bluuebunny/crossref_metadata_2025 huggingface dataset:
The Evolution of Protein Kinase Inhibitors from Antagonists to Agonists of Cellular Signaling
Authors: Dar Arvin C. , Shokat Kevan M.
Published: March 2011

Kinases are highly regulated enzymes with diverse mechanisms controlling their catalytic output. Over time, chemical discovery efforts for kinases have produced ATP-competitive compounds, allosteric regulators, irreversible binders, and highly specific inhibitors. These distinct classes of small molecules have revealed many novel aspects about kinase-mediated signaling, and some have progressed from simple tool compounds into clinically validated therapeutics. This review explores several small-molecule inhibitors for kinases highlighting elaborate mechanisms by which kinase function is modulated. A complete surprise of targeted kinase drug discovery has been the finding of ATP-competitive inhibitors that behave as agonists, rather than antagonists, of their direct kinase target. These studies hint at a connection between ATP-binding site occupancy and networks of communication that are independent of kinase catalysis. Indeed, kinase inhibitors that induce changes in protein localization, protein-protein interactions, and even enhancement of catalytic activity of the target kinase have been found. The relevance of these findings to the therapeutic efficacy of kinase inhibitors and to the future identification of new classes of drug targets is discussed.
Mass Spectrometry in the Postgenomic Era
Authors: Chait Brian T.
Published: March 2011

Mass spectrometry (MS) is rapidly becoming an essential tool for biologists and biochemists in their efforts to throw light on molecular mechanisms within cellular systems. Used in unison with genome sequence data, MS has developed into the method of choice for identifying proteins, elucidating their posttranslational modifications, and reading out their functional interactions. Variations of the method have even begun to enable accurate mass determination of intact protein complexes, allowing for direct determination of subunit stoichiometry and the interactions between the subunits. Advances in mass spectrometric technologies have also led to great improvements in our ability to probe and define many of the other key molecular players in cells, including the all important lipid components. We provide here some perspectives on the explosion of applications of MS to protein science, systems biology, proteomics, lipidomics, and cell biology in general.
The Role of Atg Proteins in Autophagosome Formation
Authors: Mizushima Noboru , Yoshimori Tamotsu , Ohsumi Yoshinori
Published: March 2011

Macroautophagy is mediated by a unique organelle, the autophagosome, which encloses a portion of cytoplasm for delivery to the lysosome. Autophagosome formation is dynamically regulated by starvation and other stresses and involves complicated membrane reorganization. Since the discovery of yeast Atg-related proteins, autophagosome formation has been dissected at the molecular level. In this review we describe the molecular mechanism of autophagosome formation with particular focus on the function of Atg proteins and the long-standing discussion regarding the origin of the autophagosome membrane.
Cooperation Between Integrins and Growth Factor Receptors in Signaling and Endocytosis
Authors: Ivaska Johanna , Heino Jyrki
Published: March 2011

All multicellular animals express receptors for growth factors (GFs) and extracellular matrix (ECM) molecules. Integrin-type ECM receptors anchor cells to their surroundings and concomitantly activate intracellular signal transduction pathways. The same signaling mechanisms are regulated by GF receptors (GFRs). Recently, intensive research efforts have revealed novel mechanisms describing how the two receptor systems collaborate at many different levels. Integrins can directly bind to GFs and promote their activation. Adhesion receptors also organize signaling platforms and assist GFRs or even activate them via ligand-independent mechanisms. Furthermore, integrins can orchestrate endocytosis and recycling of GFRs. Here, we review the present knowledge about the interplay between integrins and GFRs and discuss recent ideas of how this collaboration may explain some previous controversies in integrin research.
Neurogenesis at the Brain–Cerebrospinal Fluid Interface
Authors: Lehtinen Maria K. , Walsh Christopher A.
Published: March 2011

Cerebral cortical progenitor cells can be classified into several different types, and each progenitor type integrates cell-intrinsic and cell-extrinsic cues to regulate neurogenesis. On one hand, cell-intrinsic mechanisms that depend upon appropriate apical-basal polarity are established by adherens junctions and apical complex proteins and are particularly important in progenitors with apical processes contacting the lateral ventricle. The apical protein complexes themselves are concentrated at the ventricular surface, and apical complex proteins regulate mitotic spindle orientation and cell fate. On the other hand, remarkably little is known about how cell-extrinsic cues signal to progenitors and couple with cell-intrinsic mechanisms to instruct neurogenesis. Recent research shows that the cerebrospinal fluid, which contacts apical progenitors at the ventricular surface and bathes the apical complex of these cells, provides growth- and survival-promoting cues for neural progenitor cells in developing and adult brain. This review addresses how the apical-basal polarity of progenitor cells regulates cell fate and allows progenitors to sample diffusible signals distributed by the cerebrospinal fluid. We also review several classes of signaling factors that the cerebrospinal fluid distributes to the developing brain to instruct neurogenesis.
The Apical Polarity Protein Network in Drosophila Epithelial Cells: Regulation of Polarity, Junctions, Morphogenesis, Cell Growth, and Survival
Authors: Tepass Ulrich
Published: March 2011

