bluuebunny/crossref_metadata_2025 huggingface dataset:
Regulation of Integrin Activation
Authors: Kim Chungho , Ye Feng , Ginsberg Mark H.
Published: March 2011

Regulation of cell-cell and cell-matrix interaction is essential for the normal physiology of metazoans and is important in many diseases. Integrin adhesion receptors can rapidly increase their affinity (integrin activation) in response to intracellular signaling events in a process termed inside-out signaling. The transmembrane domains of integrins and their interactions with the membrane are important in inside-out signaling. Moreover, integrin activation is tightly regulated by a complex network of signaling pathways. Here, we review recent progress in understanding how the membrane environment can, in cooperation with integrin-binding proteins, regulate integrin activation.
Dynamic Organizing Principles of the Plasma Membrane that Regulate Signal Transduction: Commemorating the Fortieth Anniversary of Singer and Nicolson's Fluid-Mosaic Model
Authors: Kusumi Akihiro , Fujiwara Takahiro K. , Chadda Rahul , Xie Min , Tsunoyama Taka A. , Kalay Ziya , Kasai Rinshi S. , Suzuki Kenichi G.N.
Published: March 2011

The recent rapid accumulation of knowledge on the dynamics and structure of the plasma membrane has prompted major modifications of the textbook fluid-mosaic model. However, because the new data have been obtained in a variety of research contexts using various biological paradigms, the impact of the critical conceptual modifications on biomedical research and development has been limited. In this review, we try to synthesize our current biological, chemical, and physical knowledge about the plasma membrane to provide new fundamental organizing principles of this structure that underlie every molecular mechanism that realizes its functions. Special attention is paid to signal transduction function and the dynamic aspect of the organizing principles. We propose that the cooperative action of the hierarchical three-tiered mesoscale (2–300 nm) domains—actin-membrane-skeleton induced compartments (40–300 nm), raft domains (2–20 nm), and dynamic protein complex domains (3–10 nm)—is critical for membrane function and distinguishes the plasma membrane from a classical Singer-Nicolson-type model.
Approaches and Incentives to Implement Integrated Pest Management that Addresses Regional and Environmental Issues
Authors: Brewer Michael J. , Goodell Peter B.
Published: March 2011

Agricultural, environmental, and social and policy interests have influenced integrated pest management (IPM) from its inception. The first 50 years of IPM paid special attention to field-based management and market-driven decision making. Concurrently, IPM strategies became available that were best applied both within and beyond the bounds of individual fields and that also provided environmental benefits. This generated an incentives dilemma for farmers: selecting IPM activities for individual fields on the basis of market-based economics versus selecting IPM activities best applied regionally that have longer-term benefits, including environmental benefits, that accrue to the broader community as well as the farmer. Over the past several decades, public-supported incentives, such as financial incentives available to farmers from conservation programs for farms, have begun to be employed to encourage use of conservation techniques, including strategies with IPM relevance. Combining private investments with public support may effectively address the incentives dilemma when advanced IPM strategies are used regionally and provide public goods such as those benefiting resource conservation. This review focuses on adaptation of IPM to these broader issues, on transitions of IPM from primarily individual field-based decision making to coordinated community decision making, and on the form of partnerships needed to gain long-lasting regional and environmental benefits.
Prospects for Managing Turfgrass Pests with Reduced Chemical Inputs
Authors: Held David W. , Potter Daniel A.
Published: March 2011

Turfgrass culture, a multibillion dollar industry in the United States, poses unique challenges for integrated pest management. Why insect control on lawns, golf courses, and sport fields remains insecticide-driven, and how entomological research and extension can best support nascent initiatives in environmental golf and sustainable lawn care are explored. High standards for aesthetics and playability, prevailing business models, risk management–driven control decisions, and difficulty in predicting pest outbreaks fuel present reliance on preventive insecticides. New insights into pest biology, sampling methodology, microbial insecticides, plant resistance, and conservation biological control are reviewed. Those gains, and innovations in reduced-risk insecticides, should make it possible to begin constructing holistic management plans for key turfgrass pests. Nurturing the public's interest in wildlife habitat preservation, including beneficial insects, may be one means to change aesthetic perceptions and gain leeway for implementing integrated pest management practices that lend stability to turfgrass settings.
Evolutionary Ecology of Odonata: A Complex Life Cycle Perspective
Authors: Stoks Robby , Córdoba-Aguilar Alex
Published: March 2011

Most insects have a complex life cycle with ecologically different larval and adult stages. We present an ontogenetic perspective to analyze and summarize the complex life cycle of Odonata within an evolutionary ecology framework. Morphological, physiological, and behavioral pathways that generate carry-over effects across the aquatic egg and larval stages and the terrestrial adult stage are identified. We also highlight several mechanisms that can decouple life stages including compensatory mechanisms at the larval and adult stages, stressful and stochastic events during metamorphosis, and stressful environmental conditions at the adult stage that may overrule effects of environmental conditions in the preceding stage. We consider the implications of these findings for the evolution, selection, and fitness of odonates; underline the role of the identified numerical and carry-over effects in shaping population and metapopulation dynamics and the community structure across habitat boundaries; and discuss implications for applied conservation issues.
Ants and the Fossil Record
Authors: LaPolla John S. , Dlussky Gennady M. , Perrichot Vincent
Published: March 2011

