bluuebunny/crossref_metadata_2025 huggingface dataset:
Wireless Technology in Disease Management and Medicine
Authors: Clifford Gari D. , Clifton David
Published: March 2011

Healthcare information, and to some extent patient management, is progressing toward a wireless digital future. This change is driven partly by a desire to improve the current state of medicine using new technologies, partly by supply-and-demand economics, and partly by the utility of wireless devices. Wired technology can be cumbersome for patient monitoring and can restrict the behavior of the monitored patients, introducing bias or artifacts. However, wireless technologies, while mitigating some of these issues, have introduced new problems such as data dropout and “information overload” for the clinical team. This review provides an overview of current wireless technology used for patient monitoring and disease management. We identify some of the major related issues and describe some existing and possible solutions. In particular, we discuss the rapidly evolving fields of telemedicine and mHealth in the context of increasingly resource-constrained healthcare systems.
Circulating Tumor Cells and Circulating Tumor DNA
Authors: Alix-Panabières Catherine , Schwarzenbach Heidi , Pantel Klaus
Published: March 2011

Solid tumors derived from epithelial tissues (carcinomas) are responsible for 90% of all new cancers in Europe, and the main four tumor entities are breast, prostate, lung, and colon cancer. Present tumor staging is mainly based on local tumor extension, metastatic lymph node involvement, and evidence of overt distant metastasis obtained by imaging technologies. However, these staging procedures are not sensitive enough to detect early tumor cell dissemination as a key event in tumor progression. Many teams have therefore focused on the development of sensitive assays that allow the specific detection of single tumor cells or small amounts of cell-free tumor DNA in the peripheral blood of cancer patients. These methods allow the detection and characterization of early metastatic spread and will provide unique insights into the biology of metastatic progression of human tumors, including the effects of therapeutic interventions.
Translation of Near-Infrared Fluorescence Imaging Technologies: Emerging Clinical Applications
Authors: Sevick-Muraca E.M.
Published: March 2011

Technical developments in near-infrared fluorescence (NIRF) imaging and tomography have enabled recent translation into investigational human studies. Noninvasive imaging of the lymphatic vasculature for diagnosis and assessment of function has been uniquely accomplished with NIR using indocyanine green (ICG), a nonspecific dye that has comparatively poor fluorescent properties compared to emerging dyes. Adjunct use of NIRF-ICG for (a) intraoperative sentinel lymph node mapping for cancer staging, (b) video-angiography during surgery, and (c) discrimination of malignant from benign breast lesions detected by mammography and ultrasongraphy also evidences the clinical utility of NIRF. Future NIRF imaging agents that consist of bright fluorescent dyes conjugated to disease-targeting moieties promise molecular imaging and image-guided surgery. In this review, emerging NIRF imaging is described within the context of nuclear imaging technologies that remain the “gold standard” of molecular imaging.
The Genetic Architecture of Schizophrenia: New Mutations and Emerging Paradigms
Authors: Rodriguez-Murillo Laura , Gogos Joseph A. , Karayiorgou Maria
Published: March 2011

Although a genetic component of schizophrenia has been acknowledged for a long time, the underlying architecture of the genetic risk remains a contentious issue. Early linkage and candidate association studies led to largely inconclusive results. More recently, the availability of powerful technologies, samples of sufficient sizes, and genome-wide panels of genetic markers facilitated systematic and agnostic scans throughout the genome for either common or rare disease risk variants of small or large effect size, respectively. Although the former had limited success, the role of rare genetic events, such as copy-number variants (CNVs) or rare point mutations, has become increasingly important in gene discovery for schizophrenia. Importantly, recent research building upon earlier findings of de novo recurrent CNVs at the 22q11.2 locus, has highlighted a de novo mutational paradigm as a major component of the genetic architecture of schizophrenia. Recent progress is bringing us closer to earlier intervention and new therapeutic targets.
Carotid Stenting Versus Endarterectomy
Authors: Doig David , Brown Martin M.
Published: March 2011

Since the landmark NASCET and ECST trials demonstrated the superiority of carotid endarterectomy over medical therapy in the prevention of stroke for patients with symptomatic carotid artery stenosis, surgical intervention as a part of secondary prevention of stroke has become widespread. However, the newer technology of carotid artery angioplasty and stenting challenges this mode of intervention, promising the benefits of a procedure under local anesthesia and potentially avoiding the surgical complications of cranial nerve palsy and hematoma. Pooled evidence from randomized controlled trials of endarterectomy versus stenting shows a higher rate of stroke or death in the stenting groups—but this finding is mitigated to an extent by the lower incidence of myocardial infarction and cranial nerve palsy in patients undergoing stenting. At present, carotid endarterectomy combined with optimal drug therapy remains the standard of care for symptomatic 70%–99% stenosis of the internal carotid artery, but stenting might be an option in younger patients and in those not suitable for endarterectomy.
Design of Peptide and Peptidomimetic Ligands with Novel Pharmacological Activity Profiles
Authors: Hruby Victor J. , Cai Minying
Published: March 2011

