bluuebunny/crossref_metadata_2025 huggingface dataset:
Mites (Acari) as a Factor in Greenhouse Management
Authors: Gerson Uri , Weintraub Phyllis G.
Published: March 2011

This review discusses the economically important pest mites (Acari) of greenhouses, aspects of their biology, and the acarine predators that attack them as well as various insect pests. Greenhouse factors affect pest mites as well as their natural enemy populations and their interactions. Conversely, pest mites affect greenhouse management in terms of the chemical and biological methods required to control their populations. Structure affects heating, cooling, and light, which can be manipulated with suitable screens. Crops often select for pests and their mite enemies. Both groups may be affected in greenhouses by adding pollen and by a CO2-enriched atmosphere. These factors impact pest mite populations, the damage they cause, and the methods used to control them. The possibility of incipient evolution occurring in greenhouses, along with the benefits and consequences for pest control, is discussed.
Mosquito Genomics: Progress and Challenges
Authors: Severson David W. , Behura Susanta K.
Published: March 2011

The whole-genome sequencing of mosquitoes has facilitated our understanding of fundamental biological processes at their basic molecular levels and holds potential for application to mosquito control and prevention of mosquito-borne disease transmission. Draft genome sequences are available for Anopheles gambiae, Aedes aegypti, and Culex quinquefasciatus. Collectively, these represent the major vectors of African malaria, dengue fever and yellow fever viruses, and lymphatic filariasis, respectively. Rapid advances in genome technologies have revealed detailed information on genome architecture as well as phenotype-specific transcriptomics and proteomics. These resources allow for detailed comparative analyses within and across populations as well as species. Next-generation sequencing technologies will likely promote a proliferation of genome sequences for additional mosquito species as well as for individual insects. Here we review the current status of genome research in mosquitoes and identify potential areas for further investigations.
Key Aspects of the Biology of Snail-Killing Sciomyzidae Flies
Authors: Murphy William L. , Knutson Lloyd V. , Chapman Eric G. , Mc Donnell Rory J. , Williams Christopher D. , Foote Benjamin A. , Vala Jean-Claude
Published: March 2011

The biology of snail-killing flies (Diptera: Sciomyzidae) has been studied intensively over the past half-century, especially over the past decade. Today, sciomyzids are biologically the best-known group of higher Diptera. The overarching research objectives are evaluation of sciomyzids as biocontrols of disease-carrying or agriculturally important snails and slugs and as a paradigm group for the study of the evolution of diverse feeding and associated behaviors in flies. We present reviews and analyses of some key features of particular scientific and societal interest, including behavioral and phenological groups; laboratory experimental studies on behavior and development; population biology, bioindicators, ecosystem service provision, and conservation; phylogenetics, molecular studies, and evolutionary biology; and biocontrol.
Nutritional Ecology of Entomophagy in Humans and Other Primates
Authors: Raubenheimer David , Rothman Jessica M.
Published: March 2011

Entomophagy is widespread among nonhuman primates and is common among many human communities. However, the extent and patterns of entomophagy vary substantially both in humans and nonhuman primates. Here we synthesize the literature to examine why humans and other primates eat insects and what accounts for the variation in the extent to which they do so. Variation in the availability of insects is clearly important, but less understood is the role of nutrients in entomophagy. We apply a multidimensional analytical approach, the right-angled mixture triangle, to published data on the macronutrient compositions of insects to address this. Results showed that insects eaten by humans spanned a wide range of protein-to-fat ratios but were generally nutrient dense, whereas insects with high protein-to-fat ratios were eaten by nonhuman primates. Although suggestive, our survey exposes a need for additional, standardized, data.
Serpentinite Mud Volcanism: Observations, Processes, and Implications
Authors: Fryer Patricia
Published: March 2011

Large serpentinite mud volcanoes form on the overriding plate of the Mariana subduction zone. Fluids from the descending plate hydrate (serpentinize) the forearc mantle and enable serpentinite muds to rise along faults to the seafloor. The seamounts are direct windows into subduction processes at depths far too deep to be accessed by any known technology. Fluid compositions vary with distance from the trench, signaling changes in chemical reactions as temperature and pressure increase. The parageneses of rocks in the mudflows permits us to constrain the physical conditions of the decollement region. If eruptive episodes are related to seismicity, seafloor observatories at these seamounts hold the potential to capture a subduction event and trace the effects of eruption on the biological communities that the slab fluids support, such as extremophile Archaea. The microorganisms that inhabit this high-pH, extreme environment support their growth by utilizing chemical constituents present in the slab fluids. Some researchers now contend that the serpentinization process itself may hold the key to the origin of life on Earth.
Ecosystem Transformations of the Laurentian Great Lake Michigan by Nonindigenous Biological Invaders
Authors: Cuhel Russell L. , Aguilar Carmen
Published: March 2011