The dominance of ants in the terrestrial biosphere has few equals among animals today, but this was not always the case. The oldest ants appear in the fossil record 100 million years ago, but given the scarcity of their fossils, it is presumed they were relatively minor components of Mesozoic insect life. The ant fossil record consists of two primary types of fossils, each with inherent biases: as imprints in rock and as inclusions in fossilized resins (amber). New imaging technology allows ancient ant fossils to be examined in ways never before possible. This is particularly helpful because it can be difficult to distinguish true ants from non-ants in Mesozoic fossils. Fossil discoveries continue to inform our understanding of ancient ant morphological diversity, as well as provide insights into their paleobiology.
Group Size and Its Effects on Collective Organization
Authors: Dornhaus Anna , Powell Scott , Bengston Sarah
Published: March 2011

Many insects and arthropods live in colonies or aggregations of varying size. Group size may affect collective organization either because the same individual behavior has different consequences when displayed in a larger group or because larger groups are subject to different constraints and selection pressures than smaller groups. In eusocial colonies, group size may have similar effects on colony traits as body size has on organismal traits. Social insects may, therefore, be useful to test theories about general principles of scaling, as they constitute a distinct level of organization. However, there is a surprising lack of data on group sizes in social insects and other group-living arthropods, and multiple confounding factors have to be controlled to detect effects of group size. If such rigorous studies are performed, group size may become as important to understanding collective organization as is body size in explaining behavior and life history of individual organisms.
Insect Responses to Major Landscape-Level Disturbance
Authors: Schowalter T.D.
Published: March 2011

Disturbances are abrupt events that dramatically alter habitat conditions and resource distribution for populations and communities. Terrestrial landscapes are subject to various disturbance events that create a matrix of patches with different histories of disturbance and recovery. Species tolerances to extreme conditions during disturbance or to altered habitat or resource conditions following disturbances determine responses to disturbance. Intolerant populations may become locally extinct, whereas other species respond positively to the creation of new habitat or resource conditions. Local extinction represents a challenge for conservation biologists. On the other hand, outbreaks of herbivorous species often are triggered by abundant or stressed hosts and relaxation of predation following disturbances. These insect responses can cause further changes in ecosystem conditions and predispose communities to future disturbances. Improved understanding of insect responses to disturbance will improve prediction of population and community dynamics, as well as ecosystem and global changes.
Insects as Weapons of War, Terror, and Torture
Authors: Lockwood Jeffrey A.
Published: March 2011

For thousands of years insects have been incorporated into human conflict, with the goals of inflicting pain, destroying food, and transmitting pathogens. Early methods used insects as “found” weapons, functioning as tactical arms (e.g., hurled nests) or in strategic habitats (e.g., mosquito-infested swamps). In the twentieth century the relationship between insects and disease was exploited; vectors were mass-produced to efficiently deliver pathogens to an enemy. The two most sophisticated programs were those of the Japanese in World War II with plague-infected fleas and cholera-coated flies and of the Americans during the Cold War with yellow fever–infected mosquitoes. With continued advances, defenses in the form of insecticides and vaccines meant that insects were no longer considered as battlefield weapons. However, in recent times sociopolitical changes have put insects back into the realm of human conflict through asymmetrical conflicts pitting combatants from nonindustrialized regions against forces from militarily and economically superior nations.
Molecular Bases of Plant Resistance to Arthropods
Authors: Smith C. Michael , Clement Stephen L.
Published: March 2011

Arthropod-resistant crops provide significant ecological and economic benefits to global agriculture. Incompatible interactions involving resistant plants and avirulent pest arthropods are mediated by constitutively produced and arthropod-induced plant proteins and defense allelochemicals synthesized by resistance gene products. Cloning and molecular mapping have identified the Mi-1.2 and Vat arthropod resistance genes as CC-NBS-LRR (coiled coil–nucleotide binding site–leucine rich repeat) subfamily NBS-LRR resistance proteins, as well as several resistance gene analogs. Genetic linkage mapping has identified more than 100 plant resistance gene loci and linked molecular markers used in cultivar development. Rice and sorghum arthropod-resistant cultivars and, to a lesser extent, raspberry and wheat cultivars are components of integrated pest management (IPM) programs in Asia, Australia, Europe, and North America. Nevertheless, arthropod resistance in most food and fiber crops has not been integrated due primarily to the application of synthetic insecticides. Plant and arthropod genomics provide many opportunities to more efficiently develop arthropod-resistant plants, but integration of resistant cultivars into IPM programs will succeed only through interdisciplinary collaboration.
Morphology and Diversity of Exocrine Glands in Lepidopteran Larvae
Authors: Vegliante Francesca , Hasenfuss Ivar
Published: March 2011

