bluuebunny/crossref_metadata_2025 huggingface dataset:
Hydrophobicity of Proteins and Interfaces: Insights from Density Fluctuations
Authors: Jamadagni Sumanth N. , Godawat Rahul , Garde Shekhar
Published: March 2011

Macroscopic characterizations of hydrophobicity (e.g., contact angle measurements) do not extend to the surfaces of proteins and nanoparticles. Molecular measures of hydrophobicity of such surfaces need to account for the behavior of hydration water. Theory and state-of-the-art simulations suggest that water density fluctuations provide such a measure; fluctuations are enhanced near hydrophobic surfaces and quenched with increasing surface hydrophilicity. Fluctuations affect conformational equilibria and dynamics of molecules at interfaces. Enhanced fluctuations are reflected in enhanced cavity formation, more favorable binding of hydrophobic solutes, increased compressibility of hydration water, and enhanced water-water correlations at hydrophobic surfaces. These density fluctuation–based measures can be used to develop practical methods to map the hydrophobicity/philicity of heterogeneous surfaces including those of proteins. They highlight that the hydrophobicity of a group is context dependent and is significantly affected by its environment (e.g., chemistry and topography) and especially by confinement. The ability to include information about hydration water in mapping hydrophobicity is expected to significantly impact our understanding of protein-protein interactions as well as improve drug design and discovery methods and bioseparation processes.
Deconstruction of Lignocellulosic Biomass to Fuels and Chemicals
Authors: Chundawat Shishir P.S. , Beckham Gregg T. , Himmel Michael E. , Dale Bruce E.
Published: March 2011

Plants represent a vast, renewable resource and are well suited to provide sustainably for humankind's transportation fuel needs. To produce infrastructure-compatible fuels from biomass, two challenges remain: overcoming plant cell wall recalcitrance to extract sugar and phenolic intermediates, and reduction of oxygenated intermediates to fuel molecules. To compete with fossil-based fuels, two primary routes to deconstruct cell walls are under development, namely biochemical and thermochemical conversion. Here, we focus on overcoming recalcitrance with biochemical conversion, which uses low-severity thermochemical pretreatment followed by enzymatic hydrolysis to produce soluble sugars. Many challenges remain, including understanding how pretreatments affect the physicochemical nature of heterogeneous cell walls; determination of how enzymes deconstruct the cell wall effectively with the aim of designing superior catalysts; and resolution of issues associated with the co-optimization of pretreatment, enzymatic hydrolysis, and fermentation. Here, we highlight some of the scientific challenges and open questions with a particular focus on problems across multiple length scales.
Novel Solvents for Sustainable Production of Specialty Chemicals
Authors: Fadhel Ali Z. , Pollet Pamela , Liotta Charles L. , Eckert Charles A.
Published: March 2011

We discuss novel solvents that improve the sustainability of various chemical reactions and processes. These alternative solvents include organic-aqueous tunable solvents; near-critical water; switchable piperylene sulfone, a volatile dimethylsulfoxide substitute; and reversible ionic liquids. These solvents are advantageous to a wide variety of reactions because they reduce waste and energy demand by coupling homogeneous reactions with heterogeneous separations, acting as in situ acid or base catalysts, and providing simple and efficient postreaction separations.
Open, Aware, and Active: Contextual Approaches as an Emerging Trend in the Behavioral and Cognitive Therapies
Authors: Hayes Steven C. , Villatte Matthieu , Levin Michael , Hildebrandt Mikaela
Published: March 2011

A wave of new developments has occurred in the behavioral and cognitive therapies that focuses on processes such as acceptance, mindfulness, attention, or values. In this review, we describe some of these developments and the data regarding them, focusing on information about components, moderators, mediators, and processes of change. These “third wave” methods all emphasize the context and function of psychological events more so than their validity, frequency, or form, and for these reasons we use the term “contextual cognitive behavioral therapy” to describe their characteristics. Both putative processes, and component and process evidence, indicate that they are focused on establishing a more open, aware, and active approach to living, and that their positive effects occur because of changes in these processes.
Treatment of Obsessive Compulsive Disorder
Authors: Franklin Martin E. , Foa Edna B.
Published: March 2011

Obsessive compulsive disorder (OCD) is characterized by the presence of intrusive, anxiety-provoking thoughts, images, or impulses along with repetitive behaviors or mental acts designed to reduce obsessional distress. OCD is associated with significant functional impairment, psychiatric comorbidity, and compromised quality of life. Fortunately, substantive progress has been made in the past several decades in the development and empirical evaluation of treatments for OCD across the developmental spectrum. The current review begins with a discussion of the clinical presentation of OCD and psychological theories regarding its etiology and maintenance. A detailed discussion follows of exposure plus response prevention, the psychosocial treatment that has garnered the most evidence for its efficacy. A summary of the extant treatment outcome literature related to exposure plus response prevention as well as cognitive therapies, pharmacotherapies, and combined approaches is then presented. Recommendations for future clinical and research directions are then provided.
The Nature and Significance of Memory Disturbance in Posttraumatic Stress Disorder
Authors: Brewin Chris R.
Published: March 2011