Lake Michigan, a 58,000-km2 freshwater inland sea, is large enough to have persistent basin-scale circulation yet small enough to enable development of approximately balanced budgets for water, energy, and elements including carbon and silicon. Introduction of nonindigenous species—whether through invasion, intentional stocking, or accidental transplantation—has transformed the lake's ecosystem function and habitat structure. Of the 79 nonindigenous species known to have established reproductive populations in the lake, only a few have brought considerable ecological pressure to bear. Four of these were chosen for this review to exemplify top-down (sea lamprey, Petromyzon marinus), middle-out (alewife, Alosa pseudoharengus), and bottom-up (the dreissenid zebra and quagga mussels, Dreissena polymorpha and Dreissena rostriformis bugensis, respectively) transformations of Lake Michigan ecology, habitability, and ultimately physical environment. Lampreys attacked and extirpated indigenous lake trout, the top predator. Alewives outcompeted native planktivorous fish and curtailed invertebrate populations. Dreissenid mussels—especially quagga mussels, which have had a much greater impact than the preceding zebra mussels—moved ecosystem metabolism basin-wide from water column to bottom dominance and engineered structures throughout the lake. Each of these nonindigenous species exerted devastating effects on commercial and sport fisheries through ecosystem structure modification.
Nanoparticle Delivery of Cancer Drugs
Authors: Wang Andrew Z. , Langer Robert , Farokhzad Omid C.
Published: March 2011

Nanomedicine, the application of nanotechnology to medicine, enabled the development of nanoparticle therapeutic carriers. These drug carriers are passively targeted to tumors through the enhanced permeability and retention effect, so they are ideally suited for the delivery of chemotherapeutics in cancer treatment. Indeed, advances in nanomedicine have rapidly translated into clinical practice. To date, there are five clinically approved nanoparticle chemotherapeutics for cancer and many more under clinical investigation. In this review, we discuss the various nanoparticle drug delivery platforms and the important concepts involved in nanoparticle drug delivery. We also review the clinical data on the approved nanoparticle therapeutics as well as the nanotherapeutics under clinical investigation.
Recent Progress in HIV-Associated Nephropathy
Authors: Wyatt Christina M. , Meliambro Kristin , Klotman Paul E.
Published: March 2011

The classic kidney disease of HIV infection, HIV-associated nephropathy (HIVAN), is an aggressive form of collapsing focal segmental glomerulosclerosis with accompanying tubular and interstitial lesions. HIVAN was first described among African-Americans and Haitian immigrants with advanced HIV disease, an early suggestion of a strong genetic association. This genetic susceptibility was recently linked to polymorphisms on chromosome 22 in individuals of African descent. The association with advanced HIV infection and evidence from HIV-transgenic mice suggested the possibility that HIV directly infects the kidney and that specific HIV gene expression induces host cellular pathways that are responsible for HIVAN pathogenesis. Although combination antiretroviral therapy has substantially reduced the impact of HIVAN in the United States, continued growth of the HIV epidemic in susceptible African populations may have important public health implications. This article reviews recent progress in the pathogenesis and treatment of HIVAN and describes the changing epidemiology of HIV-related kidney disease.
New Paradigms for HIV/AIDS Vaccine Development
Authors: Picker Louis J. , Hansen Scott G. , Lifson Jeffrey D.
Published: March 2011

HIV-1 and its simian counterpart SIV have been exquisitely tailored by evolution to evade host immunity. By virtue of specific adaptations that thwart individual innate or adaptive immune mechanisms, and an overall replication strategy that provides for rapid establishment of a large, systemic viral population, capable of dynamic adaptation to almost all immune selection pressures, these viruses, once established, almost invariably stay one step ahead of the host's immune system, and in the vast majority of infected individuals, replicate indefinitely. Although many vaccine approaches tested to date have been able to enhance the magnitude of the immune responses to HIV/SIV infection, most of these responses, whether cellular or humoral, have largely failed to be both effectively antiviral and targeted to prevent the emergence of fully functional escape variants. Recent advances, however, have provided strong evidence that the initial stages of infection following mucosal transmission of these viruses are more vulnerable to immune intervention, and have led to the development of vaccine strategies that elicit responses able to effectively intervene in these early stages of infection, either preventing acquisition of infection or establishing early, stringent, and durable control. Here, we place HIV/AIDS vaccine development in the context of the basic immunobiology of HIV and SIV, review the evidence for their vulnerability to immune responses immediately after mucosal transmission, and discuss how this newly recognized vulnerability might be exploited for the development of an effective HIV/AIDS vaccine.
Novel Therapies for Hepatitis C: Insights from the Structure of the Virus
Authors: Fusco Dahlene N. , Chung Raymond T.
Published: March 2011

For the first time since the discovery of the hepatitis C virus (HCV), therapeutic options for hepatitis C have expanded. Several agents directly effective against HCV are now in development, including both direct-acting antiviral agents (DAAs) and host cofactor inhibitors. DAAs have been developed to inhibit several HCV proteins, including the NS3/4A serine protease, the NS5B RNA polymerase, NS5A, and NS4B. Host cofactor inhibitors include, but are not limited to, cyclophilin inhibitors, miR122 antagonists, and statins. Development of these agents represents a major advance in HCV therapeutics. This review provides a guide to HCV drugs in various stages of development, including an introduction to their mechanism of action, state of clinical development, efficacy, and side effects.
Multiple Sclerosis: New Insights in Pathogenesis and Novel Therapeutics
Authors: Ontaneda Daniel , Hyland Megan , Cohen Jeffrey A.
Published: March 2011