The morphology of 21 exocrine glands and 13 supposedly exocrine structures recorded for lepidopteran larvae is reviewed. The epitracheal glands, for which a double role (exocrine and endocrine) has been demonstrated, are examined as well. Function is well known for at least 8 glands but completely unknown for 6 glands, for 10 putative glandular structures, and for the exocrine component of the epitracheal glands. Functional studies on the remaining structures are insufficient; in some cases (mandibular gland and adenosma) homologous glands may play a different role depending on the species, and only a few taxa have been examined. The secretions of 13 glandular types have been analyzed chemically. The histology of 11 glands is known at the ultrastructural level, whereas that of 6 glands and 7 putative glandular structures is completely unknown. Comparative anatomical studies of the osmeterium, adenosma, and Verson's glands may yield useful information for phylogenetic reconstructions.
Transmission of Flea-Borne Zoonotic Agents
Authors: Eisen Rebecca J. , Gage Kenneth L.
Published: March 2011

Flea-borne zoonoses such as plague (Yersinia pestis) and murine typhus (Rickettsia typhi) caused significant numbers of human cases in the past and remain a public health concern. Other flea-borne human pathogens have emerged recently (e.g., Bartonella henselae, Rickettsia felis), and their mechanisms of transmission and impact on human health are not fully understood. Our review focuses on the ecology and epidemiology of the flea-borne bacterial zoonoses mentioned above with an emphasis on recent advancements in our understanding of how these organisms are transmitted by fleas, maintained in zoonotic cycles, and transmitted to humans. Emphasis is given to plague because of the considerable number of studies generated during the first decade of the twenty-first century that arose, in part, because of renewed interest in potential agents of bioterrorism, including Y. pestis.
Sound Strategies: The 65-Million-Year-Old Battle Between Bats and Insects
Authors: Conner William E. , Corcoran Aaron J.
Published: March 2011

The intimate details regarding the coevolution of bats and moths have been elucidated over the past 50 years. The bat-moth story began with the evolution of bat sonar, an exquisite ultrasonic system for tracking prey through the night sky. Moths countered with ears tuned to the high frequencies of bat echolocation and with evasive action through directed turns, loops, spirals, drops, and power dives. Some bat species responded by moving the frequency and intensity of their echolocation cries away from the peak sensitivity of moth ears, and the arms race was on. Tiger moths countered by producing anti-bat sounds. Do the sounds advertise moth toxicity, similar to the bright coloration of butterflies; do they startle the bat, giving the moth a momentary advantage in their aerobatic battle; or do they jam the sonar of the bat? The answer is yes. They do all and more in different situations and in different species. Any insect that flies at night must deal with bat predation. Beetles, mantids, true crickets, mole crickets, katydids, green lacewings, and locusts have anti-bat strategies, and we have just scratched the surface. In an exciting new twist, researchers are taking the technologies developed in the laboratory back into the field, where they are poised to appreciate the full richness of this remarkable predator-prey interaction.
Progress in Understanding Harmful Algal Blooms: Paradigm Shifts and New Technologies for Research, Monitoring, and Management
Authors: Anderson Donald M. , Cembella Allan D. , Hallegraeff Gustaaf M.
Published: March 2011

The public health, tourism, fisheries, and ecosystem impacts from harmful algal blooms (HABs) have all increased over the past few decades. This has led to heightened scientific and regulatory attention, and the development of many new technologies and approaches for research and management. This, in turn, is leading to significant paradigm shifts with regard to, e.g., our interpretation of the phytoplankton species concept (strain variation), the dogma of their apparent cosmopolitanism, the role of bacteria and zooplankton grazing in HABs, and our approaches to investigating the ecological and genetic basis for the production of toxins and allelochemicals. Increasingly, eutrophication and climate change are viewed and managed as multifactorial environmental stressors that will further challenge managers of coastal resources and those responsible for protecting human health. Here we review HAB science with an eye toward new concepts and approaches, emphasizing, where possible, the unexpected yet promising new directions that research has taken in this diverse field.
The Fate of Terrestrial Organic Carbon in the Marine Environment
Authors: Blair Neal E. , Aller Robert C.
Published: March 2011

Understanding the fate of terrestrial organic carbon (Corg) delivered to oceans by rivers is critical for constraining models of biogeochemical cycling and Earth surface evolution. Corg fate is dependent on both intrinsic characteristics (molecular structure, matrix) and the environmental conditions to which fluvial Corg is subjected. Three distinct patterns are evident on continental margins supplied by rivers: (a) high-energy, mobile muds with enhanced oxygen exposure and efficient metabolite exchange have very low preservation of both terrestrial and marine Corg (e.g., Amazon subaqueous delta); (b) low-energy facies with extreme accumulation have high Corg preservation (e.g., Ganges-Brahmaputra); and (c) small, mountainous river systems that sustain average accumulation rates but deliver a large fraction of low-reactivity, fossil Corg in episodic events have the highest preservation efficiencies. The global patterns of terrestrial Corg preservation reflect broadly different roles for passive and active margin systems in the sedimentary Corg cycle.
Benthic Foraminiferal Biogeography: Controls on Global Distribution Patterns in Deep-Water Settings
Authors: Gooday Andrew J. , Jorissen Frans J.
Published: March 2011

