with one of a small group of human papillomaviruses (HPV). Virus-like particle-based vaccines have recently been developed to prevent infection with two cancer-associated HPV genotypes (HPV16, HPV18) and have been ∼95% effective at preventing HPV-associated disease caused by these genotypes in virus-naive subjects. Although immunization induces virus-neutralizing antibody sufficient to prevent infection, persistence of antibody as measured by current assays does not appear necessary to maintain protection over time. Investigators have not identified a reliable surrogate immunological marker of protection against disease following immunization. The prophylactic vaccines are not therapeutic for existing infection. Trials of HPV-specific immunotherapy have shown some efficacy for existing disease, although animal modeling suggests that a combination of immunization and local enhancement of innate immunity may be necessary for optimal therapeutic outcome. HPV prophylactic vaccines are the first vaccines designed to prevent a human cancer and are the practical outcome of a global collaborative effort between basic and applied scientists, clinicians, and industry.
Nucleic Acid Recognition by the Innate Immune System
Authors: Barbalat Roman , Ewald Sarah E. , Mouchess Maria L. , Barton Gregory M.
Published: March 2011

Receptors of the innate immune system recognize conserved microbial features and provide key signals that initiate immune responses. Multiple transmembrane and cytosolic receptors have evolved to recognize RNA and DNA, including members of the Toll-like receptor and RIG-I-like receptor families and several DNA sensors. This strategy enables recognition of a broad range of pathogens; however, in some cases, this benefit is weighed against the cost of potential self recognition. Recognition of self nucleic acids by the innate immune system contributes to the pathology associated with several autoimmune or autoinflammatory diseases. In this review, we highlight our current understanding of nucleic acid sensing by innate immune receptors and discuss the regulatory mechanisms that normally prevent inappropriate responses to self.
Stromal Cell–Immune Cell Interactions
Authors: Roozendaal Ramon , Mebius Reina E.
Published: March 2011

Interaction between different types of hematopoietic cells is essential for proper functioning of the immune system. For instance, the cytokines produced by antigen-presenting dendritic cells will determine the type of T cell response that is induced. However, hematopoietic cells are also strongly influenced by the surrounding nonhematopoietic cells. The cells that form these microenvironments are collectively called stromal cells. Here, we focus on the stromal cells present within secondary lymphoid organs and discuss their importance for various aspects of the immune system.
Law, Environment, and the “Nondismal” Social Sciences
Authors: Boyd William , Kysar Douglas A. , Rachlinski Jeffrey J.
Published: March 2011

Over the past 30 years, the influence of economics over the study of environmental law and policy has expanded considerably, becoming in the process the predominant framework for analyzing regulations that address pollution, natural resource use, and other environmental issues. This review seeks to complement the expansion of economic reasoning and methodology within the field of environmental law and policy by identifying insights to be gleaned from various “nondismal” social sciences. In particular, three areas of inquiry are highlighted as illustrative of interdisciplinary work that might help to complement law and economics and, in some cases, compensate for it: the study of how human individuals perceive, judge, and decide; the observation and interpretation of how knowledge schemes are created, used, and regulated; and the analysis of how states and other actors coordinate through international and global regulatory regimes. The hope is to provide some examples of how environmental law and policy research can be improved by deeper and more diverse engagement with social science.
Credible Causal Inference for Empirical Legal Studies
Authors: Ho Daniel E. , Rubin Donald B.
Published: March 2011

We review advances toward credible causal inference that have wide application for empirical legal studies. Our chief point is simple: Research design trumps methods of analysis. We explain matching and regression discontinuity approaches in intuitive (nontechnical) terms. To illustrate, we apply these to existing data on the impact of prison facilities on inmate misconduct, which we compare to experimental evidence. What unifies modern approaches to causal inference is the prioritization of research design to create—without reference to any outcome data—subsets of comparable units. Within those subsets, outcome differences may then be plausibly attributed to exposure to the treatment rather than control condition. Traditional methods of analysis play a small role in this venture. Credible causal inference in law turns on substantive legal, not mathematical, knowledge.
The Triumph and Tragedy of Tobacco Control: A Tale of Nine Nations
Authors: Feldman Eric A. , Bayer Ronald
Published: March 2011

The use of law and policy to limit tobacco consumption illustrates one of the greatest triumphs of public health in the late twentieth and early twenty-first centuries, as well as one of its most fundamental failures. Overall decreases in tobacco consumption throughout the developed world represent millions of saved lives and unquantifiable suffering averted. Yet those benefits have not been equally distributed. The poor and the undereducated have enjoyed fewer of the gains. In this review, we build on existing tobacco control scholarship and expand it both conceptually and comparatively. Our focus is the social gradient of smoking both within and across borders and how policy makers have been most effective in limiting smoking prevalence among the more privileged segments of society. To illustrate that point, we reference a range of literature on tobacco taxation, advertising, and public smoking in five economically advanced democracies—France, Germany, Japan, the United Kingdom, and the United States—and four less developed nations—India, China, Brazil, and South Africa—that together comprise 40% of the world's population.
Race and Inequality in the War on Drugs
Authors: Provine Doris Marie
Published: March 2011

Drug use is pervasive, generally private, and of long standing. The social effects are sometimes problematic, but it is a large step to declare a war on drug use. This review considers how that approach came to be adopted in the United States and why it persists despite its evident shortcomings. This war could not be maintained without societal racism and the manipulation of racial stereotypes to make drugs something to be feared. Beneath society's adherence to a failed criminalization approach is a startling indifference to its racial impact, which includes a vast increase in the number and representation of poor minorities in the prison system, particularly young African American males. Tracing the war on drugs to its roots reveals a broader domain in which harsh legislation, prosecution, and incarceration combine to harm and stigmatize minority populations, while a pervasive ideology of color blindness discourages serious discussion of inherent racial bias in the criminal justice system.