Concepts of multiple sclerosis (MS) have shifted from the traditional view of a T cell–mediated, demyelinating disease of the white matter to include a broad range of immunopathogenic mechanisms, axonal damage, and widespread gray matter pathology. The cause of MS remains unknown, but recent epidemiological work has focused on genetic factors; environmental factors such as vitamin D, sunlight, and Epstein-Barr virus; and the controversial theory of chronic cerebrospinal venous insufficiency. Revised criteria facilitate making the diagnosis of MS. Emerging therapies are rapidly expanding treatment options, including both parenterally administered and oral medications. Strategies to preserve tissue, promote repair, and restore function are under development, and it is anticipated that they will provide better options for patients with progressive disease.
Aquaporins in Clinical Medicine
Authors: Verkman A.S.
Published: March 2011

The aquaporins are a family of membrane water channels, some of which also transport glycerol. They are involved in a wide range of physiological functions (including water/salt homeostasis, exocrine fluid secretion, and epidermal hydration) and human diseases (including glaucoma, cancer, epilepsy, and obesity). At the cellular level, aquaporin-mediated osmotic water transport across cell plasma membranes facilitates transepithelial fluid transport, cell migration, and neuroexcitation; aquaporin-mediated glycerol transport regulates cell proliferation, adipocyte metabolism, and epidermal water retention. Genetic diseases caused by loss-of-function mutations in aquaporins include nephrogenic diabetes insipidus and congenital cataracts. The neuroinflammatory demyelinating disease neuromyelitis optica is marked by pathogenic autoantibodies against astrocyte water channel aquaporin-4. There remain broad opportunities for the development of aquaporin-based diagnostics and therapeutics. Disease-relevant aquaporin polymorphisms are beginning to be explored. There is great promise in the development of small-molecule aquaporin modulators for therapy of some types of refractory edema, brain swelling, neuroinflammation, glaucoma, epilepsy, cancer, pain, and obesity.
Human Genome Sequencing in Health and Disease
Authors: Gonzaga-Jauregui Claudia , Lupski James R. , Gibbs Richard A.
Published: March 2011

Following the “finished,” euchromatic, haploid human reference genome sequence, the rapid development of novel, faster, and cheaper sequencing technologies is making possible the era of personalized human genomics. Personal diploid human genome sequences have been generated, and each has contributed to our better understanding of variation in the human genome. We have consequently begun to appreciate the vastness of individual genetic variation from single nucleotide to structural variants. Translation of genome-scale variation into medically useful information is, however, in its infancy. This review summarizes the initial steps undertaken in clinical implementation of personal genome information, and describes the application of whole-genome and exome sequencing to identify the cause of genetic diseases and to suggest adjuvant therapies. Better analysis tools and a deeper understanding of the biology of our genome are necessary in order to decipher, interpret, and optimize clinical utility of what the variation in the human genome can teach us. Personal genome sequencing may eventually become an instrument of common medical practice, providing information that assists in the formulation of a differential diagnosis. We outline herein some of the remaining challenges.
Contemporary Management of Male Infertility
Authors: Stahl Peter J. , Stember Doron S. , Goldstein Marc
Published: March 2011

Knowledge of normal male reproductive function and familiarity with the diagnostic evaluation and treatment of male subfertility is beneficial for most physicians. Male subfertility is often correctable, may be genetically transmissible, and may be associated with occult health-threatening conditions. Herein we present an overview of male reproductive medicine, which has been revolutionized in the past two decades by dramatic scientific and therapeutic advances. The development of intracytoplasmic sperm injection and its successful application to sperm retrieved from the epididymis or testis have made biological paternity possible in men previously considered sterile. Microsurgical techniques for vasal-epididymal reconstruction and sperm retrieval have been refined. Novel tests of semen quality have been developed. Medical therapies to improve sperm production, such as estrogen receptor modulation and aromatase inhibition, have been used increasingly in clinical practice. Finally, associations between male subfertility and a spectrum of health-threatening conditions have been recognized.
CCR5 Antagonism in HIV Infection: Current Concepts and Future Opportunities
Authors: Wilkin Timothy J. , Gulick Roy M.
Published: March 2011

CCR5 antagonists inhibit HIV-1 entry by blocking the interaction of HIV-1 with the CCR5 cellular receptor. In patients with established HIV-1 infection, some viral strains use an alternative coreceptor for HIV-1 entry, CXCR4; CCR5 antagonists are not effective in patients harboring these viral strains. Coreceptor tropism testing of viral strains in an individual patient is necessary prior to treating with a CCR5 antagonist. There is one CCR5 antagonist, maraviroc, that is FDA-approved for treatment of HIV-1 infection. This drug is used most commonly for the treatment of HIV-1 infection in patients who have failed other antiretroviral regimens. In addition to virologic effects, CCR5 antagonists are under investigation for immune-modulating effects and for HIV-1 prevention. Ongoing research will further elucidate the role of CCR5 antagonists in combating HIV disease.
Reducing Medical Errors and Adverse Events
Authors: Pham Julius Cuong , Aswani Monica S. , Rosen Michael , Lee HeeWon , Huddle Matthew , Weeks Kristina , Pronovost Peter J.
Published: March 2011

