bluuebunny/crossref_metadata_2025 huggingface dataset:
Therapeutic Potential for HDAC Inhibitors in the Heart
Authors: McKinsey Timothy A.
Published: March 2011

Reversible protein acetylation provides a central mechanism for controlling gene expression and cellular signaling events. Two pharmacological inhibitors of protein deacetylation are currently approved for the treatment of human cancer, and numerous follow-on compounds are in clinical development for oncology and non-oncology indications. The inhibitors target members of a family of enzymes known as histone deacetylases (HDACs). Surprisingly, HDAC inhibitors have also been shown to be efficacious in preclinical models of heart failure. This review highlights roles of HDACs in the heart and the therapeutic potential of HDAC inhibitors for the treatment of heart failure.
Using Genome-Wide Association Studies to Identify Genes Important in Serious Adverse Drug Reactions
Authors: Daly Ann K.
Published: March 2011

Genome-wide association (GWA) studies have detected novel associations for serious, idiosyncratic, adverse drug reactions including liver toxicity, hypersensitivity, skin rash, and myotoxicity. Human leukocyte antigen (HLA) genotype has been established as an important predictor of susceptibility to drug-induced liver injury, including injury with some drugs where immune-related toxicity was not suspected previously. Similarly, GWA studies have shown a key role for HLA genotype in susceptibility to carbamazepine-related skin rash and hypersensitivity. HLA genotype is not a risk factor for all forms of drug-induced liver injury or for myotoxicity or cardiotoxicity. For simvastatin-related myotoxicity, a strong association with SLCO1B1, which encodes the hepatic statin uptake transporter, has been detected. Genome-wide studies have not yet found clear associations for drug-induced cardiotoxicity, but for bisphosphonate-induced necrosis of the jaw, polymorphisms in the cytochrome P450 CYP2C8 may predict susceptibility. Larger GWA studies and whole-genome sequencing may provide additional insights into all these toxicities.
Xenobiotic Metabolomics: Major Impact on the Metabolome
Authors: Johnson Caroline H. , Patterson Andrew D. , Idle Jeffrey R. , Gonzalez Frank J.
Published: March 2011

Xenobiotics are encountered by humans on a daily basis and include drugs, environmental pollutants, cosmetics, and even components of the diet. These chemicals undergo metabolism and detoxication to produce numerous metabolites, some of which have the potential to cause unintended effects such as toxicity. They can also block the action of enzymes or receptors used for endogenous metabolism or affect the efficacy and/or bioavailability of a coadministered drug. Therefore, it is essential to determine the full metabolic effects that these chemicals have on the body. Metabolomics, the comprehensive analysis of small molecules in a biofluid, can reveal biologically relevant perturbations that result from xenobiotic exposure. This review discusses the impact that genetic, environmental, and gut microflora variation has on the metabolome, and how these variables may interact, positively and negatively, with xenobiotic metabolism.
Developments in Laboratory Studies of Gas-Phase Reactions for Atmospheric Chemistry with Applications to Isoprene Oxidation and Carbonyl Chemistry
Authors: Seakins Paul W. , Blitz Mark A.
Published: March 2011

Laboratory studies of gas-phase chemical processes are a key tool in understanding the chemistry of our atmosphere and hence tackling issues such as climate change and air quality. Laboratory techniques have improved considerably with greater emphasis on product detection, allowing the measurement of site-specific rate coefficients. Radical chemistry lies at the heart of atmospheric chemistry. In this review we consider issues around radical generation and recycling from the oxidation of isoprene and from the chemical reactions and photolysis of carbonyl species. Isoprene is the most globally significant hydrocarbon, but uncertainties exist about its oxidation in unpolluted environments. Recent experiments and calculations that cast light on radical generation are reviewed. Carbonyl compounds are the dominant first-generation products from hydrocarbon oxidation. Chemical oxidation can recycle radicals, or photolysis can be a net radical source. Studies have demonstrated that high-resolution and temperature-dependent studies are important for some significant species.
Solvation Dynamics and Proton Transfer in Nanoconfined Liquids
Authors: Thompson Ward H.
Published: March 2011

Nanoconfined liquids are of interest because of both their fundamental properties and their potential utility in an array of applications. The structure and dynamics of the liquid can be dramatically impacted by the geometrical constraints and the interactions with the interface. Understanding the molecular-level origins of these changes and how they are determined by the characteristics of the confining framework is the subject of ongoing experimental and theoretical studies. The progress and remaining challenges in these efforts are reviewed in the context of solvation dynamics and proton transfer reactions, processes that are strongly affected by nanoscale confinement.
Detecting Nanodomains in Living Cell Membrane by Fluorescence Correlation Spectroscopy
Authors: He Hai-Tao , Marguet Didier
Published: March 2011