Benthic foraminifera, shell-bearing protists, are familiar from geological studies. Although many species are well known, undescribed single-chambered forms are common in the deep sea. Coastal and sublittoral species often have restricted distributions, but wide ranges are more frequent among deep-water species, particularly at abyssal depths. This probably reflects the transport of tiny propagules by currents across ocean basins that present few insurmountable barriers to dispersal, combined with slow rates of evolution. Undersampling of the vast deep-sea habitat, however, makes it very difficult to establish the ranges of less common foraminiferal species, and endemism may be more prevalent than currently realized. On continental slopes, some species have restricted distributions, but wide-ranging bathyal species that exhibit considerable morphological variation are more common. This may be linked to the greater heterogeneity of continental slopes compared with oceans basins. Improved knowledge of deep-sea foraminiferal biogeography requires sound morphology-based taxonomy combined with molecular genetic studies.
Marine Viruses: Truth or Dare
Authors: Breitbart Mya
Published: March 2011

Over the past two decades, marine virology has progressed from a curiosity to an intensely studied topic of critical importance to oceanography. At concentrations of approximately 10 million viruses per milliliter of surface seawater, viruses are the most abundant biological entities in the oceans. The majority of these viruses are phages (viruses that infect bacteria). Through lysing their bacterial hosts, marine phages control bacterial abundance, affect community composition, and impact global biogeochemical cycles. In addition, phages influence their hosts through selection for resistance, horizontal gene transfer, and manipulation of bacterial metabolism. Recent work has also demonstrated that marine phages are extremely diverse and can carry a variety of auxiliary metabolic genes encoding critical ecological functions. This review is structured as a scientific “truth or dare,” revealing several well-established “truths” about marine viruses and presenting a few “dares” for the research community to undertake in future studies.
Overturning in the North Atlantic
Authors: Lozier M. Susan
Published: March 2011

The global overturning of ocean waters involves the equatorward transport of cold, deep waters and the poleward transport of warm, near-surface waters. Such movement creates a net poleward transport of heat that, in partnership with the atmosphere, establishes the global and regional climates. Although oceanographers have long assumed that a reduction in deep water formation at high latitudes in the North Atlantic translates into a slowing of the ocean's overturning and hence in Earth's climate, observational and modeling studies over the past decade have called this assumed linkage into question. The observational basis for linking water mass formation with the ocean's meridional overturning is reviewed herein. Understanding this linkage is crucial to efforts aimed at predicting the consequences of the warming and freshening of high-latitude surface waters to the climate system.
Recalcitrant Dissolved Organic Carbon Fractions
Authors: Hansell Dennis A.
Published: March 2011

Marine dissolved organic carbon (DOC) exhibits a spectrum of reactivity, from very fast turnover of the most bioavailable forms in the surface ocean to long-lived materials circulating within the ocean abyss. These disparate reactivities group DOC by fractions with distinctive functions in the cycling of carbon, ranging from support of the microbial loop to involvement in the biological pump to a hypothesized major source/sink of atmospheric CO2 driving paleoclimate variability. Here, the major fractions constituting the global ocean's recalcitrant DOC pool are quantitatively and qualitatively characterized with reference to their roles in carbon biogeochemistry. A nomenclature for the fractions is proposed based on those roles.
Lagrangian Motion, Coherent Structures, and Lines of Persistent Material Strain
Authors: Samelson R.M.
Published: March 2011

Lagrangian motion in geophysical fluids may be strongly influenced by coherent structures that support distinct regimes in a given flow. The problems of identifying and demarcating Lagrangian regime boundaries associated with dynamical coherent structures in a given velocity field can be studied using approaches originally developed in the context of the abstract geometric theory of ordinary differential equations. An essential insight is that when coherent structures exist in a flow, Lagrangian regime boundaries may often be indicated as material curves on which the Lagrangian-mean principal-axis strain is large. This insight is the foundation of many numerical techniques for identifying such features in complex observed or numerically simulated ocean flows. The basic theoretical ideas are illustrated with a simple, kinematic traveling-wave model. The corresponding numerical algorithms for identifying candidate Lagrangian regime boundaries and lines of principal Lagrangian strain (also called Lagrangian coherent structures) are divided into parcel and bundle schemes; the latter include the finite-time and finite-size Lyapunov exponent/Lagrangian strain (FTLE/FTLS and FSLE/FSLS) metrics. Some aspects and results of oceanographic studies based on these approaches are reviewed, and the results are discussed in the context of oceanographic observations of dynamical coherent structures.
Oceanographic and Biological Effects of Shoaling of the Oxygen Minimum Zone
Authors: Gilly William F. , Beman J. Michael , Litvin Steven Y. , Robison Bruce H.
Published: March 2011