Disturbances in aspects of memory described in current learning and cognitive theories are much more strongly associated with the presence of psychiatric disorder than with mere exposure to traumatic events. In posttraumatic stress disorder (PTSD), there are numerous associated changes that involve memory capacity, the content of memories for trauma, and a variety of memory processes. Whereas some changes appear to reflect the effects of the disorder, other evidence supports a predictive or causal role for memory disturbance. The following aspects of memory are likely to play a causal role in the development or maintenance of PTSD: verbal memory deficits, negative conceptual knowledge concerning the self, overgeneral memory, avoidance or suppression of memories, and negative interpretation of memory symptoms. Other aspects of memory likely to play a causal role that are in addition specific to PTSD are the integration of the trauma with identity, impairment in retrieval of voluntary trauma memories, and increased incidence of sensation-based memories or flashbacks.
Efficacy Studies to Large-Scale Transport: The Development and Validation of Multisystemic Therapy Programs
Authors: Henggeler Scott W.
Published: March 2011

The 35-year progression of multisystemic therapy (MST) from modest university-based efficacy studies to large-scale transport to community practice settings is described in this review. The success of early efficacy research led to effectiveness trials, and their success in decreasing rates of youth rearrest and incarceration led to multisite transportability trials and adaptations of the MST model for treating youth presenting other types of challenging clinical problems. To support the transport of MST programs to community settings, an intensive quality improvement system modeled after that used in clinical trials has been implemented in community-based MST programs for the past 15 years. With the association between therapist treatment fidelity and youth outcomes well established, transportability research has demonstrated the significant roles played by clinical supervisors, expert consultants, and provider organizations in supporting therapist adherence and youth outcomes. This body of work has been facilitated by federal and state initiatives to support evidence-based services.
Superconducting Microresonators: Physics and Applications
Authors: Zmuidzinas Jonas
Published: March 2011

Interest in superconducting microresonators has grown dramatically over the past decade. Resonator performance has improved substantially through the use of improved geometries and materials as well as a better understanding of the underlying physics. These advances have led to the adoption of superconducting microresonators in a large number of low-temperature experiments and applications. This review outlines these developments, with particular attention given to the use of superconducting microresonators as detectors.
Mechanical Instabilities of Gels
Authors: Dervaux Julien , Amar Martine Ben
Published: March 2011

Although the study of gels undoubtedly takes its roots within the field of physicochemistry, the interest in gels has flourished and they have progressively become an important object in the study of the mechanics of polymeric materials and volumetric growth, raising some fascinating problems, some of them remaining unsolved. Because gels are multiphase objects, their study represents an important step in the understanding of the mechanics of complex soft matter as well as for the process of shape generation in biological bodies. The scope of this article is to review the understanding we have of the mechanical behavior of gels, with a strong focus on the development of instabilities in swelling gels.
Biogeochemistry of Microbial Coal-Bed Methane
Authors: Strąpoć Dariusz , Mastalerz Maria , Dawson Katherine , Macalady Jennifer , Callaghan Amy V. , Wawrik Boris , Turich Courtney , Ashby Matthew
Published: March 2011

Microbial methane accumulations have been discovered in multiple coal-bearing basins over the past two decades. Such discoveries were originally based on unique biogenic signatures in the stable isotopic composition of methane and carbon dioxide. Basins with microbial methane contain either low-maturity coals with predominantly microbial methane gas or uplifted coals containing older, thermogenic gas mixed with more recently produced microbial methane. Recent advances in genomics have allowed further evaluation of the source of microbial methane, through the use of high-throughput phylogenetic sequencing and fluorescent in situ hybridization, to describe the diversity and abundance of bacteria and methanogenic archaea in these subsurface formations. However, the anaerobic metabolism of the bacteria breaking coal down to methanogenic substrates, the likely rate-limiting step in biogenic gas production, is not fully understood. Coal molecules are more recalcitrant to biodegradation with increasing thermal maturity, and progress has been made in identifying some of the enzymes involved in the anaerobic degradation of these recalcitrant organic molecules using metagenomic studies and culture enrichments. In recent years, researchers have attempted lab and subsurface stimulation of the naturally slow process of methanogenic degradation of coal.
Archean Microbial Mat Communities
Authors: Tice Michael M. , Thornton Daniel C.O. , Pope Michael C. , Olszewski Thomas D. , Gong Jian
Published: March 2011

Much of the Archean record of microbial communities consists of fossil mats and stromatolites. Critical physical emergent properties governing the evolution of large-scale (centimeters to meters) topographic relief on the mat landscape are (a) mat surface roughness relative to the laminar sublayer and (b) cohesion. These properties can be estimated for fossil samples under many circumstances. A preliminary analysis of Archean mat cohesion suggests that mats growing in shallow marine environments from throughout this time had cohesions similar to those of modern shallow marine mats. There may have been a significant increase in mat strength at the end of the Archean.
An Evolutionary Perspective on Self-Organized Division of Labor in Social Insects
Authors: Duarte Ana , Weissing Franz J. , Pen Ido , Keller Laurent
Published: March 2011