Medical errors account for ∼98,000 deaths per year in the United States. They increase disability and costs and decrease confidence in the health care system. We review several important types of medical errors and adverse events. We discuss medication errors, healthcare-acquired infections, falls, handoff errors, diagnostic errors, and surgical errors. We describe the impact of these errors, review causes and contributing factors, and provide an overview of strategies to reduce these events. We also discuss teamwork/safety culture, an important aspect in reducing medical errors.
Crisis in Hospital-Acquired, Healthcare-Associated Infections
Authors: Calfee David P.
Published: March 2011

Healthcare-associated infections (HAIs) cause significant morbidity and mortality. Recognition of the burden, cost, and preventability of HAIs has resulted in new initiatives to encourage adherence to recommended infection prevention practices and new research to better understand the pathogenesis of HAIs and to develop novel approaches to prevention. Although substantial progress in HAI prevention has been made over the past decade, many opportunities for improvement remain and new challenges continue to arise. Optimal protection of patients from the harms associated with HAIs will require not only allocation of adequate financial resources and additional scientific research, but also a strong commitment to excellence among all healthcare providers, including consistent use of proven prevention practices and appropriate use of antimicrobial agents. Although it is a daunting task, there has never been a better opportunity for the healthcare system to make the changes necessary to achieve the goal of elimination of HAIs.
Omics and Drug Response
Authors: Meyer Urs A. , Zanger Ulrich M. , Schwab Matthias
Published: March 2011

A new generation of technologies commonly named omics permits assessment of the entirety of the components of biological systems and produces an explosion of data and a major shift in our concepts of disease. These technologies will likely shape the future of health care. One aspect of these advances is that the data generated document the uniqueness of each human being in regard to disease risk and treatment response. These developments have reemphasized the concept of personalized medicine. Here we review the impact of omics technologies on one key aspect of personalized medicine: the individual drug response. We describe how knowledge of different omics may affect treatment decisions, namely drug choice and drug dose, and how it can be used to improve clinical outcomes.
The Chemical Biology of Naphthoquinones and Its Environmental Implications
Authors: Kumagai Yoshito , Shinkai Yasuhiro , Miura Takashi , Cho Arthur K.
Published: March 2011

Quinones are a group of highly reactive organic chemical species that interact with biological systems to promote inflammatory, anti-inflammatory, and anticancer actions and to induce toxicities. This review describes the chemistry, biochemistry, and cellular effects of 1,2- and 1,4-naphthoquinones and their derivatives. The naphthoquinones are of particular interest because of their prevalence as natural products and as environmental chemicals, present in the atmosphere as products of fuel and tobacco combustion. 1,2- and 1,4-naphthoquinones are also toxic metabolites of naphthalene, the major polynuclear aromatic hydrocarbon present in ambient air. Quinones exert their actions through two reactions: as prooxidants, reducing oxygen to reactive oxygen species; and as electrophiles, forming covalent bonds with tissue nucleophiles. The targets for these reactions include regulatory proteins such as protein tyrosine phosphatases; Kelch-like ECH-associated protein 1, the regulatory protein for NF-E2-related factor 2; and the glycolysis enzyme glyceraldehyde-3-phosphate dehydrogenase. Through their actions on regulatory proteins, quinones affect various cell signaling pathways that promote and protect against inflammatory responses and cell damage. These actions vary with the specific quinone and its concentration. Effects of exposure to naphthoquinones as environmental chemicals can vary with the physical state, i.e., whether the quinone is particle bound or is in the vapor state. The exacerbation of pulmonary diseases by air pollutants can, in part, be attributed to quinone action.
Drugs for Allosteric Sites on Receptors
Authors: Wenthur Cody J. , Gentry Patrick R. , Mathews Thomas P. , Lindsley Craig W.
Published: March 2011

The presence of druggable, topographically distinct allosteric sites on a wide range of receptor families has offered new paradigms for small molecules to modulate receptor function. Moreover, ligands that target allosteric sites offer significant advantages over the corresponding orthosteric ligands in terms of selectivity, including subtype selectivity within receptor families, and can also impart improved physicochemical properties. However, allosteric ligands are not a panacea. Many chemical issues (e.g., flat structure-activity relationships) and pharmacological issues (e.g., ligand-biased signaling) that are allosteric centric have emerged. Notably, the fact that allosteric sites are less evolutionarily conserved leads to improved selectivity; however, this can also lead to species differences that can hinder safety assessment. Many allosteric ligands possess molecular switches, wherein a small structural change (chemical or metabolic) can modulate the mode of pharmacology or receptor subtype selectivity. As the field has matured, as described here, key principles and strategies have emerged for the design of ligands/drugs for allosteric sites.
Novel Computational Approaches to Polypharmacology as a Means to Define Responses to Individual Drugs
Authors: Xie Lei , Xie Li , Kinnings Sarah L. , Bourne Philip E.
Published: March 2011