Peptide hormones and neurotransmitters are of central importance in most aspects of intercellular communication and are involved in virtually all degenerative diseases. In this review, we discuss physicochemical approaches to the design of novel peptide and peptidomimetic agonists, antagonists, inverse agonists, and related compounds that have unique biological activity profiles, reduced toxic side effects, and, if desired, the ability to cross the blood-brain barrier. Designing ligands for specific biological and medical needs is emphasized, as is the close collaboration of chemists and biologists to maximize the chances for success. Special emphasis is placed on the use of conformational (ϕ-ψ space) and topographical (χ space) considerations in design.
The Expression and Function of Organic Anion Transporting Polypeptides in Normal Tissues and in Cancer
Authors: Obaidat Amanda , Roth Megan , Hagenbuch Bruno
Published: March 2011

Organic anion transporting polypeptides (OATPs) are members of the SLCO gene superfamily of proteins. The 11 human OATPs are classified into 6 families and subfamilies on the basis of their amino acid sequence similarities. OATPs are expressed in several epithelial tissues throughout the body and transport mainly amphipathic molecules with molecular weights of more than 300 kDa. Members of the OATP1 and OATP2 families are functionally the best-characterized OATPs. Among these are the multispecific OATP1A2, OATP1B1, OATP1B3, and OATP2B1. They transport various endo- and xenobiotics, including hormones and their conjugates as well as numerous drugs such as several anticancer agents. Recent reports demonstrate that some OATPs are up- or downregulated in several cancers and that OATP expression might affect cancer development. On the basis of the findings summarized in this review, we propose that OATPs could be valuable targets for anticancer therapy.
Adaptive Trial Designs
Authors: Lai Tze Leung , Lavori Philip William , Shih Mei-Chiung
Published: March 2011

We review adaptive designs for clinical trials, giving special attention to the control of the Type I error in late-phase confirmatory trials, when the trial planner wishes to adjust the final sample size of the study in response to an unblinded analysis of interim estimates of treatment effects. We point out that there is considerable inefficiency in using the adaptive designs that employ conditional power calculations to reestimate the sample size and that maintain the Type I error by using certain weighted test statistics. Although these adaptive designs have little advantage over familiar group-sequential designs, our review also describes recent developments in adaptive designs that are both flexible and efficient. We also discuss the use of Bayesian designs, when the context of use demands control over operating characteristics (Type I and II errors) and correction of the bias of estimated treatment effects.
The Best of Both Worlds? Bitopic Orthosteric/Allosteric Ligands of G Protein–Coupled Receptors
Authors: Valant Celine , Robert Lane J. , Sexton Patrick M. , Christopoulos Arthur
Published: March 2011

It is now acknowledged that G protein–coupled receptors, the largest class of drug targets, adopt multiple active states that can be preferentially stabilized by orthosteric ligands or allosteric modulators, thus giving rise to the phenomenon of pathway-biased signaling. In the past few years, researchers have begun to explore the potential of linking orthosteric and allosteric pharmacophores to yield bitopic hybrid ligands. This approach is an extension of the more traditional bivalent ligand concept and shares some of the same challenges, including the choice and role of the linker between the two pharmacophores and the validation of mechanism of action. Nonetheless, the promise of bitopic ligands is the generation of novel chemical tools that have improved affinity and/or selectivity profiles. Previously identified functionally selective compounds (and medicines) also may act via a bitopic mechanism, suggesting that the phenomenon is more widespread than currently appreciated.
Drug Transporters in Drug Efficacy and Toxicity
Authors: DeGorter M.K. , Xia C.Q. , Yang J.J. , Kim R.B.
Published: March 2011

Drug transporters are now widely acknowledged as important determinants governing drug absorption, excretion, and, in many cases, extent of drug entry into target organs. There is also a greater appreciation that altered drug transporter function, whether due to genetic polymorphisms, drug-drug interactions, or environmental factors such as dietary constituents, can result in unexpected toxicity. Such effects are in part due to the interplay between various uptake and efflux transporters with overlapping functional capabilities that can manifest as marked interindividual variability in drug disposition in vivo. Here we review transporters of the solute carrier (SLC) and ATP-binding cassette (ABC) superfamilies considered to be of major importance in drug therapy and outline how understanding the expression, function, and genetic variation in such drug transporters will result in better strategies for optimal drug design and tissue targeting as well as reduce the risk for drug-drug interactions and adverse drug responses.
Exploiting the Cancer Genome: Strategies for the Discovery and Clinical Development of Targeted Molecular Therapeutics
Authors: Yap Timothy A. , Workman Paul
Published: March 2011