Division of labor is a complex phenomenon observed throughout nature. Theoretical studies have focused either on its emergence through self-organization mechanisms or on its adaptive consequences. We suggest that the interaction of self-organization, which undoubtedly characterizes division of labor in social insects, and evolution should be further explored. We review the factors empirically shown to influence task choice. In light of these factors, we review the most important self-organization and evolutionary models for division of labor and outline their advantages and limitations. We describe ways to unify evolution and self-organization in the theoretical study of division of labor and recent results in this area. Finally, we discuss some benchmarks and primary challenges of this approach.
New Pathways and Processes in the Global Nitrogen Cycle
Authors: Thamdrup Bo
Published: March 2011

Our understanding of the players and pathways of the global nitrogen cycle has advanced substantially over recent years with discoveries of several new groups of organisms and new types of metabolism. This review focuses on recently discovered processes that add new functionality to the nitrogen cycle and on the organisms that perform these functions. The processes include denitrification and other dissimilatory nitrogen transformations in eukaryotes, anaerobic ammonium oxidation, and anaerobic methane oxidation with nitrite. Of these, anaerobic ammonium oxidation coupled to nitrite reduction by anammox bacteria has been well documented in natural environments and constitutes an important sink for fixed nitrogen. Benthic foraminifera also contribute substantially to denitrification in some sediments, in what potentially represents an ancestral eukaryotic metabolism. The ecophysiology of the novel organisms and their interactions with classical types of nitrogen metabolism are important for understanding the nitrogen cycle and its tight links to the cycling of carbon today, in the past, and in the future.
The Role of Mountain Ranges in the Diversification of Birds
Authors: Fjeldså Jon , Bowie Rauri C.K. , Rahbek Carsten
Published: March 2011

Avian faunas vary greatly among montane areas; those at high latitudes are biologically impoverished, whereas those of some low-latitude mountains are biologically very complex. Their high level of species richness is caused by the aggregation of many small-ranged species, which has been difficult to explain from purely macroecological models focusing on contemporary ecological processes. Because the individual mountain tracts harbor species that represent different evolutionary trajectories, it seems plausible to relate these species assemblages to high persistence (or absence of extinction) in addition to high levels of speciation. The distribution of small-ranged species is concentrated near tropical coasts, where moderation of the climate in topographically complex areas creates cloud forests and stable local conditions. The stability underpins specialization and resilience of local populations, and thereby the role of these places as cradles of biodiversity.
Health Behavior in Developing Countries
Authors: Dupas Pascaline
Published: March 2011

The disease burden in low-income countries is extremely high. Malaria, respiratory infections, diarrhea, AIDS, and other diseases are estimated to kill more than 15 million people each year, most of them children. Yet the great majority of these diseases can be prevented or treated. This article reviews microeconomic studies of health-seeking behavior in low-income countries. Factors examined include information, peers, liquidity constraints, and nonrational preferences, such as present bias. I then discuss the implications for policy, including the scope for mandates, subsidies, and incentives.
Imperfect Credit Markets, Household Wealth Distribution, and Development
Authors: Matsuyama Kiminori
Published: March 2011

This article discusses some key results in the theoretical literature on credit market imperfections, household wealth distribution, and development by conducting three types of analysis, which progressively build on one another. The first, a single dynasty model, explains how a household may be caught in a poverty trap because of credit market imperfections but says little about the effects of distribution on development. The second, a model of interacting dynasties with a fixed threshold, explains a collective poverty trap, with path dependence in the wealth distribution dynamics, but says little about the effects of inequality on development, owing to its absolute notion of the rich and the poor. The third, models of interacting dynasties with variable thresholds, offers a richer framework for understanding the dynamics of inequality and development under credit market imperfections, owing to its relative notion of the rich and poor.
International Trade, Foreign Direct Investment, and Security
Authors: Dixit Avinash
Published: March 2011

The main focus of this review is on international trade and foreign direct investment when the institutions that provide the security of property rights and enforcement of contracts are imperfect. Some issues of national security related to poor governance of international transactions are also considered. The discussion organizes a selective overview of the literature and offers some suggestions for future research.
Ocean Circulations, Heat Budgets, and Future Commitment to Climate Change
Authors: Pierce David W. , Barnett Tim P. , Gleckler Peter J.
Published: March 2011

Earth's surface will continue to warm for decades, and the sea level to rise for centuries, even if the atmospheric concentration of greenhouse gases (GHGs) is held fixed at current levels. This is referred to as “committed” climate change because it is essentially unavoidable. Committed climate change arises due to the large thermal inertia of the oceans and their consequent time lag in adjusting to altered GHG concentrations. This work describes the basic heat balance of the oceans, the physical reasons for the long time lag in ocean temperature and sea-level rise, and the observational evidence for human-induced ocean warming over the past 50 years.
The Political Ecology of Land Degradation
Authors: Andersson Elina , Brogaard Sara , Olsson Lennart
Published: March 2011