Polypharmacology, which focuses on designing therapeutics to target multiple receptors, has emerged as a new paradigm in drug discovery. Polypharmacological effects are an attribute of most, if not all, drug molecules. The efficacy and toxicity of drugs, whether designed as single- or multitarget therapeutics, result from complex interactions between pharmacodynamic, pharmacokinetic, genetic, epigenetic, and environmental factors. Ultimately, to predict a drug response phenotype, it is necessary to understand the change in information flow through cellular networks resulting from dynamic drug-target interactions and the impact that this has on the complete biological system. Although such is a future objective, we review recent progress and challenges in computational techniques that enable the prediction and analysis of in vitro and in vivo drug-response phenotypes.
Old Versus New Oral Anticoagulants: Focus on Pharmacology
Authors: Fareed Jawed , Thethi Indermohan , Hoppensteadt Debra
Published: March 2011

Since the discovery of heparin nearly a century ago, there have been large gaps in the development of anticoagulants. The discovery of warfarin was the first step toward using oral anticoagulants, but warfarin use has been associated with its own challenges from the perspectives of the prescribing physician and the patient. Warfarin, along with other coumarins, has a narrow therapeutic index, requires frequent monitoring, exhibits interindividual response variations, and is associated with several adverse effects. Frequent drug and food interactions contribute to potential safety and efficacy compromise. The indications for use of oral anticoagulants have increased, as these drugs are used not only for thrombosis management but also for cardiovascular indications, producing more challenges for oral anticoagulant use. Factor Xa and thrombin targeting has provided a rational approach to develop new oral anticoagulants with improvements over warfarin. In this review, the pharmacology of warfarin and the pharmacology of the newly developed oral anti-Xa and antithrombin agents are discussed.
Drug Hypersensitivity and Human Leukocyte Antigens of the Major Histocompatibility Complex
Authors: Bharadwaj Mandvi , Illing Patricia , Theodossis Alex , Purcell Anthony W. , Rossjohn Jamie , McCluskey James
Published: March 2011

The human leukocyte antigen (HLA) genes are the most polymorphic in the human genome and are critical in regulating specific immunity, hence their historical discovery as “immune response” genes. HLA allotypes are also implicated in unwanted immune reactions, including drug hypersensitivity syndrome, in which small therapeutic drugs interact with antigenic peptides to drive T cell responses restricted by host HLA. Abacavir, allo-purinol, and carbamazepine are three commonly used drugs that cause a T cell–mediated hypersensitivity that is HLA linked, with each drug exhibiting striking specificity for presentation by defined HLA allotypes. Recent findings have begun to unearth the mechanistic basis for these HLA associations, and here we review recent advances in the field of HLA-associated drug hypersensitivities.
Therapeutic Targeting of the Interleukin-6 Receptor
Authors: Tanaka Toshio , Narazaki Masashi , Kishimoto Tadamitsu
Published: March 2011

Interleukin (IL)-6 is a typical cytokine featuring redundancy and pleiotropic activity. It contributes to host defense against pathogens, but dysregulation of IL-6 production plays a significant pathological role in various autoimmune and inflammatory diseases. Because IL-6 blockade was expected to constitute a novel strategy for the treatment of such diseases, tocilizumab, a humanized anti-IL-6 receptor antibody (anti-IL-6RAb), was developed. Clinical trials have demonstrated the efficacy of anti-IL-6RAb for patients with rheumatoid arthritis, Castleman's disease, and juvenile idiopathic arthritis, resulting in approval of this innovative biologic for the treatment of these diseases, and it can be expected to become a novel drug for various other autoimmune and inflammatory diseases. In murine models of autoimmune diseases, anti-IL-6RAb induces Treg and inhibits Th17 and/or Th1 differentiation, indicating that anti-IL-6RAb may be able to repair Th17/Treg imbalance in human diseases as well.
The PI3K, Metabolic, and Autophagy Networks: Interactive Partners in Cellular Health and Disease
Authors: Shanware Naval P. , Bray Kevin , Abraham Robert T.
Published: March 2011

A fundamental imperative for mammalian cells is to coordinate cell metabolism and growth with environmentally induced stress. This review focuses on three highly integrated networks—the phosphoinositide 3-kinase (PI3K) signaling cascade, intermediate metabolism, and autophagy—that work together to maintain cellular homeostasis under basal conditions and to drive cell-mass accumulation and cell cycle progression in the presence of appropriate mitogenic stimuli. Dysfunction within any one of these networks results in compensatory responses from the other networks. These responses underpin several pathologies associated with major human diseases such as cancer. We discuss the PI3K, metabolism, and autophagy networks and provide selected insights into internetwork cross-talk mechanisms. In recognition of the extensive interactions observed in both healthy and diseased cells, we propose that the three networks be merged into a “metabolism-signaling supernetwork.” A detailed understanding of this supernetwork will facilitate the development of novel therapies for cancer and other complex diseases.
Systematic Approaches to Toxicology in the Zebrafish
Authors: Peterson Randall T. , MacRae Calum A.
Published: March 2011