Cell membranes actively participate in numerous cellular functions. Inasmuch as bioactivities of cell membranes are known to depend crucially on their lateral organization, much effort has been focused on deciphering this organization on different length scales. Within this context, the concept of lipid rafts has been intensively discussed over recent years. In line with its ability to measure diffusion parameters with great precision, fluorescence correlation spectroscopy (FCS) measurements have been made in association with innovative experimental strategies to monitor modes of molecular lateral diffusion within the plasma membrane of living cells. These investigations have allowed significant progress in the characterization of the cell membrane lateral organization at the suboptical level and have provided compelling evidence for the in vivo existence of raft nanodomains. We review these FCS-based studies and the characteristic structural features of raft nanodomains. We also discuss the findings in regards to the current view of lipid rafts as a general membrane-organizing principle.
Cooperativity, Local-Nonlocal Coupling, and Nonnative Interactions: Principles of Protein Folding from Coarse-Grained Models
Authors: Chan Hue Sun , Zhang Zhuqing , Wallin Stefan , Liu Zhirong
Published: March 2011

Coarse-grained, self-contained polymer models are powerful tools in the study of protein folding. They are also essential to assess predictions from less rigorous theoretical approaches that lack an explicit-chain representation. Here we review advances in coarse-grained modeling of cooperative protein folding, noting in particular that the Levinthal paradox was raised in response to the experimental discovery of two-state-like folding in the late 1960s, rather than to the problem of conformational search per se. Comparisons between theory and experiment indicate a prominent role of desolvation barriers in cooperative folding, which likely emerges generally from a coupling between local conformational preferences and nonlocal packing interactions. Many of these principles have been elucidated by native-centric models, wherein nonnative interactions may be treated perturbatively. We discuss these developments as well as recent applications of coarse-grained chain modeling to knotted proteins and to intrinsically disordered proteins.
Hydrated Acid Clusters
Authors: Leopold Kenneth R.
Published: March 2011

The nature of acids in an aqueous environment is fundamental to many aspects of chemistry. The defining feature of an acid is its ability to transfer a proton to water, but this seemingly simple process can be complex and highly dependent on solvation. This review describes studies aimed at obtaining molecular-level descriptions of acid-water interactions through the study of neutral acid-water complexes. Current understanding of the nature of hydrated protons is first summarized, and a parallel discussion of structural aspects of acid-water complexes is then presented. The nature of proton transfer, and its evolution with cluster size, is described. The review concludes with several examples that lie at the intersection between fundamental work on hydrated acids and important physiochemical processes in the atmosphere.
Ionic Liquids: Structure and Photochemical Reactions
Authors: Castner Edward W. , Margulis Claudio J. , Maroncelli Mark , Wishart James F.
Published: March 2011

Ionic liquids are subjects of intense current interest within the physical chemistry community. A great deal of progress has been made in just the past five years toward identifying the factors that cause these salts to have low melting points and other useful properties. Supramolecular structure and organization have emerged as important and complicated topics that may be key to understanding how chemical reactions and other processes are affected by ionic liquids. New questions are posed, and an active debate is ongoing regarding the nature of nanoscale ordering in ionic liquids. The topic of reactivity in ionic liquids is still relatively unexplored; however, the results that have been obtained indicate that distributed kinetics and dynamical heterogeneity may sometimes, but not always, be influencing factors.
Nonadiabatic Events and Conical Intersections
Authors: Matsika Spiridoula , Krause Pascal
Published: March 2011

Nonadiabatic events, in which the Born-Oppenheimer approximation breaks down, are ubiquitous in chemistry and biology. It is now widely accepted that they are facilitated by conical intersections (CIs), actual degeneracies between electronic states. We review the basic theory of CIs and how they can be studied using modern quantum chemistry and nuclear dynamics. We highlight their importance by presenting their role in radiationless decay pathways present in the building blocks of DNA and proteins. The presence of CIs may contribute to the photostability of these important biomolecules.
Melting and Freezing of Metal Clusters
Authors: Aguado Andrés , Jarrold Martin F.
Published: March 2011

Recent developments allow heat capacities to be measured for size-selected clusters isolated in the gas phase. For clusters with tens to hundreds of atoms, the heat capacities determined as a function of temperature usually have a single peak attributed to a melting transition. The melting temperatures and latent heats show large size-dependent fluctuations. In some cases, the melting temperatures change by hundreds of degrees with the addition of a single atom. Theory has played a critical role in understanding the origin of the size-dependent fluctuations, and in understanding the properties of the liquid-like and solid-like states. In some cases, the heat capacities have extra features (an additional peak or a dip) that reveal a more complex behavior than simple melting. In this article we provide a description of the methods used to measure the heat capacities and provide an overview of the experimental and theoretical results obtained for sodium and aluminum clusters.
Roaming Radicals
Authors: Bowman Joel M. , Shepler Benjamin C.
Published: March 2011

Roaming is a recently verified unusual pathway to molecular products from unimolecular dissociation of an energized molecule. Here we present the evidence for this pathway for H2CO and CH3CHO. Theoretical analysis shows that this path visits the plateau region of the potential energy surface near dissociation to radical products. It is not clear whether roaming is a distinct isolated pathway, in addition to the conventional one via the well-known molecular saddle-point transition state. Evidence is presented to suggest that the two pathways may originate from a single, but highly complicated, dividing surface. Other examples of unusual reaction dynamics are also reviewed.
Multiresonant Coherent Multidimensional Spectroscopy
Authors: Wright John C.
Published: March 2011