Long-term declines in oxygen concentrations are evident throughout much of the ocean interior and are particularly acute in midwater oxygen minimum zones (OMZs). These regions are defined by extremely low oxygen concentrations (<20–45 μmol kg−1), cover wide expanses of the ocean, and are associated with productive oceanic and coastal regions. OMZs have expanded over the past 50 years, and this expansion is predicted to continue as the climate warms worldwide. Shoaling of the upper boundaries of the OMZs accompanies OMZ expansion, and decreased oxygen at shallower depths can affect all marine organisms through multiple direct and indirect mechanisms. Effects include altered microbial processes that produce and consume key nutrients and gases, changes in predator-prey dynamics, and shifts in the abundance and accessibility of commercially fished species. Although many species will be negatively affected by these effects, others may expand their range or exploit new niches. OMZ shoaling is thus likely to have major and far-reaching consequences.
Plankton and Particle Size and Packaging: From Determining Optical Properties to Driving the Biological Pump
Authors: Stemmann L. , Boss E.
Published: March 2011

Understanding pelagic ecology and quantifying energy fluxes through the trophic web and from the surface to the deep ocean requires the ability to detect and identify all organisms and particles in situ and in a synoptic manner. An idealized sensor should observe both the very small living or dead particles such as picoplankton and detritus, respectively, and the large particles such as aggregates and meso- to macroplankton. Such an instrument would reveal an astonishing amount and diversity of living and nonliving particles present in a parcel of water. Unfortunately such sensors do not exist. However, complex interactions constrain the space, temporal, and size distributions of these objects in such ways that general rules can be inferred from the measurement of their optical properties. Recent technological developments allow for the in situ measurement of the optical properties and size distributions of particles and plankton in a way such that synoptic surveys are possible. This review deals with particle and plankton size distributions (PSDs) as well as how particles' geometry and nature affect their optical properties. Finally, we propose the integration of the PSD into size-structured mathematical models of biogeochemical fluxes.
Shifting Patterns of Life in the Pacific Arctic and Sub-Arctic Seas
Authors: Grebmeier Jacqueline M.
Published: March 2011

Recent changes in the timing of sea ice formation and retreat, along with increasing seawater temperatures, are driving shifts in marine species composition that may signal marine ecosystem reorganization in the Pacific Arctic sector. Interannual variability in seasonal sea ice retreat in the northern Bering Sea has been observed over the past decade; north of the Bering Strait, the Chukchi Sea ecosystem has had consistent earlier spring sea ice retreat and later fall sea ice formation. The latitudinal gradient in sea ice persistence, water column chlorophyll, and carbon export to the sediments has a direct impact on ecosystem structure in this Arctic/sub-Arctic complex. Large-scale decadal patterns in the benthic biological system are driven by sea ice extent, hydrographic forcing, and export production that influences benthic processes. Shifts in species composition and northward faunal range expansions indicate a changing system. The shifting patterns of life and change in key biological processes have the potential for a system-wide reorganization of the marine ecosystem.
The Rare Bacterial Biosphere
Authors: Pedrós-Alió Carlos
Published: March 2011

All communities are dominated by a few species that account for most of the biomass and carbon cycling. On the other hand, a large number of species are represented by only a few individuals. In the case of bacteria, these rare species were until recently invisible. Owing to their low numbers, conventional molecular techniques could not retrieve them. Isolation in pure culture was the only way to identify some of them, but current culturing techniques are unable to isolate most of the bacteria in nature. The recent development of fast and cheap high-throughput sequencing has begun to allow access to the rare species. In the case of bacteria, the exploration of this rare biosphere has several points of interest. First, it will eventually produce a reasonable estimate of the total number of bacterial taxa in the oceans; right now, we do not even know the right order of magnitude. Second, it will answer the question of whether “everything is everywhere.” Third, it will require hypothesizing and testing the ecological mechanisms that allow subsistence of many species in low numbers. And fourth, it will open an avenue of research into the immense reserve of genes with potential applications hidden in the rare biosphere.
Role of Endoplasmic Reticulum Stress in Metabolic Disease and Other Disorders
Authors: Ozcan Lale , Tabas Ira
Published: March 2011

Perturbations in the normal functions of the endoplasmic reticulum (ER) trigger a signaling network that coordinates adaptive and apoptotic responses. There is accumulating evidence implicating prolonged ER stress in the development and progression of many diseases, including neurodegeneration, atherosclerosis, type 2 diabetes, liver disease, and cancer. With the improved understanding of the underlying molecular mechanisms, therapeutic interventions that target the ER stress response would be potential strategies to treat various diseases driven by prolonged ER stress.
Physician Workforce Projections in an Era of Health Care Reform
Authors: Kirch Darrell G. , Henderson Mackenzie K. , Dill Michael J.
Published: March 2011