Our biological understanding of the molecular basis of cancer has benefited from advances in basic research, accelerated recently by cancer genome sequencing and other high-throughput, genome-wide profiling technologies. Given the diverse heterogeneity among tumors, the traditional cytotoxic chemotherapy and one-size-fits-all approaches to cancer discovery and development are not appropriate for molecularly targeted agents. Selection of new drug targets is based on achieving cancer selectivity through exploiting specific dependencies and vulnerabilities predicted from tumor genetics. Discovery of highly target-selective agents is enhanced by integrating multiple modern technologies, particularly structure-based design. Efficient clinical evaluation requires smart, hypothesis-testing studies using validated pharmacodynamic and predictive biomarkers. We discuss and exemplify biomarker-driven clinical development and the concept of the Pharmacologic Audit Trail. We detail the exciting approaches offered by drugging the cancer genome, focusing on blocking oncogene addiction, drugging the oncogenic lipid kinome, addressing nononcogene addiction, exploiting synthetic lethality, and overcoming apoptotic resistance, leading to personalized molecular medicine.
Epigenetic Mechanisms of Depression and Antidepressant Action
Authors: Vialou Vincent , Feng Jian , Robison Alfred J. , Nestler Eric J.
Published: March 2011

Epigenetic mechanisms, which control chromatin structure and function, mediate changes in gene expression that occur in response to diverse stimuli. Recent research has established that environmental events and behavioral experience induce epigenetic changes at particular gene loci and that these changes help shape neuronal plasticity and function and hence behavior. Some of these changes can be stable and can even persist for a lifetime. Increasing evidence supports the hypothesis that aberrations in chromatin remodeling and subsequent effects on gene expression within limbic brain regions contribute to the pathogenesis of depression and other stress-related disorders such as post-traumatic stress disorder and other anxiety syndromes. Likewise, the gradually developing but persistent therapeutic effects of antidepressant medications may be achieved in part via epigenetic mechanisms. This review discusses recent advances in our understanding of the epigenetic regulation of stress-related disorders and focuses on three distinct aspects of stress-induced epigenetic pathology: the effects of stress and antidepressant treatment during adulthood, the lifelong effects of early-life stress on subsequent stress vulnerability, and the possible transgenerational transmission of stress-induced abnormalities.
G Protein–Coupled Receptor Deorphanizations
Authors: Civelli Olivier , Reinscheid Rainer K. , Zhang Yan , Wang Zhiwei , Fredriksson Robert , Schiöth Helgi B.
Published: March 2011

G protein–coupled receptors (GPCRs) are major regulators of intercellular interactions. They initiate these actions by being activated by a wide variety of natural ligands. Historically, ligands were discovered first, but the advent of molecular biology reversed this trend. Most GPCRs are identified on the basis of their DNA sequences and thus are initially unmatched to known natural ligands. They are termed orphan GPCRs. Discovering their ligands—i.e., “deorphanizing” the GPCRs—gave birth to the field of reverse pharmacology. This review discusses the present status of GPCR deorphanization, presents a few examples of successes and surprises, and highlights difficulties encountered in these efforts.
Integrative Continuum: Accelerating Therapeutic Advances in Rare Autoimmune Diseases
Authors: Van Herle Katja , Behne Jacinta M. , Van Herle Andre , Blaschke Terrence F. , Smith Terry J. , Yeaman Michael R.
Published: March 2011

Autoimmune diseases are chronic, life threatening, and of burgeoning public health concern. They rank among the 10 most common causes of death in women, and some have incidence rates surpassing those of heart disease and cancer. Emerging information regarding molecular and cellular mechanisms affords opportunities for the discovery of novel therapeutic strategies or the repurposing of FDA-approved pharmacologic agents. Yet, obstacles to drug development amplify as an inverse function of the incidence of rare autoimmune disease; challenges include heterogeneous clinical presentation, paucity of definitive biomarkers, and poorly validated measures of therapeutic response. An integrative continuum model to address these challenges is being applied to neuromyelitis optica (NMO)—a potentially devastating neurodegenerative process that has had limited therapeutic options. This model links target discovery with pharmacologic application to accelerate improved clinical efficacy. The application of such innovative strategies may help researchers overcome barriers to therapeutic advances in NMO and other rare autoimmune diseases.
Silver Spoons and Other Personal Reflections
Authors: Gilman Alfred G.
Published: March 2011

The intent is to tell a story—hopefully one that is at various times serious, light-hearted, or provocative—that describes my life in biomedical science, especially focusing on the 50 years from 1961 (as a college senior) to the present.
Designed Ankyrin Repeat Proteins (DARPins): Binding Proteins for Research, Diagnostics, and Therapy
Authors: Plückthun Andreas
Published: March 2011

Designed ankyrin repeat proteins (DARPins) can recognize targets with specificities and affinities that equal or surpass those of antibodies, but because of their robustness and extreme stability, they allow a multitude of more advanced formats and applications. This review highlights recent advances in DARPin design, illustrates their properties, and gives some examples of their use. In research, they have been established as intracellular, real-time sensors of protein conformations and as crystallization chaperones. For future therapies, DARPins have been developed by advanced, structure-based protein engineering to selectively induce apoptosis in tumors by uncoupling surface receptors from their signaling cascades. They have also been used successfully for retargeting viruses. In ongoing clinical trials, DARPins have shown good safety and efficacy in macular degeneration diseases. These developments all ultimately exploit the high stability, solubility, and aggregation resistance of these molecules, permitting a wide range of conjugates and fusions to be produced and purified.
Perinatal Environmental Exposures Affect Mammary Development, Function, and Cancer Risk in Adulthood
Authors: Fenton Suzanne E. , Reed Casey , Newbold Retha R.
Published: March 2011