Land degradation, as a threat to smallholders in the tropics, attracts less attention than other global challenges. In addition, gaps between scientific understandings of land degradation and international policy regimes are problematic. We identify the three most significant debates including their different policy implications: desertification in the Sahel, nutrient depletion in Africa, and rural reforms in China. Using a political ecology frame across disciplines, scales of inquiry, and regional experiences, we nuance the often polarized scientific debate while seeking to bridge the gap between science and policy. Three main findings emerge: State-led rural reforms in China represent an important approach to land degradation; a renewed focus on agriculture and sustainability in development discourses opens new ways for tackling nutrient depletion with combined sociotechnological reforms; and a policy void in Africa paves the way for market mechanisms, such as payment for environmental services, that are insufficiently understood and put fairness at risk.
Improving Societal Outcomes of Extreme Weather in a Changing Climate: An Integrated Perspective
Authors: Morss Rebecca E. , Wilhelmi Olga V. , Meehl Gerald A. , Dilling Lisa
Published: March 2011

Despite hazard mitigation efforts and scientific and technological advances, extreme weather events continue to cause substantial losses. The impacts of extreme weather result from complex interactions among physical and human systems across spatial and temporal scales. This article synthesizes current interdisciplinary knowledge about extreme weather, including temperature extremes (heat and cold waves), precipitation extremes (including floods and droughts), and storms and severe weather (including tropical cyclones). We discuss hydrometeorological aspects of extreme weather; projections of changes in extremes with anthropogenic climate change; and how social vulnerability, coping, and adaptation shape the societal impacts of extreme weather. We find four critical gaps where work is needed to improve outcomes of extreme weather: (a) reducing vulnerability; (b) enhancing adaptive capacity, including decision-making flexibility; (c) improving the usability of scientific information in decision making, and (d) understanding and addressing local causes of harm through participatory, community-based efforts formulated within the larger policy context.
Banking Crises: A Review
Authors: Laeven Luc
Published: March 2011

This review surveys the theoretical and empirical literature on the causes and consequences of banking crises, and summarizes the lessons learned from policy interventions to resolve banking crises. Despite their different origins, banking crises display similar patterns. Their causes lie in unsustainable macroeconomic policies, market failures, regulatory distortions, and government interference in the allocation of capital; they are frequently characterized by boom-bust cycles in credit and asset prices; and they are generally resolved through large-scale government intervention. When not handled effectively and swiftly, banking crises tend to impose enormous costs to society by curtailing the flow of credit to the real economy. The article concludes with a review of proposals to enhance financial stability in an increasingly integrated financial system, which include making banking regulation more macroprudential—focusing on the cycle and systemic risk rather than the risk of individual banks—and improving market discipline by limiting explicit and implicit government insurance of bank liabilities.
A Review of Empirical Capital Structure Research and Directions for the Future
Authors: Graham John R. , Leary Mark T.
Published: March 2011

This article reviews empirical capital structure research, concentrating on papers published since 2005. We begin by documenting three dimensions of capital structure variation: cross firm, cross industry, and within firm through time. We summarize how well the traditional trade-off and pecking order approaches explain these sources of variation and highlight their empirical shortcomings. We review recent research that attempts to address these shortcomings, much of which follows seven broad themes: (a) Important variables have been mismeasured in empirical tests, (b) the impact of leverage on nonfinancial stakeholders is important, (c) the supply side of capital affects corporate capital structure, (d) richer features of financial contracts have been underresearched, (e) value effects due to capital structure appear to be modest over wide ranges of leverage, (f) estimates of leverage adjustment speeds are biased, and (g) capital structure dynamics have not been adequately considered. Much progress has been made in addressing these issues, some of which has led to the study of an expanded range of capital structure topics, including debt maturity, loan and covenant characteristics, collateral effects, and alternative financing sources such as leasing and credit lines. We conclude by summarizing unanswered questions and areas for future research.
The Economics of Mutual Funds
Authors: Musto David K.
Published: March 2011

This review surveys the literature on the economics of mutual funds in general, and open-end mutual funds in particular. This mutual fund design has been very successful, though it carries risks that have recently been realized at large scales. It also frustrates the analysis of performance in ways only recently appreciated. Among the topics reviewed are tax efficiency, transactions costs, risk shifting, window dressing, governance, marketing, price setting, and concerns that arise at the family level.
Valuation and Risk Management of Collateralized Debt Obligations and Related Securities
Authors: Bluhm Christian , Wagner Christoph
Published: March 2011