Multiresonant coherent multidimensional spectroscopy is a frequency-domain method that uses tunable excitation pulses to excite multiple quantum coherences (MQCs) and/or state populations using fully coherent or partially coherent excitation pathways. Pairs of states that are coupled by intra- and intermolecular interactions re-emit light at their frequency differences. The MQCs are coherent and interfere constructively to create phase-matched output beams. Scanning the excitation frequencies with fixed-excitation-pulse time delays creates multidimensional spectra, whereas scanning the time delays with fixed excitation frequencies measures the MQCs’ coherent and incoherent dynamics. Multiresonant methods can excite any combination of vibrational and/or electronic states and use any coherence pathway. Cross-peaks occur between states when the excitation of one perturbs the other. This requirement for coupling acts to eliminate spectral congestion. Spectral resolution is increased because multiresonant methods narrow inhomogeneous broadening, enhance peaks from specific components, and spread the resolution over multiple dimensions.
A Successful Bacterial Coup d'État: How Rhodococcus fascians Redirects Plant Development
Authors: Stes Elisabeth , Vandeputte Olivier M. , El Jaziri Mondher , Holsters Marcelle , Vereecke Danny
Published: March 2011

Rhodococcus fascians is a gram-positive phytopathogen that induces differentiated galls, known as leafy galls, on a wide variety of plants, employing virulence genes located on a linear plasmid. The pathogenic strategy consists of the production of a mixture of six synergistically acting cytokinins that overwhelm the plant's homeostatic mechanisms, ensuring the activation of a signaling cascade that targets the plant cell cycle and directs the newly formed cells to differentiate into shoot meristems. The shoots that are formed upon infection remain immature and never convert to source tissues resulting in the establishment of a nutrient sink that is a niche for the epiphytic and endophytic R. fascians subpopulations. Niche formation is accompanied by modifications of the transcriptome, metabolome, physiology, and morphology of both host and pathogen. Here, we review a decade of research and set the outlines of the molecular basis of the leafy gall syndrome.
Evolution of Plant Pathogenesis inPseudomonas syringae: A Genomics Perspective
Authors: O'Brien Heath E. , Thakur Shalabh , Guttman David S.
Published: March 2011

The phytopathogenic bacterium Pseudomonas syringae causes serious diseases in a wide range of important crop plants, with recent severe outbreaks on the New Zealand kiwifruit crop and among British horse chestnut trees. Next-generation genome sequencing of over 25 new strains has greatly broadened our understanding of how this species adapts to a diverse range of plant hosts. Not unexpectedly, the genomes were found to be highly dynamic, and extensive polymorphism was found in the distribution of type III secreted effectors (T3SEs) and other virulence-associated genes, even among strains within the same pathovar. An underexplored area brought to light by these data is the specific metabolic adaptations required for growth on woody hosts. These studies provide a tremendous wealth of candidates for more refined functional characterization, which is greatly enhancing our ability to disentangle the web of host-pathogen interactions that determine disease outcomes.
TheClavibacter michiganensisSubspecies: Molecular Investigation of Gram-Positive Bacterial Plant Pathogens
Authors: Eichenlaub Rudolf , Gartemann Karl-Heinz
Published: March 2011

Clavibacter michiganensis subspecies are actinomycete plant pathogens residing mainly in the xylem vessels that infect economically important host plants. In the Clavibacter subspecies michiganensis and sepedonicus, infecting tomato and potato, respectively, essential factors for disease induction are plasmid encoded and loss of the virulence plasmids converts these biotrophic pathogens into endophytes. The genes responsible for successful colonization of the host plant, including evasion/suppression of plant defense reactions, are chromosomally encoded. Several serine proteases seem to be involved in colonization. They are secreted by Clavibacter, but their targets remain unknown. A type 3 secretion system (T3SS) translocating effectors into the plant cells is absent in these gram-positive pathogens. With the development of the modern ‘omics technologies for RNA and proteins based on the known genome sequences, a new phase in the investigation of the mechanisms of plant pathogenicity has begun to allow the genome-wide investigation of the Clavibacter-host interaction.
Plant-Parasite Coevolution: Bridging the Gap between Genetics and Ecology
Authors: Brown James K. M. , Tellier Aurélien
Published: March 2011

We review current ideas about coevolution of plants and parasites, particularly processes that generate genetic diversity. Frequencies of host resistance and parasite virulence alleles that interact in gene-for-gene (GFG) relationships coevolve in the familiar boom-and-bust cycle, in which resistance is selected when virulence is rare, and virulence is selected when resistance is common. The cycle can result in stable polymorphism when diverse ecological and epidemiological factors cause negative direct frequency-dependent selection (ndFDS) on host resistance, parasite virulence, or both, such that the benefit of a trait to fitness declines as its frequency increases. Polymorphism can also be stabilized by overdominance, when heterozygous hosts have greater resistance than homozygotes to diverse pathogens. Genetic diversity can also persist in the form of statistical polymorphism, sustained by random processes acting on gene frequencies and population size. Stable polymorphism allows alleles to be long-lived and genetic variation to be detectable in natural populations. In agriculture, many of the factors promoting stability in host-parasite interactions have been lost, leading to arms races of host defenses and parasite effectors.
What Can Plant Autophagy Do for an Innate Immune Response?
Authors: Hayward Andrew P. , Dinesh-Kumar S.P.
Published: March 2011