Puberty is an important transition that enables reproduction of mammalian species. Precocious puberty, specifically early thelarche (the appearance of breast “buds”), in girls of multiple ethnic backgrounds is a major health problem in the United States and other countries. The cause for a continued decrease in the age of breast development in girls is unknown, but environmental factors likely play a major role. Laboratory and epidemiological studies have identified several individual environmental factors that affect breast development, but further progress is needed. Current research needs include increased attention to and recording of prenatal and neonatal environmental exposures, testing of marketed chemicals for effects on the mammary gland, and understanding of the mammary gland–specific mechanisms that are altered by chemicals. Such research is required to halt the increasing trend toward puberty at earlier ages.
Adherence to Medications: Insights Arising from Studies on the Unreliable Link Between Prescribed and Actual Drug Dosing Histories
Authors: Blaschke Terrence F. , Osterberg Lars , Vrijens Bernard , Urquhart John
Published: March 2011

Satisfactory adherence to aptly prescribed medications is essential for good outcomes of patient care and reliable evaluation of competing modes of drug treatment. The measure of satisfactory adherence is a dosing history that includes timely initiation of dosing plus punctual and persistent execution of the dosing regimen throughout the specified duration of treatment. Standardized terminology for initiation, execution, and persistence of drug dosing is essential for clarity of communication and scientific progress. Electronic methods for compiling drug dosing histories are now the recognized standard for quantifying adherence, the parameters of which support model-based, continuous projections of drug actions and concentrations in plasma that are confirmable by intermittent, direct measurements at single time points. The frequency of inadequate adherence is usually underestimated by pre-electronic methods and thus is clinically unrecognized as a frequent cause of failed treatment or underestimated effectiveness. Intermittent lapses in dosing are potential sources of toxicity through hazardous rebound effects or recurrent first-dose effects.
Astronomical Chemistry
Authors: Klemperer William
Published: March 2011

The discovery of polar polyatomic molecules in higher-density regions of the interstellar medium by means of their rotational emission detected by radioastronomy has changed our conception of the universe from essentially atomic to highly molecular. We discuss models for molecule formation, emphasizing the general lack of thermodynamic equilibrium. Detailed chemical kinetics is needed to understand molecule formation as well as destruction. Ion molecule reactions appear to be an important class for the generally low temperatures of the interstellar medium. The need for the intrinsically high-quality factor of rotational transitions to definitively pin down molecular emitters has been well established by radioastronomy. The observation of abundant molecular ions both positive and, as recently observed, negative provides benchmarks for chemical kinetic schemes. Of considerable importance in guiding our understanding of astronomical chemistry is the fact that the larger molecules (with more than five atoms) are all organic.
Coarse-Grained (Multiscale) Simulations in Studies of Biophysical and Chemical Systems
Authors: Kamerlin Shina C.L. , Vicatos Spyridon , Dryga Anatoly , Warshel Arieh
Published: March 2011

Recent years have witnessed an explosion in computational power, leading to attempts to model ever more complex systems. Nevertheless, there remain cases for which the use of brute-force computer simulations is clearly not the solution. In such cases, great benefit can be obtained from the use of physically sound simplifications. The introduction of such coarse graining can be traced back to the early usage of a simplified model in studies of proteins. Since then, the field has progressed tremendously. In this review, we cover both key developments in the field and potential future directions. Additionally, particular emphasis is given to two general approaches, namely the renormalization and reference potential approaches, which allow one to move back and forth between the coarse-grained (CG) and full models, as these approaches provide the foundation for CG modeling of complex systems.
Dynamics of Nanoconfined Supercooled Liquids
Authors: Richert R.
Published: March 2011

Near their glass transition temperature Tg, supercooled liquids display dramatic changes regarding the dynamics if subject to geometrical restrictions on the scale of 2 to 200 nm. Confinement-induced shifts of Tg of 25 K have been reported, equivalent to relaxation times that differ by several orders of magnitude compared with the bulk liquid at the same temperature. Both acceleration and frustration of structural relaxations have been observed, and the effects can depend strongly on the physical and chemical properties of the interface, on soft versus hard confinement, and on the size and dimensionality of the confining topology. This review attempts to extract a unifying picture from the past 20 years of diverse observations that involve experiments, simulations, and model considerations.
Lessons in Fluctuation Correlation Spectroscopy
Authors: Digman Michelle A. , Gratton Enrico
Published: March 2011