In 2020, the United States may face shortages of 45,400 primary care physicians and 46,100 medical specialists—a total of 91,500 too few doctors. Unfortunately, health workforce shortages like these are being advanced as cause for repealing or “defunding” the Affordable Care Act (ACA). The extension of health insurance coverage to millions of Americans is a critical first step toward a healthier America. It would be a national failure to leave millions of Americans without health insurance coverage because they will generate additional demand. Rather, the solution is to find ways to meet that demand. Workforce projections utilizing real data and carefully formulated assumptions to assess how and why supply and demand change over time can greatly assist policy makers in finding those solutions. With implementation of the ACA under way, it is time to understand what lessons such projections can teach, and to begin to heed those lessons.
Targeting Metastatic Melanoma
Authors: Flaherty Keith T.
Published: March 2011

Metastatic melanoma has historically been one of the most treatment-refractory types of cancer. Recent headway has been made in understanding the genetic underpinnings of this cancer. A subset of oncogenic events is amenable to targeting with drug therapy. BRAF-targeted therapies represent the first major breakthrough in systemic therapy for melanoma leveraging the new genetic knowledge. Ongoing translational research seeks to identify the most scientifically rational combination treatment strategies to build on single-agent targeted therapy.
Geographic Variation in Health Care
Authors: Rosenthal Tom
Published: March 2011

Measurements of health care spending and outcomes in a geographic area and comparisons of one area to another have been used to make observations about health delivery systems and guide health care policy. Medicare claims files are a ready source of data about health care utilization and have served as the basis for a large number of studies in the United States. If ecologic studies are to accurately reflect local practices, potential variables must be accounted for. In the United States, differences in disease burden and socioeconomic factors are important variables affecting health care spending and outcomes. The assertion that regional variation in Medicare spending in the last two years of life is indicative of widespread waste in the U.S. health care system became a controversial part of the health care reform debate in 2009–2010.
Relationships Between Medicine and Industry: Approaches to the Problem of Conflicts of Interest
Authors: Raad Raymond , Appelbaum Paul S.
Published: March 2011

Relationships between physicians and industry are prevalent in medical education, clinical practice, and research, as well as at the level of medical institutions. These relationships can be valuable for the advancement of medicine but have also received increased scrutiny in recent years because they create conflicts of interest that pose a risk of biasing the judgments of physicians. Responses to these conflicts of interest by medical institutions, journals, and governments have utilized four main tools: education, disclosure, management, and prohibition. Each of the four has its advantages and drawbacks. Medicine faces the challenge of tailoring the use of these tools to minimize the risk of bias while allowing useful medical–industry collaborations to proceed. Viewing the dilemmas created by physicians' relationships with industry as a version of the principal–agent problem, which is much discussed by economists, may help in developing creative approaches to these issues.
Direct-to-Consumer Genetic Testing: Perceptions, Problems, and Policy Responses
Authors: Caulfield Timothy , McGuire Amy L.
Published: March 2011

Direct-to-consumer (DTC) genetic testing has attracted a great amount of attention from policy makers, the scientific community, professional groups, and the media. Although it is unclear what the public demand is for these services, there does appear to be public interest in personal genetic risk information. As a result, many commentators have raised a variety of social, ethical, and regulatory issues associated with this emerging industry, including privacy issues, ensuring that DTC companies provide accurate information about the risks and limitations of their services, the possible adverse impact of DTC genetic testing on healthcare systems, and concern about how individuals may interpret and react to genetic risk information.
Molecular Mechanisms Deployed by Virally Encoded G Protein–Coupled Receptors in Human Diseases
Authors: Montaner Silvia , Kufareva Irina , Abagyan Ruben , Gutkind J. Silvio
Published: March 2011

G protein–coupled receptors (GPCRs) represent the largest family of cell surface molecules involved in signal transduction. Surprisingly, open reading frames for multiple GPCRs were hijacked in the process of coevolution between Herpesviridae family viruses and their human and mammalian hosts. Virally encoded GPCRs (vGPCRs) evolved as parts of viral genomes, and this evolution allowed the power of host GPCR signaling circuitries to be harnessed in order to ensure viral replicative success. Phylogenetically, vGPCRs are distantly related to human chemokine receptors, although they feature several unique characteristics. Here, we describe the molecular mechanisms underlying vGPCR-mediated viral pathogenesis. These mechanisms include constitutive activity, aberrant coupling to human G proteins and β-arrestins, binding and activation by human chemokines, and dimerization with other GPCRs expressed in infected cells. The likely structural basis for these molecular events is described for the two closest viral homologs of human GPCRs. This information may aid in the development of novel targeted therapeutic strategies against viral diseases.
Systems Pharmacology: Network Analysis to Identify Multiscale Mechanisms of Drug Action
Authors: Zhao Shan , Iyengar Ravi
Published: March 2011