Autophagy plays an established role in the execution of senescence, starvation, and stress responses in plants. More recently, an emerging role for autophagy has been discovered during the plant innate immune response. Recent papers have shown autophagy to restrict, and conversely, to also promote programmed cell death (PCD) at the site of pathogen infection. These initial studies have piqued our excitement, but they have also revealed gaps in our understanding of plant autophagy regulation, in our ability to monitor autophagy in plant cells, and in our ability to manipulate autophagic activity. In this review, we present the most pressing questions now facing the field of plant autophagy in general, with specific focus on autophagy as it occurs during a plant-pathogen interaction. To begin to answer these questions, we place recent findings in the context of studies of autophagy and immunity in other systems, and in the context of the mammalian immune response in particular.
RNA-RNA Recombination in Plant Virus Replication and Evolution
Authors: Sztuba-Solińska Joanna , Urbanowicz Anna , Figlerowicz Marek , Bujarski Jozef J.
Published: March 2011

RNA-RNA recombination is one of the strongest forces shaping the genomes of plant RNA viruses. The detection of recombination is a challenging task that prompted the development of both in vitro and in vivo experimental systems. In the divided genome of Brome mosaic virus system, both inter- and intrasegmental crossovers are described. Other systems utilize satellite or defective interfering RNAs (DI-RNAs) of Turnip crinkle virus, Tomato bushy stunt virus, Cucumber necrosis virus, and Potato virus X. These assays identified the mechanistic details of the recombination process, revealing the role of RNA structure and proteins in the replicase-mediated copy-choice mechanism. In copy choice, the polymerase and the nascent RNA chain from which it is synthesized switch from one RNA template to another. RNA recombination was found to mediate the rearrangement of viral genes, the repair of deleterious mutations, and the acquisition of nonself sequences influencing the phylogenetics of viral taxa. The evidence for recombination, not only between related viruses but also among distantly related viruses, and even with host RNAs, suggests that plant viruses unabashedly test recombination with any genetic material at hand.
Application of High-Throughput DNA Sequencing in Phytopathology
Authors: Studholme David J. , Glover Rachel H. , Boonham Neil
Published: March 2011

The new sequencing technologies are already making a big impact in academic research on medically important microbes and may soon revolutionize diagnostics, epidemiology, and infection control. Plant pathology also stands to gain from exploiting these opportunities. This manuscript reviews some applications of these high-throughput sequencing methods that are relevant to phytopathology, with emphasis on the associated computational and bioinformatics challenges and their solutions. Second-generation sequencing technologies have recently been exploited in genomics of both prokaryotic and eukaryotic plant pathogens. They are also proving to be useful in diagnostics, especially with respect to viruses.
The Pathogen-Actin Connection: A Platform for Defense Signaling in Plants
Authors: Day Brad , Henty Jessica L. , Porter Katie J. , Staiger Christopher J.
Published: March 2011

The cytoskeleton, a dynamic network of cytoplasmic polymers, plays a central role in numerous fundamental processes, such as development, reproduction, and cellular responses to biotic and abiotic stimuli. As a platform for innate immune responses in mammalian cells, the actin cytoskeleton is a central component in the organization and activation of host defenses, including signaling and cellular repair. In plants, our understanding of the genetic and biochemical responses in both pathogen and host that are required for virulence and resistance has grown enormously. Additional advances in live-cell imaging of cytoskeletal dynamics have markedly altered our view of actin turnover in plants. In this review, we outline current knowledge of host resistance following pathogen perception, both in terms of the genetic interactions that mediate defense signaling, as well as the biochemical and cellular processes that are required for defense signaling.
Water Relations in the Interaction of Foliar Bacterial Pathogens with Plants
Authors: Beattie Gwyn A.
Published: March 2011

This review examines the many ways in which water influences the relations between foliar bacterial pathogens and plants. As a limited resource in aerial plant tissues, water is subject to manipulation by both plants and pathogens. A model is emerging that suggests that plants actively promote localized desiccation at the infection site and thus restrict pathogen growth as one component of defense. Similarly, many foliar pathogens manipulate water relations as one component of pathogenesis. Nonvascular pathogens do this using effectors and other molecules to alter hormonal responses and enhance intercellular watersoaking, whereas vascular pathogens use many mechanisms to cause wilt. Because of water limitations on phyllosphere surfaces, bacterial colonists, including pathogens, benefit from the protective effects of cellular aggregation, synthesis of hygroscopic polymers, and uptake and production of osmoprotective compounds. Moreover, these bacteria employ tactics for scavenging and distributing water to overcome water-driven barriers to nutrient acquisition, movement, and signal exchange on plant surfaces.
Genetic Susceptibility and the Setting of Occupational Health Standards
Authors: Schulte Paul , Howard John
Published: March 2011