Molecular diffusion and transport processes are fundamental in physical, chemical, and biological systems. Current approaches to measuring molecular transport in cells and tissues based on perturbation methods, e.g., fluorescence recovery after photobleaching, are invasive; single-point fluctuation correlation methods are local; and single-particle tracking requires the observation of isolated particles for relatively long periods of time. We discuss here the detection of molecular transport by exploiting spatiotemporal correlations measured among points at large distances (>1 μm). We illustrate the evolution of the conceptual framework that started with single-point fluorescence fluctuation analysis based on the transit of fluorescent molecules through a small volume of illumination. This idea has evolved to include the measurement of fluctuations at many locations in the sample using microscopy imaging methods. Image fluctuation analysis has become a rich and powerful technique that can be used to extract information about the spatial distribution of molecular concentration and transport in cells and tissues.
Coarse-Grained Simulations of Macromolecules: From DNA to Nanocomposites
Authors: de Pablo Juan J.
Published: March 2011

This review discusses multiscale modeling and simulations of macromolecules and macromolecular systems in the context of two specific examples. In the first, recent attempts to develop coarse-grained representations of DNA are reviewed, and a discussion of recent predictions of such models is presented, particularly in the context of DNA melting and rehybridization. The second example considers polymer nanocomposites; a review of recent simulations is presented, with an emphasis on the description of entanglements in such systems and new methods for the study of the segregation of nanoparticles that arises in copolymers, in which composition heterogeneity can be used to control nanoparticle position and develop an increased understanding of nanoparticle-polymer interactions.
Probing Free-Energy Surfaces with Differential Scanning Calorimetry
Authors: Sanchez-Ruiz Jose M.
Published: March 2011

Many aspects of protein folding can be understood in terms of projections of the highly dimensional energy landscape onto a few (or even only one) particularly relevant coordinates. These free-energy surfaces can be probed conveniently from experimental differential scanning calorimetry (DSC) thermograms, as DSC provides a direct relation with the protein partition function. Free-energy surfaces thus obtained are consistent with two fundamental scenarios predicted by the energy-landscape perspective: (a) well-defined macrostates separated by significant free-energy barriers, in some cases, and, in many other cases, (b) marginal or even vanishingly small barriers, which furthermore show a good correlation with kinetics for fast- and ultrafast-folding proteins. Overall, the potential of DSC to assess free-energy surfaces for a wide variety of proteins makes it possible to address fundamental issues, such as the molecular basis of the barrier modulations produced by natural selection in response to functional requirements or to ensure kinetic stability.
Theoretical and Computational Protein Design
Authors: Samish Ilan , MacDermaid Christopher M. , Perez-Aguilar Jose Manuel , Saven Jeffery G.
Published: March 2011

From exponentially large numbers of possible sequences, protein design seeks to identify the properties of those that fold to predetermined structures and have targeted structural and functional properties. The interactions that confer structure and function involve intermolecular forces and large numbers of interacting amino acids. As a result, the identification of sequences can be subtle and complex. Sophisticated methods for characterizing sequences consistent with a particular structure have been developed, assisting the design of novel proteins. Developments in such computational protein design are discussed, along with recent accomplishments, ranging from the redesign of existing proteins to the design of new functionalities and nonbiological applications.
Simulating Chemistry Using Quantum Computers
Authors: Kassal Ivan , Whitfield James D. , Perdomo-Ortiz Alejandro , Yung Man-Hong , Aspuru-Guzik Alán
Published: March 2011

The difficulty of simulating quantum systems, well known to quantum chemists, prompted the idea of quantum computation. One can avoid the steep scaling associated with the exact simulation of increasingly large quantum systems on conventional computers, by mapping the quantum system to another, more controllable one. In this review, we discuss to what extent the ideas in quantum computation, now a well-established field, have been applied to chemical problems. We describe algorithms that achieve significant advantages for the electronic-structure problem, the simulation of chemical dynamics, protein folding, and other tasks. Although theory is still ahead of experiment, we outline recent advances that have led to the first chemical calculations on small quantum information processors.
Toward a Molecular Theory of Early and Late Events in Monomer to Amyloid Fibril Formation
Authors: Straub John E. , Thirumalai D.
Published: March 2011

Quantitative understanding of the kinetics of fibril formation and the molecular mechanism of transition from monomers to fibrils is needed to obtain insights into the growth of amyloid fibrils and more generally self-assembly multisubunit protein complexes. Significant advances using computations of protein aggregation in a number of systems have established generic and sequence-specific aspects of the early steps in oligomer formation. Theoretical considerations, which view oligomer and fibril growth as diffusion in a complex energy landscape, and computational studies, involving minimal lattice and coarse-grained models, have revealed general principles governing the transition from monomeric protein to ordered fibrillar aggregates. Detailed atomistic calculations have explored the early stages of the protein aggregation pathway for a number of amyloidogenic proteins, most notably amyloid β- (Aβ-) protein and fragments from proteins linked to various diseases. These computational studies have provided insights into the role of sequence, role of water, and specific interatomic interactions underlying the thermodynamics and dynamics of elementary kinetic steps in the aggregation pathway. Novel methods are beginning to illustrate the structural basis for the production of Aβ-peptides through interactions with secretases in the presence of membranes. We show that a variety of theoretical approaches, ranging from scaling arguments to minimal models to atomistic simulations, are needed as a complement to experimental studies probing the principles governing protein aggregation.
Role of Solvation Effects in Protein Denaturation: From Thermodynamics to Single Molecules and Back
Authors: England Jeremy L. , Haran Gilad
Published: March 2011