Systems approaches have long been used in pharmacology to understand drug action at the organ and organismal levels. The application of computational and experimental systems biology approaches to pharmacology allows us to expand the definition of systems pharmacology to include network analyses at multiple scales of biological organization and to explain both therapeutic and adverse effects of drugs. Systems pharmacology analyses rely on experimental “omics” technologies that are capable of measuring changes in large numbers of variables, often at a genome-wide level, to build networks for analyzing drug action. A major use of omics technologies is to relate the genomic status of an individual to the therapeutic efficacy of a drug of interest. Combining pathway and network analyses, pharmacokinetic and pharmacodynamic models, and a knowledge of polymorphisms in the genome will enable the development of predictive models of therapeutic efficacy. Network analyses based on publicly available databases such as the U.S. Food and Drug Administration's Adverse Event Reporting System allow us to develop an initial understanding of the context within which molecular-level drug-target interactions can lead to distal effectors in a process that results in adverse phenotypes at the organ and organismal levels. The current state of systems pharmacology allows us to formulate a set of questions that could drive future research in the field. The long-term goal of such research is to develop polypharmacology for complex diseases and predict therapeutic efficacy and adverse event risk for individuals prior to commencement of therapy.
AMPK and mTOR in Cellular Energy Homeostasis and Drug Targets
Authors: Inoki Ken , Kim Joungmok , Guan Kun-Liang
Published: March 2011

The mammalian target of rapamycin (mTOR) is a central controller of cell growth and proliferation. mTOR forms two distinct complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). mTORC1 is regulated by multiple signals such as growth factors, amino acids, and cellular energy and regulates numerous essential cellular processes including translation, transcription, and autophagy. The AMP-activated protein kinase (AMPK) is a cellular energy sensor and signal transducer that is regulated by a wide array of metabolic stresses. These two pathways serve as a signaling nexus for regulating cellular metabolism, energy homeostasis, and cell growth, and dysregulation of each pathway may contribute to the development of metabolic disorders such as obesity, type 2 diabetes, and cancer. This review focuses on our current understanding of the relationship between AMPK and mTORC1 signaling and discusses their roles in cellular and organismal energy homeostasis.
Cyclic Nucleotide Compartmentalization: Contributions of Phosphodiesterases and ATP-Binding Cassette Transporters
Authors: Cheepala Satish , Hulot Jean-Sebastien , Morgan Jessica A. , Sassi Yassine , Zhang Weiqiang , Naren Anjaparavanda P. , Schuetz John D.
Published: March 2011

Cyclic nucleotides [e.g., cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP)] are ubiquitous second messengers that affect multiple cell functions from maturation of the egg to cell division, growth, differentiation, and death. The concentration of cAMP can be regulated by processes within membrane domains (local regulation) as well as throughout a cell (global regulation). The phosphodiesterases (PDEs) that degrade cAMP have well-known roles in both these processes. It has recently been discovered that ATP-binding cassette (ABC) transporters contribute to both local and global regulation of cAMP. This regulation may require the formation of macromolecular complexes. Some of these transporters are ubiquitously expressed, whereas others are more tissue restricted. Because some PDE inhibitors are also ABC transporter inhibitors, it is conceivable that the therapeutic benefits of their use result from the combined inhibition of both PDEs and ABC transporters. Deciphering the individual contributions of PDEs and ABC transporters to such drug effects may lead to improved therapeutic benefits.
Pharmaceutical and Toxicological Properties of Engineered Nanomaterials for Drug Delivery
Authors: Palombo Matthew , Deshmukh Manjeet , Myers Daniel , Gao Jieming , Szekely Zoltan , Sinko Patrick J.
Published: March 2011

Novel engineered nanomaterials (ENMs) are being developed to enhance therapy. The physicochemical properties of ENMs can be manipulated to control/direct biodistribution and target delivery, but these alterations also have implications for toxicity. It is well known that size plays a significant role in determining ENM effects since simply nanosizing a safe bulk material can render it toxic. However, charge, shape, rigidity, and surface modifications also have a significant influence on the biodistribution and toxicity of nanoscale drug delivery systems (NDDSs). In this review, NDDSs are considered in terms of platform technologies, materials, and physical properties that impart their pharmaceutical and toxicological effects. Moving forward, the development of safe and effective nanomedicines requires standardized protocols for determining the physical characteristics of ENMs as well as assessing their potential long-term toxicity. When such protocols are established, the remarkable promise of nanomedicine to improve the diagnosis and treatment of human disease can be fulfilled.
Factors Controlling Nanoparticle Pharmacokinetics: An Integrated Analysis and Perspective
Authors: Moghimi S.M. , Hunter A.C. , Andresen T.L.
Published: March 2011

Intravenously injected nanoparticulate drug carriers provide a wide range of unique opportunities for site-specific targeting of therapeutic agents to many areas within the vasculature and beyond. Pharmacokinetics and biodistribution of these carriers are controlled by a complex array of interrelated core and interfacial physicochemical and biological factors. Pertinent to realizing therapeutic goals, definitive maps that establish the interdependency of nanoparticle size, shape, and surface characteristics in relation to interfacial forces, biodistribution, controlled drug release, excretion, and adverse effects must be outlined. These concepts are critically evaluated and an integrated perspective is provided on the basis of the recent application of nanoscience approaches to nanocarrier design and engineering. The future of this exciting field is bright; some regulatory-approved products are already on the market and many are in late-phase clinical trials. With concomitant advances in extensive computational knowledge of the genomics and epigenomics of interindividual variations in drug responses, the boundaries toward development of personalized nanomedicines can be pushed further.
Addiction Circuitry in the Human Brain
Authors: Volkow Nora D. , Wang Gene-Jack , Fowler Joanna S. , Tomasi Dardo
Published: March 2011