As more is learned about genetic susceptibility to occupational and environmental hazards, there will be increasing pressure to use genetic susceptibility information in setting occupational health standards. Historically, this has not been done, but a growing body of research assesses inherited genetic factors as modifiers of the effects of hazardous exposures. Additionally, acquired genetic and epigenetic characteristics could also be used in standard setting. However, for both inherited and acquired genetic characteristics, many scientific, ethical, legal, and social issues could arise. Investigators need to examine the potential role and implications of using genetic information in standard setting. In this review, we focus primarily on inherited genetic factors and their role in occupational health standard setting.
Proportion of the Decline in Cardiovascular Mortality Disease due to Prevention Versus Treatment: Public Health Versus Clinical Care
Authors: Ford Earl S. , Capewell Simon
Published: March 2011

Mortality rates from coronary heart disease (CHD), which had risen during the twentieth century in many countries, started declining in some countries during the 1960s. Once initial skepticism about the validity of the observed trends dissipated, researchers attempted to generate explanations about the events that had transpired using a variety of techniques, including ecological examinations of the trends in risk factors for CHD and changes in management of CHD, multivariate risk equations, and increasingly sophisticated modeling techniques. Improvements in risk factors as well as changes in cardiac treatments have both contributed to the reductions in CHD mortality, although estimates of their contributions have varied among countries. Models suggest that additional large reductions in CHD mortality are feasible by either improving the distribution of risk factors in the population or raising the percentage of patients receiving evidence-based treatments.
Action on the Social Determinants of Health and Health Inequities Goes Global
Authors: Friel Sharon , Marmot Michael G.
Published: March 2011

Marked health inequities exist between regions, between countries, and within countries. Reducing these inequities in health requires attention to the unfair distribution of power, money, and resources and the conditions of everyday life. These are the social determinants of health. The World Health Organization (WHO) Commission on Social Determinants of Health (CSDH) brought together a global evidence base of what could be done to reduce these health inequities, demonstrating that economic and social policy, if done well, can improve health and health equity. A global movement for health equity was reignited by the WHO Commission on Social Determinants of Health when it made a call to action upon delivering its final report.
The Health Care Workforce: Will It Be Ready as the Boomers Age? A Review of How We Can Know (or Not Know) the Answer
Authors: Ricketts Thomas C.
Published: March 2011

The baby-boom generation will reach the age of eligibility for Medicare starting in 2011. This large group of Americans will require more health care, and more health care workers will be needed to meet those needs. Understanding the needs as well as the size of the workforce needed requires substantial analysis and extensive data. Two major approaches can be used to make these estimates, and the choice of both methods and assumptions can affect the outcomes of any analysis. For the United States to make workforce policy decisions with the best information, we must invest in systems and resources to generate those data and support policy-making bodies that can interpret and make recommendations consistent with the analyses.
Climate Change, Noncommunicable Diseases, and Development: The Relationships and Common Policy Opportunities
Authors: Friel S. , Bowen K. , Campbell-Lendrum D. , Frumkin H. , McMichael A.J. , Rasanathan K.
Published: March 2011

The rapid growth in noncommunicable diseases (NCDs), including injury and poor mental health, in low- and middle-income countries and the widening social gradients in NCDs within most countries worldwide pose major challenges to health and social systems and to development more generally. As Earth's surface temperature rises, a consequence of human-induced climate change, incidences of severe heat waves, droughts, storms, and floods will increase and become more severe. These changes will bring heightened risks to human survival and will likely exacerbate the incidence of some NCDs, including cardiovascular disease, some cancers, respiratory health, mental disorders, injuries, and malnutrition. These two great and urgent contemporary human challenges—to improve global health, especially the control of NCDs, and to protect people from the effects of climate change—would benefit from alignment of their policy agendas, offering synergistic opportunities to improve population and planetary health. Well-designed climate change policy can reduce the incidence of major NCDs in local populations.
Using Marketing Muscle to Sell Fat: The Rise of Obesity in the Modern Economy
Authors: Zimmerman Frederick J.
Published: March 2011

The large increase in obesity in the past 30 years has often been explained in rational choice terms; for example, a decline in food prices has engendered greater food consumption. On closer examination, this kind of explanation does not fit the facts of the current obesity epidemic. Instead, an unprecedented expansion in the scope, power, and ubiquity of food marketing has coincided with an unprecedented expansion in food consumption in predictable ways.

Ongoing protestations that the causes of the recent increase in obesity are unknown may overstate the case. Ample evidence indicates that the obesity epidemic is, at least to a large degree, the result of increased marketing power over the American diet. Only by reigning in or countering marketing power can rationality be restored to the dietary choices of Americans.
Cardiovascular Disease: Rise, Fall, and Future Prospects
Authors: Luepker Russell V.
Published: March 2011

Cardiovascular disease (CVD) became the leading cause of chronic disease morbidity and mortality in industrialized countries in the twentieth century. In many nations, it peaked and began to decline, while in developing countries it is rising. The contributions of risk factors, sociocultural changes, and medical care are debated, but all play a role in understanding these disease patterns. Public health approaches such as dietary change along with widespread use of medications such as aspirin, statins, diuretics, and beta-blockers may impact future trends in this chronic disease epidemic.
Molecular Mechanism of β-Arrestin-Biased Agonism at Seven-Transmembrane Receptors
Authors: Reiter Eric , Ahn Seungkirl , Shukla Arun K. , Lefkowitz Robert J.
Published: March 2011