Over the course of a few decades, asset securitization has evolved into a vast and diverse financial instrument. Bases for the marketability of these securities are valuation and risk management techniques allowing for reasonable pricing formulas and hedging schemes. Therefore, a key issue is the modeling of cash flows of a portfolio of assets as well as the statistical modeling of uncertainties of such cash flows in the future. This article reviews some aspects of so-called collateralized debt obligations (CDOs) and related instruments. The modeling of underlying credit risks plays an important role in this context. As such, this review naturally has a special focus on the modeling of structured credit portfolios.
The Wind in the Willows: Flows in Forest Canopies in Complex Terrain
Authors: Belcher Stephen E. , Harman Ian N. , Finnigan John J.
Published: March 2011

Forest canopies are important components of the terrestrial carbon budget, which has motivated a worldwide effort, FLUXNET, to measure CO2 exchange between forests and the atmosphere. These measurements are difficult to interpret and to scale up to estimate exchange across a landscape. Here we review the effects of complex terrain on the mean flow, turbulence, and scalar exchange in canopy flows, as exemplified by adjustment to forest edges and hills, including the effects of stable stratification. We focus on the fundamental fluid mechanics, in which developments in theory, measurements, and modeling, particularly through large-eddy simulation, are identifying important processes and providing scaling arguments. These developments set the stage for the development of predictive models that can be used in combination with measurements to estimate exchange at the landscape scale.
“Vegetable Dynamicks”: The Role of Water in Plant Movements
Authors: Dumais Jacques , Forterre Yoël
Published: March 2011

Although they lack muscle, plants have evolved a remarkable range of mechanisms to create motion, from the slow growth of shoots to the rapid snapping of carnivorous plants and the explosive rupture of seed pods. Here we review the key fluid mechanics principles used by plants to achieve movements, summarizing current knowledge and recent discoveries. We begin with a brief overview of water transport and material properties in plants and emphasize that the poroelastic timescale of water diffusion through soft plant tissue imposes constraints on the possible mechanisms for motion. We then discuss movements that rely only on the transport of water, from irreversible growth to reversible swelling/shrinking due to osmotic or humidity gradients. We next show how plants use mechanical instabilities—snap buckling, cavitation, and fracture—to speed up their movements beyond the limits imposed by simple hydraulic mechanisms. Finally, we briefly discuss alternative schemes, involving capillarity or complex fluids.
The Gyrokinetic Description of Microturbulence in Magnetized Plasmas
Authors: Krommes John A.
Published: March 2011

Nonlinear gyrokinetics is the major formalism used for both the analytical and numerical descriptions of low-frequency microturbulence in magnetized plasmas. Its derivation from noncanonical Lagrangian methods and field-theoretic variational principles is summarized. Basic properties of gyrokinetic physics are discussed, including polarization and the concept of the gyrokinetic vacuum, equilibrium statistical mechanics, and the two fundamental constituents of gyrokinetic turbulence, namely drift waves and zonal flows. Numerical techniques are described briefly, and illustrative simulation results are presented. Advanced topics include the transition to turbulence, the nonlinear saturation of turbulence by coupling to damped gyrokinetic eigenmodes, phase-space cascades, subcritical turbulence, and momentum conservation.
Liquid Rope Coiling
Authors: Ribe Neil M. , Habibi Mehdi , Bonn Daniel
Published: March 2011

A thin stream or rope of viscous fluid falling from a sufficient height onto a surface forms a steadily rotating helical coil. Tabletop laboratory experiments in combination with a numerical model for slender liquid ropes reveal that finite-amplitude coiling can occur in four distinct regimes (viscous, gravitational, inertio-gravitational, and inertial) corresponding to different balances among the three principal forces acting on the rope. The model further shows that the onset of coiling has distinct viscous, gravitational, and inertial modes that connect smoothly with the corresponding finite-amplitude regimes. In addition to steady coiling, slender liquid ropes falling onto surfaces can exhibit a remarkable variety of nonstationary behaviors, including propagating spiral waves of air bubbles, supercoiling, the leaping-shampoo (Kaye) effect for non-Newtonian fluids, and the fluid-mechanical sewing machine in which the rope leaves complex stitch patterns on a moving surface.
Air-Entrainment Mechanisms in Plunging Jets and Breaking Waves
Authors: Kiger Kenneth T. , Duncan James H.
Published: March 2011

Air entrainment in liquids is a complex phenomenon that has important applications in industry and the environment. This article addresses recent research on how air is entrained during the impact of a liquid stream on a pool of the same material in a variety of scenarios. At the fundamental level, these scenarios include the prototype flows of impacting stationary laminar and turbulent steady jets, the transient impact of isolated masses of liquid, the impact of jets with organized disturbances, and translating steady and transient jets. Although significant advances have been made recently, the complexity of this multiphase, three-dimensional, and frequently turbulent flow phenomenon leaves many unanswered questions. To help elucidate the problems still to be addressed in future research, the final section of the article examines air entrainment in the more complex application of plunging breaking waves and points out the many parts of this process that are poorly understood.
Axis Formation in Hydra
Authors: Bode Hans
Published: March 2011