As the current paradigms of drug discovery evolve, it has become clear that a more comprehensive understanding of the interactions between small molecules and organismal biology will be vital. The zebrafish is emerging as a complement to existing in vitro technologies and established preclinical in vivo models that can be scaled for high-throughput. In this review, we highlight the current status of zebrafish toxicology studies, identify potential future niches for the model in the drug development pipeline, and define the hurdles that must be overcome as zebrafish technologies are refined for systematic toxicology.
Bonding in Beryllium Clusters
Authors: Heaven Michael C. , Merritt Jeremy M. , Bondybey Vladimir E.
Published: March 2011

Beryllium clusters provide an ideal series for exploring the evolution from discrete molecules to the metallic state. The beryllium dimer has a formal bond order of zero, but the molecule is weakly bound. In contrast, bulk-phase beryllium is a hard metal with a high melting point. Theoretical calculations indicate that the bond energies increase dramatically for Ben clusters in the range n=2–6. A triplet ground state is found for n=6, indicating an early emergence of metallic properties. There is an extensive body of theoretical work on smaller Ben clusters, in part because this light element can be treated using high-level methods. However, the apparent simplicity of beryllium is deceptive, and the calculations have proved to be challenging owing to strong electron correlation and configuration interaction effects. Consequently, these clusters have become benchmark systems for the evaluation of a wide spectrum of quantum chemistry methods.
The Density Matrix Renormalization Group in Quantum Chemistry
Authors: Chan Garnet Kin-Lic , Sharma Sandeep
Published: March 2011

The density matrix renormalization group is a method that is useful for describing molecules that have strongly correlated electrons. Here we provide a pedagogical overview of the basic challenges of strong correlation, how the density matrix renormalization group works, a survey of its existing applications to molecular problems, and some thoughts on the future of the method.
Laboring in the Vineyard of Physical Chemistry
Authors: Widom Benjamin
Published: March 2011

Prologue This is an account mostly of what I have seen and worked on in physical chemistry, from my time in graduate school six decades ago to the present. It is a personal story about kinetics, thermodynamics, and statistical mechanics—in which subjects I continue to be educated, thanks to patient instruction by my students and associates.

When I had the invitation from Steve Leone to write this article I said “yes” because (a) “yes” is my default setting; (b) it was a great honor to have been invited to do it; and (c) I was too busy at the time to think about what the consequences of saying “yes” would be. I must now do my best to fulfill my promise.
Solid-State NMR Studies of Amyloid Fibril Structure
Authors: Tycko Robert
Published: March 2011

Current interest in amyloid fibrils stems from their involvement in neurodegenerative and other diseases and from their role as an alternative structural state for many peptides and proteins. Solid-state nuclear magnetic resonance (NMR) methods have the unique capability of providing detailed structural constraints for amyloid fibrils, sufficient for the development of full molecular models. In this article, recent progress in the application of solid-state NMR to fibrils associated with Alzheimer's disease, prion fibrils, and related systems is reviewed, along with relevant developments in solid-state NMR techniques and technology.
Detection of Diseased Plants by Analysis of Volatile Organic Compound Emission
Authors: Jansen R.M.C. , Wildt J. , Kappers I.F. , Bouwmeester H.J. , Hofstee J.W. , van Henten E.J.
Published: March 2011

This review focuses on the detection of diseased plants by analysis of volatile organic compound (VOC) emissions. It includes an overview of studies that report on the impact of infectious and noninfectious diseases on these emissions and discusses the specificity of disease-induced emissions. The review also provides an overview of processes that affect the gas balance of plant volatiles, including their loss processes. These processes are considered as important because they contribute to the time-dynamic concentration profiles of plant-emitted volatiles. In addition, we describe the most popular techniques currently in use to measure volatiles emitted from plants, with emphasis on agricultural application. Dynamic sampling coupled with gas chromatography and followed by an appropriate detector is considered as the most appropriate method for application in agriculture. It is recommended to evaluate the state-of-the-art in the fields concerned with this method and to explore the development of a new instrument based on the specific needs for application in agricultural practice. However, to apply such an instrument in agriculture remains a challenge, mainly due to high costs.
Norman Borlaug: The Man I Worked With and Knew
Authors: Rajaram Sanjaya
Published: March 2011

Much has been written about Norman Borlaug the agricultural scientist and humanitarian whose achievements are recognized with many accolades; to add to those writings is a difficult task. This brief paper is an attempt to provide a personal perspective on Norman Borlaug that can come only from someone who has worked closely with him throughout his professional life. I have endeavored to recollect my early impressions of working with Borlaug as a wheat breeder in Mexico and to highlight his innovative approach to wheat breeding, as well as his views on global population and food security, fertilizers, organic agriculture, biotechnology, and conventional academia. His work ethic was instrumental in his vision for the international agricultural system as an instrument of change in the world. His spirit serves as a reminder to future agricultural scientists that the battle must be vigorously engaged and can be won.
Diverse Targets of Phytoplasma Effectors: From Plant Development to Defense Against Insects
Authors: Sugio Akiko , MacLean Allyson M. , Kingdom Heather N. , Grieve Victoria M. , Manimekalai R. , Hogenhout Saskia A.
Published: March 2011