The concept of biased agonism has recently come to the fore with the realization that seven-transmembrane receptors (7TMRs, also known as G protein–coupled receptors, or GPCRs) activate complex signaling networks and can adopt multiple active conformations upon agonist binding. As a consequence, the “efficacy” of receptors, which was classically considered linear, is now recognized as pluridimensional. Biased agonists selectively stabilize only a subset of receptor conformations induced by the natural “unbiased” ligand, thus preferentially activating certain signaling mechanisms. Such agonists thus reveal the intriguing possibility that one can direct cellular signaling with unprecedented precision and specificity and support the notion that biased agonists may identify new classes of therapeutic agents that have fewer side effects. This review focuses on one particular class of biased ligands that has the ability to alter the balance between G protein–dependent and β-arrestin-dependent signal transduction.
The Ultrafast Pathway of Photon-Induced Electrocyclic Ring-Opening Reactions: The Case of 1,3-Cyclohexadiene
Authors: Deb Sanghamitra , Weber Peter M.
Published: March 2011

The photochemically induced electrocyclic ring-opening reaction of 1,3-cyclohexadiene to 1,3,5-hexatriene serves as a prototype for many important reactions in chemistry and in biological systems. Based on experimental and computational studies, a detailed picture of the reaction has now emerged: Excitation to the Franck-Condon region places the molecule on a steeply repulsive part of the 1B potential energy surface, which propels the molecule in exactly the conrotatory direction that conforms to the Woodward-Hoffmann rules of orbital symmetry. Bypassing a cusp in a symmetry-breaking direction, the wave packet enters the 2A state within 55 fs. It continues to move directly toward the 2A/1A conical intersection, where it crosses in approximately 80 fs to the ground state. This article summarizes the published experimental and theoretical work to describe the current understanding of the reaction while pointing to important questions that remain to be addressed.
New Developments in the Physical Chemistry of Shock Compression
Authors: Dlott Dana D.
Published: March 2011

This review discusses new developments in shock compression science with a focus on molecular media. Some basic features of shock and detonation waves, nonlinear excitations that can produce extreme states of high temperature and high pressure, are described. Methods of generating and detecting shock waves are reviewed, especially those using tabletop lasers that can be interfaced with advanced molecular diagnostics. Newer compression methods such as shockless compression and precompression shock that generate states of cold dense molecular matter are discussed. Shock compression creates a metallic form of hydrogen, melts diamond, and makes water a superionic liquid with unique catalytic properties. Our understanding of detonations at the molecular level has improved a great deal as a result of advanced nonequilibrium molecular simulations. Experimental measurements of detailed molecular behavior behind a detonation front might be available soon using femtosecond lasers to produce nanoscale simulated detonation fronts.
BTB-Kelch protein Krp1 regulates proliferation and differentiation of myoblasts
Authors: Paxton Camille W. , Cosgrove Ruth A. , Drozd Anja C. , Wiggins Emma L. , Woodhouse Sam , Watson Rachel A. , Spence Heather J. , Ozanne Brad W. , Pell Jennifer M.
Published: March 2011

The BTB-Kelch protein Krp1 is highly and specifically expressed in skeletal muscle, where it is proposed to have a role in myofibril formation. We observed significant upregulation of Krp1 in C2 cells early in myoblast differentiation, well before myofibrillogenesis. Krp1 has a role in cytoskeletal organization and cell motility; since myoblast migration and elongation/alignment are important events in early myogenesis, we hypothesized that Krp1 is involved with earlier regulation of differentiation. Krp1 protein levels were detectable by 24 h after induction of differentiation in C2 cells and were significantly upregulated by 48 h, i.e., following the onset myogenin expression and preceding myosin heavy chain (MHC) upregulation. Upregulation of Krp1 required a myogenic stimulus as signaling derived from increased myoblast cell density was insufficient to activate Krp1 expression. Examination of putative Krp1 proximal promoter regions revealed consensus E box elements associated with myogenic basic helix-loop-helix binding. The activity of a luciferase promoter-reporter construct encompassing this 2,000-bp region increased in differentiating C2 myoblasts and in C2 cells transfected with myogenin and/or MyoD. Knockdown of Krp1 via short hairpin RNA resulted in increased C2 cell number and proliferation rate as assessed by bromodeoxyuridine incorporation, whereas overexpression of Krp1-myc had the opposite effect; apoptosis was unchanged. No effects of changed Krp1 protein levels on cell migration were observed, either by scratch wound assay or live cell imaging. Paradoxically, both knockdown and overexpression of Krp1 inhibited myoblast differentiation assessed by expression of myogenin, MEF2C, MHC, and cell fusion.
Dysregulation of Ca2+ signaling in astrocytes from mice lacking amyloid precursor protein
Authors: Linde Cristina I. , Baryshnikov Sergey G. , Mazzocco-Spezzia A. , Golovina Vera A.
Published: March 2011