A hydra has a simple structure consisting of a head, body column, and foot along a single axis called the oral-aboral axis. The tissue dynamics of a hydra consist of a steady state of production and loss of tissue involving the entire animal. Axis formation and its maintenance is controlled by the head organizer, which is located at the apex of the animal. The head organizer produces two signals, the head activator and head inhibitor, which are transmitted to, and are distributed in, descending gradients among the epithelial cells along the body column. The two gradients control axial patterning along the oral-aboral axis. In the context of the tissue dynamics of the adult hydra, these three elements controlling axis formation and axial patterning are in a steady state of production and loss. The canonical Wnt pathway plays a major role in setting up and maintaining the head organizer.
CRISPR-Cas Systems in Bacteria and Archaea: Versatile Small RNAs for Adaptive Defense and Regulation
Authors: Bhaya Devaki , Davison Michelle , Barrangou Rodolphe
Published: March 2011

Bacteria and archaea have evolved defense and regulatory mechanisms to cope with various environmental stressors, including virus attack. This arsenal has been expanded by the recent discovery of the versatile CRISPR-Cas system, which has two novel features. First, the host can specifically incorporate short sequences from invading genetic elements (virus or plasmid) into a region of its genome that is distinguished by clustered regularly interspaced short palindromic repeats (CRISPRs). Second, when these sequences are transcribed and precisely processed into small RNAs, they guide a multifunctional protein complex (Cas proteins) to recognize and cleave incoming foreign genetic material. This adaptive immunity system, which uses a library of small noncoding RNAs as a potent weapon against fast-evolving viruses, is also used as a regulatory system by the host. Exciting breakthroughs in understanding the mechanisms of the CRISPR-Cas system and its potential for biotechnological applications and understanding evolutionary dynamics are discussed.
Genomic Imprinting: A Mammalian Epigenetic Discovery Model
Authors: Barlow Denise P.
Published: March 2011

Genomic imprinting is an epigenetic process leading to parental-specific expression of one to two percent of mammalian genes that offers one of the best model systems for a molecular analysis of epigenetic regulation in development and disease. In the twenty years since the first imprinted gene was identified, this model has had a significant impact on decoding epigenetic information in mammals. So far it has led to the discovery of long-range cis-acting control elements whose epigenetic state regulates small clusters of genes and of unusual macro noncoding RNAs (ncRNAs) that directly repress genes in cis, and critically, it has demonstrated that one biological role of DNA methylation is to allow expression of genes normally repressed by default. This review describes the progress in understanding how imprinted protein-coding genes are silenced; in particular, it focuses on the role of macro ncRNAs that have broad relevance as a potential new layer of regulatory information in the mammalian genome.
Genetic and Epigenetic Networks in Intellectual Disabilities
Authors: van Bokhoven Hans
Published: March 2011

Mutations in more than 450 different genes have been associated with intellectual disability (ID) and related cognitive disorders (CDs), such as autism. It is to be expected that this number will increase three to fourfold in the next years due to the rapid implementation of innovative high-throughput sequencing technology in genetics labs. Numerous functional relationships have been identified between the products of individual ID genes, and common molecular and cellular pathways onto which these networks converge are beginning to emerge. Prominent examples are genes involved in synaptic plasticity, Ras and Rho GTPase signaling, and epigenetic genes that encode modifiers of the chromatin structure. It thus seems that there might be common pathological patterns in ID, despite its bewildering genetic heterogeneity. These common pathways provide attractive opportunities for knowledge-based therapeutic interventions.
The Repatterning of Eukaryotic Genomes by Random Genetic Drift
Authors: Lynch Michael , Bobay Louis-Marie , Catania Francesco , Gout Jean-François , Rho Mina
Published: March 2011

Recent observations on rates of mutation, recombination, and random genetic drift highlight the dramatic ways in which fundamental evolutionary processes vary across the divide between unicellular microbes and multicellular eukaryotes. Moreover, population-genetic theory suggests that the range of variation in these parameters is sufficient to explain the evolutionary diversification of many aspects of genome size and gene structure found among phylogenetic lineages. Most notably, large eukaryotic organisms that experience elevated magnitudes of random genetic drift are susceptible to the passive accumulation of mutationally hazardous DNA that would otherwise be eliminated by efficient selection. Substantial evidence also suggests that variation in the population-genetic environment influences patterns of protein evolution, with the emergence of certain kinds of amino-acid substitutions and protein-protein complexes only being possible in populations with relatively small effective sizes. These observations imply that the ultimate origins of many of the major genomic and proteomic disparities between prokaryotes and eukaryotes and among eukaryotic lineages have been molded as much by intrinsic variation in the genetic and cellular features of species as by external ecological forces.
Perspectives on Human Population Structure at the Cusp of the Sequencing Era
Authors: Novembre John , Ramachandran Sohini
Published: March 2011