Protein stability often is studied in vitro through the use of urea and guanidinium chloride, chemical cosolvents that disrupt protein native structure. Much controversy still surrounds the underlying mechanism by which these molecules denature proteins. Here we review current thinking on various aspects of chemical denaturation. We begin by discussing classic models of protein folding and how the effects of denaturants may fit into this picture through their modulation of the collapse, or coil-globule transition, which typically precedes folding. Subsequently, we examine recent molecular dynamics simulations that have shed new light on the possible microscopic origins of the solvation effects brought on by denaturants. It seems likely that both denaturants operate by facilitating solvation of hydrophobic regions of proteins. Finally, we present recent single-molecule fluorescence studies of denatured proteins, the analysis of which corroborates the role of denaturants in shifting the equilibrium of the coil-globule transition.
Theoretical Study of Negative Molecular Ions
Authors: Simons Jack
Published: March 2011

Although this review provides references to tabulations of molecular electron affinities, primarily it focuses on explaining why theory plays an important role in understanding the behavior of anions, explaining the challenges that anions pose to theory, making connections between the theories used to compute electron affinities and the potentials (e.g., charge-dipole, charge-quadrupole, valence attraction and exchange repulsion, dispersion, and polarization) that govern the electron-molecule interaction, and discussing how species with negative electron affinities may possess metastable anion states and how such states should be treated. In addition to references to published literature, many links are given to websites of practicing theoretical chemists who study molecular anions; these links (which appear in boldface) offer the reader a broad avenue to access much more information about molecular anions than can be covered in a review or even through conventional literature sources.
Aspergillus flavus
Authors: Amaike Saori , Keller Nancy P.
Published: March 2011

Aspergillus flavus is saprophytic soil fungus that infects and contaminates preharvest and postharvest seed crops with the carcinogenic secondary metabolite aflatoxin. The fungus is also an opportunistic animal and human pathogen causing aspergillosis diseases with incidence increasing in the immunocompromised population. Whole genome sequences of A. flavus have been released and reveal 55 secondary metabolite clusters that are regulated by different environmental regimes and the global secondary metabolite regulators LaeA and VeA. Characteristics of A. flavus associated with pathogenicity and niche specialization include secondary metabolite production, enzyme elaboration, and a sophisticated oxylipin host crosstalk associated with a quorum-like development program. One of the more promising strategies in field control involves the use of atoxic strains of A. flavus in competitive exclusion studies. In this review, we discuss A. flavus as an agricultural and medical threat and summarize recent research advances in genomics, elucidation of parameters of pathogenicity, and control measures.
Chris Lamb: A Visionary Leader in Plant Science
Authors: Dixon Richard A.
Published: March 2011

Christopher John Lamb (1950–2009) made major contributions to the field of plant defense gene activation, particularly through his studies on signal transduction mechanisms. Between 1994 and 2004, he published a series of seminal papers that outlined the involvement of hydrogen peroxide, nitric oxide, lipid transfer proteins, and aspartic proteases as critical components of local and/or systemic resistance during plant-microbe interactions. Prior to this, he had been one of the first to establish the fact that induced defense responses resulted from transcriptional activation of sets of coordinately regulated genes. Chris obtained his B.S and PhD degrees in biochemistry from the University of Cambridge, United Kingdom, moving to the Botany School at the University of Oxford as a postdoctoral fellow in 1975 and to the Biochemistry Department in Oxford as a Departmental Demonstrator in 1978. He was appointed founding director of the Plant Biology Laboratory at the Salk Institute for Biological Studies in La Jolla, California in 1982, and occupied the last ten years of his life as Director of the John Innes Center, Norwich, United Kingdom. In spite of spending most of his career as a director at two of the world's most prestigious institutes, formal recognition of his achievements came late in life, with election to the Royal Society of London in 2008 and endowment of the honor of Commander of the British Empire (CBE) for his contributions to British plant science by Queen Elizabeth II in 2009. Sadly, Chris did not live to attend the official ceremony at which he would receive his CBE.
Diversity ofPuccinia striiformison Cereals and Grasses
Authors: Hovmøller Mogens S. , Sørensen Chris K. , Walter Stephanie , Justesen Annemarie F.
Published: March 2011

Yellow (stripe) rust is a common fungal disease on cereals and grasses. It is caused by Puccinia striiformis sensu lato, which is biotrophic and heteroecious. The pathogen is specialized on the primary host at both species and cultivar levels, whereas several Berberis spp. may serve as alternate hosts. One lineage infects mainly cereals and at least two lineages are restricted to grasses. P. striiformis on cereals has a typical clonal population structure in many areas, resulting from asexual reproduction, but high diversity, suggesting frequent recombination, has been observed in certain areas in Asia. Yellow rust is spreading by airborne spores potentially across long distances, which may contribute to sudden disease epidemics in new areas. This has been the case since 2000, where large-scale epidemics in warmer wheat-growing areas have been ascribed to the emergence of two closely related yellow rust strains with increased aggressiveness and tolerance to warm temperatures.
A Coevolutionary Framework for Managing Disease-Suppressive Soils
Authors: Kinkel Linda L. , Bakker Matthew G. , Schlatter Daniel C.
Published: March 2011