Phytoplasma research begins to bloom ( 75 ). Indeed, this review shows that substantial progress has been made with the identification of phytoplasma effectors that alter flower development, induce witches' broom, affect leaf shape, and modify plant-insect interactions. Phytoplasmas have a unique life cycle among pathogens, as they invade organisms of two distinct kingdoms, namely plants (Plantae) and insects (Animalia), and replicate intracellularly in both. Phytoplasmas release effectors into host cells of plants and insects to target host molecules, and in plants these effectors unload from the phloem to access distal tissues and alter basic developmental processes. The effectors provide phytoplasmas with a fitness advantage by modulating their plant and insect hosts. We expect that further research on the functional characterization of phytoplasma effectors will generate new knowledge that is relevant to fundamental aspects of plant sciences and entomology, and for agriculture by improving yields of crops affected by phytoplasma diseases.
Not As They Seem
Authors: Bruening George
Published: March 2011

I recount the early influences that directed me toward a career in research and then describe some efforts investigating Cowpea mosaic virus and the satellite RNA of Tobacco ringspot virus. These descriptions have a common theme of surprise, how things often can be not as they are expected to be. Finally, I examine the widely held belief that a plant transgene derived from a distant taxonomic source presents a greater risk than a transgene derived from a closely related plant and contend that this also is a situation in which things may not be as they initially seem.
The Emergence of Ug99 Races of the Stem Rust Fungus is a Threat to World Wheat Production
Authors: Singh Ravi P. , Hodson David P. , Huerta-Espino Julio , Jin Yue , Bhavani Sridhar , Njau Peter , Herrera-Foessel Sybil , Singh Pawan K. , Singh Sukhwinder , Govindan Velu
Published: March 2011

Race Ug99 of the fungus Puccinia graminis tritici that causes stem or black rust disease on wheat was first detected in Uganda in 1998. Seven races belonging to the Ug99 lineage are now known and have spread to various wheat-growing countries in the eastern African highlands, as well as Zimbabwe, South Africa, Sudan, Yemen, and Iran. Because of the susceptibility of 90% of the wheat varieties grown worldwide, the Ug99 group of races was recognized as a major threat to wheat production and food security. Its spread, either wind-mediated or human-aided, to other countries in Africa, Asia, and beyond is evident. Screening in Kenya and Ethiopia has identified a low frequency of resistant wheat varieties and breeding materials. Identification and transfer of new sources of race-specific resistance from various wheat relatives is underway to enhance the diversity of resistance. Although new Ug99-resistant varieties that yield more than current popular varieties are being released and promoted, major efforts are required to displace current Ug99 susceptible varieties with varieties that have diverse race-specific or durable resistance and mitigate the Ug99 threat.
Physical Activity for Health: What Kind? How Much? How Intense? On Top of What?
Authors: Powell Kenneth E. , Paluch Amanda E. , Blair Steven N.
Published: March 2011

Physical activity improves health. Different types of activity promote different types of physiologic changes and different health outcomes. A curvilinear reduction in risk occurs for a variety of diseases and conditions across volume of activity, with the steepest gradient at the lowest end of the activity scale. Some activity is better than none, and more is better than some. Even light-intensity activity appears to provide benefit and is preferable to sitting still. When increasing physical activity toward a desired level, small and well-spaced increments will reduce the incidence of adverse events and improve adherence.

Prior research on the relationship between activity and health has focused on the value of moderate to vigorous activity on top of an indefinite and shifting baseline. Given emerging evidence that light activities have health benefits and with advances in tools for measuring activities of all intensities, it may be time to shift to zero activity as the conceptual starting point for study.
New Directions in Toxicity Testing
Authors: Krewski Daniel , Westphal Margit , Al-Zoughool Mustafa , Croteau Maxine C. , Andersen Melvin E.
Published: March 2011

In 2007, the U.S. National Research Council (NRC) published a groundbreaking report entitled Toxicity Testing in the 21st Century: A Vision and a Strategy. The purpose of this report was to develop a long-range strategic plan to update and advance the way environmental agents are tested for toxicity. The vision focused on the identification of critical perturbations of toxicity pathways that lead to adverse human health outcomes using modern scientific tools and technologies. This review describes how emerging scientific methods will move the NRC vision forward and improve the manner in which the potential health risks associated with exposure to environmental agents are assessed. The new paradigm for toxicity testing is compatible with the widely used four-stage risk assessment framework originally proposed by the NRC in 1983 in the so-called Red Book. The Nrf2 antioxidant pathway provides a detailed example of how relevant pathway perturbations will be identified within the context of the new NRC vision for the future of toxicity testing. The implications of the NRC vision for toxicity testing for regulatory risk assessment are also discussed.
Accelerating Evidence Reviews and Broadening Evidence Standards to Identify Effective, Promising, and Emerging Policy and Environmental Strategies for Prevention of Childhood Obesity
Authors: Brennan Laura , Castro Sarah , Brownson Ross C. , Claus Julie , Orleans C. Tracy
Published: March 2011