Human groups show structured levels of genetic similarity as a consequence of factors such as geographical subdivision and genetic drift. Surveying this structure gives us a scientific perspective on human origins, sheds light on evolutionary processes that shape both human adaptation and disease, and is integral to effectively carrying out the mission of global medical genetics and personalized medicine. Surveys of population structure have been ongoing for decades, but in the past three years, single-nucleotide-polymorphism (SNP) array technology has provided unprecedented detail on human population structure at global and regional scales. These studies have confirmed well-known relationships between distantly related populations and uncovered previously unresolvable relationships among closely related human groups. SNPs represent the first dense genome-wide markers, and as such, their analysis has raised many challenges and insights relevant to the study of population genetics with whole-genome sequences. Here we draw on the lessons from these studies to anticipate the directions that will be most fruitful to pursue during the emerging whole-genome sequencing era.
SLAM Family Receptors and SAP Adaptors in Immunity
Authors: Cannons Jennifer L. , Tangye Stuart G. , Schwartzberg Pamela L.
Published: March 2011

The signaling lymphocyte activation molecule (SLAM)-associated protein, SAP, was first identified as the protein affected in most cases of X-linked lymphoproliferative (XLP) syndrome, a rare genetic disorder characterized by abnormal responses to Epstein-Barr virus infection, lymphoproliferative syndromes, and dysgammaglobulinemia. SAP consists almost entirely of a single SH2 protein domain that interacts with the cytoplasmic tail of SLAM and related receptors, including 2B4, Ly108, CD84, Ly9, and potentially CRACC. SLAM family members are now recognized as important immunomodulatory receptors with roles in cytotoxicity, humoral immunity, autoimmunity, cell survival, lymphocyte development, and cell adhesion. In this review, we cover recent findings on the roles of SLAM family receptors and the SAP family of adaptors, with a focus on their regulation of the pathways involved in the pathogenesis of XLP and other immune disorders.
Systems Biology in Immunology: A Computational Modeling Perspective
Authors: Germain Ronald N. , Meier-Schellersheim Martin , Nita-Lazar Aleksandra , Fraser Iain D.C.
Published: March 2011

Systems biology is an emerging discipline that combines high-content, multiplexed measurements with informatic and computational modeling methods to better understand biological function at various scales. Here we present a detailed review of the methods used to create computational models and to conduct simulations of immune function. We provide descriptions of the key data-gathering techniques employed to generate the quantitative and qualitative data required for such modeling and simulation and summarize the progress to date in applying these tools and techniques to questions of immunological interest, including infectious disease. We include comments on what insights modeling can provide that complement information obtained from the more familiar experimental discovery methods used by most investigators and the reasons why quantitative methods are needed to eventually produce a better understanding of immune system operation in health and disease.
Human TLRs and IL-1Rs in Host Defense: Natural Insights from Evolutionary, Epidemiological, and Clinical Genetics
Authors: Casanova Jean-Laurent , Abel Laurent , Quintana-Murci Lluis
Published: March 2011

Toll-like receptors (TLRs) and interleukin-1 receptors (IL-1Rs) have TIR intracellular domains that engage two main signaling pathways, via the TIR-containing adaptors MyD88 (which is not used by TLR3) and TRIF (which is used only by TLR3 and TLR4). Extensive studies in inbred mice in various experimental settings have attributed key roles in immunity to TLR- and IL-1R-mediated responses, but what contribution do human TLRs and IL-1Rs actually make to host defense in the natural setting? Evolutionary genetic studies have shown that human intracellular TLRs have evolved under stronger purifying selection than surface-expressed TLRs, for which the frequency of missense and nonsense alleles is high in the general population. Epidemiological genetic studies have yet to provide convincing evidence of a major contribution of common variants of human TLRs, IL-1Rs, or their adaptors to host defense. Clinical genetic studies have revealed that rare mutations affecting the TLR3-TRIF pathway underlie herpes simplex virus encephalitis, whereas mutations in the TIR-MyD88 pathway underlie pyogenic bacterial diseases in childhood. A careful reconsideration of the contributions of TLRs and IL-1Rs to host defense in natura is required.
Natural Innate and Adaptive Immunity to Cancer
Authors: Vesely Matthew D. , Kershaw Michael H. , Schreiber Robert D. , Smyth Mark J.
Published: March 2011

The immune system can identify and destroy nascent tumor cells in a process termed cancer immunosurveillance, which functions as an important defense against cancer. Recently, data obtained from numerous investigations in mouse models of cancer and in humans with cancer offer compelling evidence that particular innate and adaptive immune cell types, effector molecules, and pathways can sometimes collectively function as extrinsic tumor-suppressor mechanisms. However, the immune system can also promote tumor progression. Together, the dual host-protective and tumor-promoting actions of immunity are referred to as cancer immunoediting. In this review, we discuss the current experimental and human clinical data supporting a cancer immunoediting process that provide the fundamental basis for further study of immunity to cancer and for the rational design of immunotherapies against cancer.
Pathogenesis and Host Control of Gammaherpesviruses: Lessons from the Mouse
Authors: Barton Erik , Mandal Pratyusha , Speck Samuel H.
Published: March 2011