This review explores a coevolutionary framework for the study and management of disease-suppressive soil microbial communities. Because antagonistic microbial interactions are especially important to disease suppression, conceptual, theoretical, and empirical work on antagonistic coevolution and its relevance to disease suppression is reviewed. In addition, principles of coevolution are used to develop specific predictions regarding the drivers of disease-suppressive potential in soil microbial communities and to highlight important areas for future research. This approach brings an evolutionary perspective to microbial community management and emphasizes the role of species interactions among indigenous nonpathogenic microbes in developing and maintaining disease-suppressive activities in soil.
Emerging Virus Diseases Transmitted by Whiteflies
Authors: Navas-Castillo Jesús , Fiallo-Olivé Elvira , Sánchez-Campos Sonia
Published: March 2011

Virus diseases that have emerged in the past two decades limit the production of important vegetable crops in tropical, subtropical, and temperate regions worldwide, and many of the causal viruses are transmitted by whiteflies (order Hemiptera, family Aleyrodidae). Most of these whitefly-transmitted viruses are begomoviruses (family Geminiviridae), although whiteflies are also vectors of criniviruses, ipomoviruses, torradoviruses, and some carlaviruses. Factors driving the emergence and establishment of whitefly-transmitted diseases include genetic changes in the virus through mutation and recombination, changes in the vector populations coupled with polyphagy of the main vector, Bemisia tabaci, and long distance traffic of plant material or vector insects due to trade of vegetables and ornamental plants. The role of humans in increasing the emergence of virus diseases is obvious, and the effect that climate change may have in the future is unclear.
Evolution and Population Genetics of Exotic and Re-Emerging Pathogens: Novel Tools and Approaches
Authors: Grünwald Niklaus J. , Goss Erica M.
Published: March 2011

Given human population growth and accelerated global trade, the rate of emergence of exotic plant pathogens is bound to increase. Understanding the processes that lead to the emergence of new pathogens can help manage emerging epidemics. Novel tools for analyzing population genetic variation can be used to infer the evolutionary history of populations or species, allowing for the unprecedented reconstruction of the demographic history of pathogens. Specifically, recent advances in the application of coalescent, maximum likelihood (ML), and Bayesian methods to population genetic data combined with increasing availability of affordable sequencing and parallel computing have created the opportunity to apply these methods to a broad range of questions regarding the evolution of emerging pathogens. These approaches are particularly powerful when used to test multiple competing hypotheses. We provide several examples illustrating how coalescent analysis provides critical insights into understanding migration pathways as well as processes of divergence, speciation, and recombination.
Understanding and Exploiting Late Blight Resistance in the Age of Effectors
Authors: Vleeshouwers Vivianne G.A.A. , Raffaele Sylvain , Vossen Jack H. , Champouret Nicolas , Oliva Ricardo , Segretin Maria E. , Rietman Hendrik , Cano Liliana M. , Lokossou Anoma , Kessel Geert , Pel Mathieu A. , Kamoun Sophien
Published: March 2011

Potato (Solanum tuberosum) is the world's third-largest food crop. It severely suffers from late blight, a devastating disease caused by Phytophthora infestans. This oomycete pathogen secretes host-translocated RXLR effectors that include avirulence (AVR) proteins, which are targeted by resistance (R) proteins from wild Solanum species. Most Solanum R genes appear to have coevolved with P. infestans at its center of origin in central Mexico. Various R and Avr genes were recently cloned, and here we catalog characterized R-AVR pairs. We describe the mechanisms that P. infestans employs for evading R protein recognition and discuss partial resistance and partial virulence phenotypes in the context of our knowledge of effector diversity and activity. Genome-wide catalogs of P. infestans effectors are available, enabling effectoromics approaches that accelerate R gene cloning and specificity profiling. Engineering R genes with expanded pathogen recognition has also become possible. Importantly, monitoring effector allelic diversity in pathogen populations can assist in R gene deployment in agriculture.
Revision of the Nomenclature of the Differential Host-Pathogen Interactions ofVenturia inaequalisandMalus
Authors: Bus Vincent G.M. , Rikkerink Erik H.A. , Caffier Valérie , Durel Charles-Eric , Plummer Kim M.
Published: March 2011

The apple scab (Venturia inaequalis–Malus) pathosystem was one of the first systems for which Flor's concept of gene-for-gene (GfG) relationships between the host plant and the pathogen was demonstrated. There is a rich resource of host resistance genes present in Malus germplasm that could potentially be marshalled to confer durable resistance against this most important apple disease. A comprehensive understanding of the host-pathogen interactions occurring in this pathosystem is a prerequisite for effectively manipulating these host resistance factors. An accurate means of identification of specific resistance and consistent use of gene nomenclature is critical for this process. A set of universally available, differentially resistant hosts is described, which will be followed by a set of defined pathogen races at a later stage. We review pertinent aspects of the history of apple scab research, describe the current status and future directions of this research, and resolve some outstanding issues.
Reactive Oxygen Species in Phytopathogenic Fungi: Signaling, Development, and Disease
Authors: Heller Jens , Tudzynski Paul
Published: March 2011