A major challenge in understanding substance-use disorders lies in uncovering why some individuals become addicted when exposed to drugs, whereas others do not. Although genetic, developmental, and environmental factors are recognized as major contributors to a person's risk of becoming addicted, the neurobiological processes that underlie this vulnerability are still poorly understood. Imaging studies suggest that individual variations in key dopamine-modulated brain circuits, including circuits involved in reward, memory, executive function, and motivation, contribute to some of the differences in addiction vulnerability. A better understanding of the main circuits affected by chronic drug use and the influence of social stressors, developmental trajectories, and genetic background on these circuits is bound to lead to a better understanding of addiction and to more effective strategies for the prevention and treatment of substance-use disorders.
Chronic Pain States: Pharmacological Strategies to Restore Diminished Inhibitory Spinal Pain Control
Authors: Zeilhofer Hanns Ulrich , Benke Dietmar , Yevenes Gonzalo E.
Published: March 2011

Potentially noxious stimuli are sensed by specialized nerve cells named nociceptors, which convey nociceptive signals from peripheral tissues to the central nervous system. The spinal dorsal horn and the trigeminal nucleus serve as first relay stations for incoming nociceptive signals. At these sites, nociceptor terminals contact a local neuronal network consisting of excitatory and inhibitory interneurons as well as of projection neurons. Blockade of neuronal inhibition in this network causes an increased sensitivity to noxious stimuli (hyperalgesia), painful sensations occurring after activation of non-nociceptive fibers (allodynia), and spontaneous pain felt in the absence of any sensory stimulation. It thus mimics the major characteristics of chronic pain states. Diminished inhibitory pain control in the spinal dorsal horn occurs naturally, e.g., through changes in the function of inhibitory neurotransmitter receptors or through altered chloride homeo-stasis in the course of inflammation or nerve damage. This review summarizes our current knowledge about endogenous mechanisms leading to diminished spinal pain control and discusses possible ways that could restore proper inhibition through facilitation of fast inhibitory neurotransmission.
Chemical Genetics–Based Target Identification in Drug Discovery
Authors: Cong Feng , Cheung Atwood K. , Huang Shih-Min A.
Published: March 2011

Identification of novel, validated targets remains a top priority in modern drug discovery. Chemical genetics represents a powerful approach to the discovery of new targets. Unlike the traditional target-based screen that relies on a predefined, sometimes poorly validated target, a chemical genetics–based phenotypic screen probes the entire molecular signaling pathway in an efficient and unbiased manner for the most drug-sensitive node. The most significant obstacle associated with this approach is identification of the efficacy targets of small-molecule probes. The huge potential of chemical genetics cannot be realized without the establishment of reliable mechanisms for target identification. In this article, we describe each essential element of the chemical genetics process, discuss common challenges that the field is facing, and critically review various biochemical and genetics approaches recently developed for target deconvolution. We also attempt to summarize lessons that we have collectively learned and provide a practical perspective to facilitate the advancement of chemical genetics.
Pharmacology of Iron Transport
Authors: Byrne Shaina L. , Krishnamurthy Divya , Wessling-Resnick Marianne
Published: March 2011

Elucidating the molecular basis for the regulation of iron uptake, storage, and distribution is necessary to understand iron homeostasis. Pharmacological tools are emerging to identify and distinguish among different iron transport pathways. Stimulatory or inhibitory small molecules with effects on iron uptake can help characterize the mechanistic elements of iron transport and the roles of the transporters involved in these processes. In particular, iron chelators can serve as potential pharmacological tools to alleviate diseases of iron overload. This review focuses on the pharmacology of iron transport, introducing iron transport membrane proteins and known inhibitors.
Small-Molecule Allosteric Activators of Sirtuins
Authors: Sinclair David A. , Guarente Leonard
Published: March 2011

The mammalian sirtuins (SIRT1–7) are NAD+-dependent lysine deacylases that play central roles in cell survival, inflammation, energy metabolism, and aging. Members of this family of enzymes are considered promising pharmaceutical targets for the treatment of age-related diseases including cancer, type 2 diabetes, inflammatory disorders, and Alzheimer's disease. SIRT1-activating compounds (STACs), which have been identified from a variety of chemical classes, provide health benefits in animal disease models. Recent data point to a common mechanism of allosteric activation by natural and synthetic STACs that involves the binding of STACs to a conserved N-terminal domain in SIRT1. Compared with polyphenols such as resveratrol, the synthetic STACs show greater potency, solubility, and target selectivity. Although considerable progress has been made regarding SIRT1 allosteric activation, key questions remain, including how the molecular contacts facilitate SIRT1 activation, whether other sirtuin family members will be amenable to activation, and whether STACs will ultimately prove safe and efficacious in humans.