The relationship between altered metabolism of the amyloid-β precursor protein (APP) and Alzheimer's disease is well established but the physiological roles of APP still remain unclear. Here, we studied Ca2+ signaling in primary cultured and freshly dissociated cortical astrocytes from APP knockout (KO) mice and from Tg5469 mice overproducing by five- to sixfold wild-type APP. Resting cytosolic Ca2+ (measured with fura-2) was not altered in cultured astrocytes from APP KO mice. The stored Ca2+ evaluated by measuring peak amplitude of cyclopiazonic acid [CPA, endoplasmic reticulum (ER) Ca2+ ATPase inhibitor]-induced Ca2+ transients in Ca2+-free medium was significantly smaller in APP KO astrocytes than in wild-type cells. Store-operated Ca2+ entry (SOCE) activated by ER Ca2+ store depletion with CPA was also greatly reduced in APP KO astrocytes. This reflected a downregulated expression in APP KO astrocytes of TRPC1 (C-type transient receptor potential) and Orai1 proteins, essential components of store-operated channels (SOCs). Indeed, silencer RNA (siRNA) knockdown of Orai1 protein expression in wild-type astrocytes significantly attenuated SOCE. SOCE was also essentially reduced in freshly dissociated APP KO astrocytes. Importantly, knockdown of APP with siRNA in cultured wild-type astrocytes markedly attenuated ATP- and CPA-induced ER Ca2+ release and extracellular Ca2+ influx. The latter correlated with downregulation of TRPC1. Overproduction of APP in Tg5469 mice did not alter, however, the stored Ca2+ level, SOCE, and expression of TRPC1/4/5 in cultured astrocytes from these mice. The data demonstrate that the functional role of APP in astrocytes involves the regulation of TRPC1/Orai1-encoded SOCs critical for Ca2+ signaling.
Activation of Dbl restores migration in polyamine-depleted intestinal epithelial cells via Rho-GTPases
Authors: Ray Ramesh M. , Bavaria Mitulkumar N. , Bhattacharya Sujoy , Johnson Leonard R.
Published: March 2011

Integrin binding to the extracellular matrix (ECM) activated Rho GTPases, Src, and focal adhesion kinase in intestinal epithelial cells (IEC)-6. Polyamine depletion inhibited activities of Rac1, RhoA, and Cdc42 and thereby migration. However, constitutively active (CA) Rac1 expression abolished the inhibitory effect of polyamine depletion, indicating that polyamines are involved in a process upstream of Rac1. In the present study, we examined the role of polyamines in the regulation of the guanine nucleotide exchange factor, diffuse B-cell lymphoma (Dbl), for Rho GTPases. Polyamine depletion decreased the level as well as the activation of Dbl protein. Dbl knockdown by siRNA altered cytoskeletal structure and decreased Rac1 activity and migration. Cells expressing CA-Dbl increased migration, Rac1 activity, and proliferation. CA-Dbl restored migration in polyamine-depleted cells by activating RhoA, Rac1, and Cdc42. CA-Dbl caused extensive reorganization of the F-actin cortex into stress fibers. Inhibition of Rac1 by NSC23766 significantly decreased migration of vector-transfected cells and CA-Dbl-transfected cells. However, the inhibition of migration was significantly higher in the vector-transfected cells compared with that seen in the CA-Dbl-transfected cells. Dbl localized in the perinuclear region in polyamine-depleted cells, whereas it localized with the stress fibers in control cells. CA-Dbl localized with stress fibers in both the control and polyamine-depleted cells. These results suggest that polyamines regulate the activation of Dbl, a membrane-proximal process upstream of Rac1.
TGF-β1-activated kinase-1 regulates inflammation and fibrosis in the obstructed kidney
Authors: Ma Frank Y. , Tesch Greg H. , Ozols Elyce , Xie Min , Schneider Michael D. , Nikolic-Paterson David J.
Published: March 2011

Activation of c-Jun amino kinase (JNK), p38 mitogen-activated protein kinase (MAPK), and the transcription factor nuclear factor-κB (NF-κB) drives renal inflammation and fibrosis. However, the upstream MAP kinase kinase kinase (MAP3K) enzyme(s) that activate these pathways in kidney disease are unknown. We determined the role of one candidate MAP3K enzyme, transforming growth factor-β1-activated kinase-1 (TAK1/ MAP3K7), in activation of JNK, p38, and NF-κB in the obstructed kidney using conditional gene deletion in adult mice, and assessed the potential protective effect of TAK1 deletion on renal pathology. TAK1 deletion in cultured tubular epithelial cells substantially inhibited IL-1 and TNF-α-induced JNK, p38, and NF-κB signaling and the proinflammatory response. Map3k7f/fCre-ERTMmice (in which tamoxifen induces global TAK1 deletion) and control Map3k7f/fmice were given tamoxifen at the time of unilateral ureteric obstruction (UUO) and then killed 2, 4, or 5 days later. Tamoxifen-treated control Map3k7f/fmice showed the expected activation of JNK, p38, and NF-κB signaling on days 2, 4, and 5, with macrophage infiltration and upregulation of mRNA levels of proinflammatory molecules (IL-1α, TNF-α, NOS2, and CCL2). Control Map3k7f/fmice also showed interstitial myofibroblast accumulation and collagen deposition in the obstructed kidney. Tamoxifen treatment of Map3k7f/fCre-ERTMmice caused a 60% reduction in renal TAK1 expression on day 4 and >80% on day 5 UUO. Coincident with TAK1 deletion, activation of JNK, p38, and NF-κB signaling was markedly suppressed on days 4 to 5 UUO, which halted renal macrophage accumulation and expression of proinflammatory molecules. TAK1 deletion also halted the development of renal fibrosis in terms of myofibroblast accumulation, collagen deposition, and expression of profibrotic molecules. In conclusion, these studies establish TAK1 as a major upstream activator of JNK, p38, and NF-κB signaling in the obstructed kidney, and they define a pathologic role for TAK1 in renal inflammation and fibrosis.
Persistent kidney dysfunction in swine renal artery stenosis correlates with outer cortical microvascular remodeling
Authors: Eirin Alfonso , Zhu Xiang-Yang , Urbieta-Caceres Victor H. , Grande Joseph P. , Lerman Amir , Textor Stephen C. , Lerman Lilach O.
Published: March 2011