Reactive oxygen species (ROS) play a major role in pathogen-plant interactions: recognition of a pathogen by the plant rapidly triggers the oxidative burst, which is necessary for further defense reactions. The specific role of ROS in pathogen defense is still unclear. Studies on the pathogen so far have focused on the importance of the oxidative stress response (OSR) systems to overcome the oxidative burst or of its avoidance by effectors. This review focuses on the role of ROS for fungal virulence and development. In the recent years, it has become obvious that (a) fungal OSR systems might not have the predicted crucial role in pathogenicity, (b) fungal pathogens, especially necrotrophs, can actively contribute to the ROS level in planta and even take advantage of the host's response, (c) fungi possess superoxide-generating NADPH oxidases similar to mammalian Nox complexes that are important for pathogenicity; however, recent data indicate that they are not directly involved in pathogen-host communication but in fungal differentiation processes that are necessary for virulence.
Somatic Hybridization in the Uredinales
Authors: Park Robert F. , Wellings Colin R.
Published: March 2011

Rust fungi are cosmopolitan in distribution and parasitize a wide range of plants, including economically important crop species such as wheat. Detailed regional, national, and continental surveys of pathogenic variability in wheat-attacking rust pathogens over periods of up to 90 years have shown that in the absence of sexual recombination, genetic diversity is generated by periodic introduction of exotic isolates, single-step mutation, and somatic hybridization. Laboratory studies have provided evidence for somatic hybridization between many rust species and formae speciales, and there is evidence for the process in nature within and between rust species on Linum, poplar, Senecio, wheat, and several grass species. Although the mechanisms involved in somatic hybridization are not well understood, they are thought to involve the fusion of dikaryotic vegetative hyphae, nuclear exchange, and possibly exchange of whole chromosomes between nuclei or parasexuality via the fusion of the two haploid nuclei, followed by mitotic crossing over and vegetative haploidization. In three cases, hybrid isolates rendered resistant plant genotypes susceptible because of new combinations of virulence. Implications for resistance breeding and future prospects in understanding the process are discussed.
Hormone Crosstalk in Plant Disease and Defense: More Than Just JASMONATE-SALICYLATE Antagonism
Authors: Robert-Seilaniantz Alexandre , Grant Murray , Jones Jonathan D.G.
Published: March 2011

Until recently, most studies on the role of hormones in plant-pathogen interactions focused on salicylic acid (SA), jasmonic acid (JA), and ethylene (ET). It is now clear that pathogen-induced modulation of signaling via other hormones contributes to virulence. A picture is emerging of complex crosstalk and induced hormonal changes that modulate disease and resistance, with outcomes dependent on pathogen lifestyles and the genetic constitution of the host. Recent progress has revealed intriguing similarities between hormone signaling mechanisms, with gene induction responses often achieved by derepression. Here, we report on recent advances, updating current knowledge on classical defense hormones SA, JA, and ET, and the roles of auxin, abscisic acid (ABA), cytokinins (CKs), and brassinosteroids in molding plant-pathogen interactions. We highlight an emerging theme that positive and negative regulators of these disparate hormone signaling pathways are crucial regulatory targets of hormonal crosstalk in disease and defense.
Hidden Fungi, Emergent Properties: Endophytes and Microbiomes
Authors: Porras-Alfaro Andrea , Bayman Paul
Published: March 2011

Endophytes are microorganisms that live within plant tissues without causing symptoms of disease. They are important components of plant microbiomes. Endophytes interact with, and overlap in function with, other core microbial groups that colonize plant tissues, e.g., mycorrhizal fungi, pathogens, epiphytes, and saprotrophs. Some fungal endophytes affect plant growth and plant responses to pathogens, herbivores, and environmental change; others produce useful or interesting secondary metabolites. Here, we focus on new techniques and approaches that can provide an integrative understanding of the role of fungal endophytes in the plant microbiome. Clavicipitaceous endophytes of grasses are not considered because they have unique properties distinct from other endophytes. Hidden from view and often overlooked, endophytes are emerging as their diversity, importance for plant growth and survival, and interactions with other organisms are revealed.
Cuticle Surface Coat of Plant-Parasitic Nematodes
Authors: Davies Keith G. , Curtis Rosane H.C.
Published: March 2011

The surface coat (SC) of the plant-parasitic nematode cuticle is an understudied area of current research, even though it likely plays key roles in both nematode-plant and nematode-microbe interactions. Although in several ways Caenorhabditis elegans is a poor model for plant-parasitic nematodes, it is a useful starting point for investigations of the cuticle and its SC, especially in the light of recent work using this species as a model for innate immunity and the generic biology underpinning much host-parasite biology. We review the research focused on the involvement of the SC of plant-parasitic nematodes. Using the insights gained from animal-parasitic nematodes and other sequenced nematodes, we discuss the key roles that the SC may play.