The childhood obesity epidemic has stimulated the emergence of many policy and environmental strategies to increase healthy eating and active living, with relatively few research recommendations identifying the most effective and generalizable strategies. Yet, local, state, and national decision makers have an urgent need to take action, particularly with respect to lower-income and racial and ethnic populations at greatest risk. With the surge of promising and emerging policy and environmental strategies, this review provides a framework, criteria, and process modeled from existing expert classification systems to assess the strength of evidence for these strategies. Likewise, this review highlights evidence gaps and ways to increase the types and amount of evidence available to inform policy and environmental strategies. These priorities include documenting independent and interdependent effects, determining applicability to different populations and settings, assessing implementation fidelity and feasibility, identifying cumulative benefits and costs, ascertaining impacts on health equity, and tracking sustainability.
The Social Determinants of Health: Coming of Age
Authors: Braveman Paula , Egerter Susan , Williams David R.
Published: March 2011

In the United States, awareness is increasing that medical care alone cannot adequately improve health overall or reduce health disparities without also addressing where and how people live. A critical mass of relevant knowledge has accumulated, documenting associations, exploring pathways and biological mechanisms, and providing a previously unavailable scientific foundation for appreciating the role of social factors in health. We review current knowledge about health effects of social (including economic) factors, knowledge gaps, and research priorities, focusing on upstream social determinants—including economic resources, education, and racial discrimination—that fundamentally shape the downstream determinants, such as behaviors, targeted by most interventions. Research priorities include measuring social factors better, monitoring social factors and health relative to policies, examining health effects of social factors across lifetimes and generations, incrementally elucidating pathways through knowledge linkage, testing multidimensional interventions, and addressing political will as a key barrier to translating knowledge into action.
Genomic and Biochemical Insights into the Specificity of ETS Transcription Factors
Authors: Hollenhorst Peter C. , McIntosh Lawrence P. , Graves Barbara J.
Published: March 2011

ETS proteins are a group of evolutionarily related, DNA-binding transcriptional factors. These proteins direct gene expression in diverse normal and disease states by binding to specific promoters and enhancers and facilitating assembly of other components of the transcriptional machinery. The highly conserved DNA-binding ETS domain defines the family and is responsible for specific recognition of a common sequence motif, 5′-GGA(A/T)-3′. Attaining specificity for biological regulation in such a family is thus a conundrum. We present the current knowledge of routes to functional diversity and DNA binding specificity, including divergent properties of the conserved ETS and PNT domains, the involvement of flanking structured and unstructured regions appended to these dynamic domains, posttranslational modifications, and protein partnerships with other DNA-binding proteins and coregulators. The review emphasizes recent advances from biochemical and biophysical approaches, as well as insights from genomic studies that detect ETS-factor occupancy in living cells.
Reorientation and Allied Dynamics in Water and Aqueous Solutions
Authors: Laage Damien , Stirnemann Guillaume , Sterpone Fabio , Rey Rossend , Hynes James T.
Published: March 2011

The reorientation of a water molecule is important for a host of phenomena, ranging over—in an only partial listing—the key dynamic hydrogen-bond network restructuring of water itself, aqueous solution chemical reaction mechanisms and rates, ion transport in aqueous solution and membranes, protein folding, and enzymatic activity. This review focuses on water reorientation and related dynamics in pure water, and for aqueous solutes with hydrophobic, hydrophilic, and amphiphilic character, ranging from tetra-methylurea to halide ions and amino acids. Attention is given to the application of theory, simulation, and experiment in the probing of these dynamics, in usefully describing them, and in assessing the description. Special emphasis is placed on a novel sudden, large-amplitude jump mechanism for water reorientation, which contrasts with the commonly assumed Debye rotational diffusion mechanism, characterized by small-amplitude angular motion. Some open questions and directions for further research are also discussed.
Environmental Risk Conditions and Pathways to Cardiometabolic Diseases in Indigenous Populations
Authors: Daniel Mark , Lekkas Peter , Cargo Margaret , Stankov Ivana , Brown Alex
Published: March 2011

This review examines environments in relation to cardiometabolic diseases in Indigenous populations in developed countries. Environmental factors are framed in terms of context (features of places) and composition (features of populations). Indigenous peoples are seen to have endured sociopolitical marginalization and material disadvantage spanning generations. Past adverse collective experiences, modified by culture, are reflected by current heterogeneity in environmental context and composition. As risk conditions, unfavorable contextual and compositional exposures influence the expression of cardiometabolic risk for individuals. Minimal research has evaluated heterogeneity in risk conditions against heterogeneity in cardiometabolic diseases between or within Indigenous populations. Thus far, the features of populations, not of places themselves, have been implicated in relation to cardiometabolic diseases. Behavioral, psychosocial, and stress-axis pathways may explain the relationships between risk conditions and cardiometabolic diseases. Implications of environmental factors and their pathways as well as important research needs are discussed in relation to ecological prevention to reduce cardiometabolic diseases.