Percutaneous transluminal renal stenting (PTRS) does not consistently improve renal function in patients with atherosclerotic renovascular disease, but the mechanisms underlying irreversible kidney injury have not been fully elucidated. We hypothesized that renal dysfunction after PTRS is linked to ongoing renal microvascular (MV) remodeling. Pigs were studied after 10 wk of atherosclerosis and renal artery stenosis (ARAS), ARAS treated with PTRS 4 wk earlier, and normal controls ( n = 10 each). Renal blood flow (RBF) and glomerular filtration rate (GFR) were studied using multidetector computer tomography. Renal microvascular architecture (micro-CT), angiogenic activity, oxidative stress, and fibrosis were evaluated ex vivo. Four weeks after PTRS, blood pressure was normalized. However, GFR and RBF remained similarly decreased in untreated ARAS and ARAS+PTRS ( P < 0.05 vs. normal). MV rarefaction was unaltered after revascularization, and the spatial density of outer cortical microvessels correlated with residual GFR. Interstitial fibrosis and altered expression of proangiogenic and profibrotic factors persisted after PTRS. Tubulointerstitial injury in ARAS persisted 4 wk after mechanically successful PTRS, and vessel loss correlated with residual renal dysfunction. MV loss and fibrosis in swine ARAS might account for persistent renal dysfunction after PTRS and underscore the need to assess renal parenchymal disease before revascularization.
Spatially selective enhancement of proprioceptive acuity following motor learning
Authors: Wong Jeremy D. , Wilson Elizabeth T. , Gribble Paul L.
Published: March 2011

It is well recognized that the brain uses sensory information to accurately produce motor commands. Indeed, most research into the relationship between sensory and motor systems has focused on how sensory information modulates motor function. In contrast, recent studies have begun to investigate the reverse: how sensory and perceptual systems are tuned based on motor function, and specifically motor learning. In the present study we investigated changes to human proprioceptive acuity following recent motor learning. Sensitivity to small displacements of the hand was measured before and after 10 min of motor learning, during which subjects grasped the handle of a robotic arm and guided a cursor to a series of visual targets randomly located within a small workspace region. We used a novel method of assessing proprioceptive acuity that avoids active movement, interhemispheric transfer, and intermodality coordinate transformations. We found that proprioceptive acuity improved following motor learning, but only in the region of the arm's workspace explored during learning. No proprioceptive improvement was observed when motor learning was performed in a different location or when subjects passively experienced limb trajectories matched to those of subjects who actively performed motor learning. Our findings support the idea that sensory changes occur in parallel with changes to motor commands during motor learning.
Influence of aging on human sound localization
Authors: Dobreva Marina S. , O'Neill William E. , Paige Gary D.
Published: March 2011

Errors in sound localization, associated with age-related changes in peripheral and central auditory function, can pose threats to self and others in a commonly encountered environment such as a busy traffic intersection. This study aimed to quantify the accuracy and precision (repeatability) of free-field human sound localization as a function of advancing age. Head-fixed young, middle-aged, and elderly listeners localized band-passed targets using visually guided manual laser pointing in a darkened room. Targets were presented in the frontal field by a robotically controlled loudspeaker assembly hidden behind a screen. Broadband targets (0.1–20 kHz) activated all auditory spatial channels, whereas low-pass and high-pass targets selectively isolated interaural time and intensity difference cues (ITDs and IIDs) for azimuth and high-frequency spectral cues for elevation. In addition, to assess the upper frequency limit of ITD utilization across age groups more thoroughly, narrowband targets were presented at 250-Hz intervals from 250 Hz up to ∼2 kHz. Young subjects generally showed horizontal overestimation (overshoot) and vertical underestimation (undershoot) of auditory target location, and this effect varied with frequency band. Accuracy and/or precision worsened in older individuals for broadband, high-pass, and low-pass targets, reflective of peripheral but also central auditory aging. In addition, compared with young adults, middle-aged, and elderly listeners showed pronounced horizontal localization deficiencies (imprecision) for narrowband targets within 1,250–1,575 Hz, congruent with age-related central decline in auditory temporal processing. Findings underscore the distinct neural processing of the auditory spatial cues in sound localization and their selective deterioration with advancing age.