Gammaherpesviruses are lymphotropic viruses that are associated with the development of lymphoproliferative diseases, lymphomas, as well as other nonlymphoid cancers. Most known gammaherpesviruses establish latency in B lymphocytes. Research on Epstein-Barr virus (EBV) and murine gammaherpesvirus 68 (MHV68/γHV68/MHV4) has revealed a complex relationship between virus latency and the stage of B cell differentiation. Available data support a model in which gammaherpesvirus infection drives B cell proliferation and differentiation. In general, the characterized gammaherpesviruses exhibit a very narrow host tropism, which has severely limited studies on the human gammaherpesviruses EBV and Kaposi's sarcoma–associated herpesvirus. As such, there has been significant interest in developing animal models in which the pathogenesis of gammaherpesviruses can be characterized. MHV68 represents a unique model to define the effects of chronic viral infection on the antiviral immune response.
U.S. War and Emergency Powers: The Virtues of Constitutional Ambiguity
Authors: Silverstein Gordon
Published: March 2011

American liberals and conservatives agree about very little concerning foreign policy, war, and emergency powers, but they do agree that the Constitution's ambiguous allocation of foreign policy powers to the legislative, executive, and judicial branches is a problem that must be fixed. For conservatives, the answer has been a reliance on constitutional reinterpretation that might establish a bright line between executive power in foreign policy and war (which they embrace) and national authority to regulate domestic and economic affairs (which they do not). For liberals, who worry that constitutional ambiguity opens the door for the abuse of executive power, the solution has been to trade formal delegation of power constrained by strict statutory limits on the exercise of that power. These efforts—liberal and conservative alike—have failed, each producing results quite the opposite of what was sought. After setting these debates in their legal, historical, and political context, this review concludes with a reexamination of the potential virtues of constitutional ambiguity.
Elaborating the Individual Difference Component in Deterrence Theory
Authors: Piquero Alex R. , Paternoster Raymond , Pogarsky Greg , Loughran Thomas
Published: March 2011

Deterrence theory and criminal justice policy hold that punishment enhances compliance and deters future criminal activity. Empirical research, however, is decidedly mixed, with some studies finding that punishment weakens compliance, some finding that sanctions have no effect on compliance, and some finding that the effect of sanctions depends on moderating factors. In this review, we do not consider whether sanctions affect compliance but instead consider the conditions under which sanctions affect compliance. Specifically, we focus on understanding the kinds-of-people dimension of sanctions and deterrence to include individual differences (in social bonding, morality, discount rate, impulsivity, social network position, decision-making competence) and situational differences (in emotions, alcohol/drug use). Upon reviewing the empirical evidence, we identify important gaps for theoretical and empirical work and comment on how this work relates to public policy.
Assessing Drug Prohibition and Its Alternatives: A Guide for Agnostics
Authors: MacCoun Robert J. , Reuter Peter
Published: March 2011

For decades, the debate over the merits of ending drug prohibition has carried on with little consequence. The recent near success of a cannabis legalization initiative in California suggests that citizens and politicians alike are more receptive to calls for change. We review basic research on deterrence and prices as well as emerging evidence on the potential empirical consequences of various alternatives to full prohibition, including depenalization, tolerated home cultivation, prescription regimes for cannabis and heroin, and retail sales of cannabis in Dutch coffee shops. The results are encouraging for advocates of these specific reforms, but the cases are inadequate for addressing the potentially more dramatic effects of full-scale commercial markets. The fundamental dilemma is that full legalization will probably reduce average harm per use but increase total consumption; the net effect of these two changes is difficult to project.
Oxide Electronics Utilizing Ultrafast Metal-Insulator Transitions
Authors: Yang Zheng , Ko Changhyun , Ramanathan Shriram
Published: March 2011

Although phase transitions have long been a centerpiece of condensed matter materials science studies, a number of recent efforts focus on potentially exploiting the resulting functional property changes in novel electronics and photonics as well as understanding emergent phenomena. This is quite timely, given a grand challenge in twenty-first-century physical sciences is related to enabling continued advances in information processing and storage beyond conventional CMOS scaling. In this brief review, we discuss synthesis of strongly correlated oxides, mechanisms of metal-insulator transitions, and exploratory electron devices that are being studied. Particular emphasis is placed on vanadium dioxide, which undergoes a sharp metal-insulator transition near room temperature at ultrafast timescales. The article begins with an introduction to metal-insulator transition in oxides, followed by a brief discussion on the mechanisms leading to the phase transition. The role of materials synthesis in influencing functional properties is discussed briefly. Recent efforts on realizing novel devices such as field effect switches, optical detectors, nonlinear circuit components, and solid-state sensors are reviewed. The article concludes with a brief discussion on future research directions that may be worth consideration.