Epithelial tissue formation and function requires the apical-basal polarization of individual epithelial cells. Apical polarity regulators (APRs) are an evolutionarily conserved group of key factors that govern polarity and several other aspects of epithelial differentiation. APRs compose a diverse set of molecules including a transmembrane protein (Crumbs), a serine/threonine kinase (aPKC), a lipid phosphatase (PTEN), a small GTPase (Cdc42), FERM domain proteins (Moesin, Yurt), and several adaptor or scaffolding proteins (Bazooka/Par3, Par6, Stardust, Patj). These proteins form a dynamic cooperative network that is engaged in negative-feedback regulation with basolateral polarity factors to set up the epithelial apical-basal axis. APRs support the formation of the apical junctional complex and the segregation of the junctional domain from the apical membrane. It is becoming increasingly clear that APRs interact with the cytoskeleton and vesicle trafficking machinery, regulate morphogenesis, and modulate epithelial cell growth and survival. Not surprisingly, APRs have multiple fundamental links to human diseases such as cancer and blindness.
Membrane Protein Insertion at the Endoplasmic Reticulum
Authors: Shao Sichen , Hegde Ramanujan S.
Published: March 2011

Integral membrane proteins of the cell surface and most intracellular compartments of eukaryotic cells are assembled at the endoplasmic reticulum. Two highly conserved and parallel pathways mediate membrane protein targeting to and insertion into this organelle. The classical cotranslational pathway, utilized by most membrane proteins, involves targeting by the signal recognition particle followed by insertion via the Sec61 translocon. A more specialized posttranslational pathway, employed by many tail-anchored membrane proteins, is composed of entirely different factors centered around a cytosolic ATPase termed TRC40 or Get3. Both of these pathways overcome the same biophysical challenges of ferrying hydrophobic cargo through an aqueous milieu, selectively delivering it to one among several intracellular membranes and asymmetrically integrating its transmembrane domain(s) into the lipid bilayer. Here, we review the conceptual and mechanistic themes underlying these core membrane protein insertion pathways, the complexities that challenge our understanding, and future directions to overcome these obstacles.
Beyond Homeostasis: A Predictive-Dynamic Framework for Understanding Cellular Behavior
Authors: Freddolino Peter L. , Tavazoie Saeed
Published: March 2011

Microbial regulatory strategies have long been understood in terms of the homeostatic framework, in which a response is interpreted as a restoring force counteracting the immediate intracellular consequences of a change in the environment. In this review, we summarize the breadth of recent discoveries of cellular behavior extending beyond the homeostatic framework. We argue that the nonrandom structure of native habitats makes environmental fluctuations inherently multidimensional. Beyond its utility for accurate perception of immediate events, the temporal regularity of this multidimensional correlation structure allows microbes to make predictions about the trajectory of their sensory environment. We describe recently discovered examples of such predictive behavior, their physiological benefits, and the underlying evolutionary forces shaping them. These observations compel us to go beyond homeostasis and consider a predictive-dynamic framework in which cellular behavior is orchestrated in response to the meaning of an environmental perturbation, not only its direct and immediate fitness consequences.
Morphogen Gradients: From Generation to Interpretation
Authors: Rogers Katherine W. , Schier Alexander F.
Published: March 2011

Morphogens are long-range signaling molecules that pattern developing tissues in a concentration-dependent manner. The graded activity of morphogens within tissues exposes cells to different signal levels and leads to region-specific transcriptional responses and cell fates. In its simplest incarnation, a morphogen signal forms a gradient by diffusion from a local source and clearance in surrounding tissues. Responding cells often transduce morphogen levels in a linear fashion, which results in the graded activation of transcriptional effectors. The concentration-dependent expression of morphogen target genes is achieved by their different binding affinities for transcriptional effectors as well as inputs from other transcriptional regulators. Morphogen distribution and interpretation are the result of complex interactions between the morphogen and responding tissues. The response to a morphogen is dependent not simply on morphogen concentration but also on the duration of morphogen exposure and the state of the target cells. In this review, we describe the morphogen concept and discuss the mechanisms that underlie the generation, modulation, and interpretation of morphogen gradients.
Regulation of Terminal Differentiation Programs in the Nervous System
Authors: Hobert Oliver
Published: March 2011

The generation of individual neuron types in the nervous system is a multistep process whose endpoint is the expression of neuron type–specific batteries of terminal differentiation genes that determine the functional properties of a neuron. This review focuses on the regulatory mechanisms that are involved in controlling the terminally differentiated state of a neuron. I review several case studies from invertebrate and vertebrate nervous systems that reveal that many terminal differentiation features of a neuron are coregulated via terminal selector transcription factors that initiate and maintain terminal differentiation programs.
The Causes and Consequences of Polyploidy in Normal Development and Cancer
Authors: Davoli Teresa , de Lange Titia
Published: March 2011

Although nearly all mammalian species are diploid, whole-genome duplications occur in select mammalian tissues as part of normal development. Such programmed polyploidization involves changes in the regulatory pathways that normally maintain the diploid state of the mammalian genome. Unscheduled whole-genome duplications, which lead primarily to tetraploid cells, also take place in a substantial fraction of human tumors and have been proposed to constitute an important step in the development of cancer aneuploidy. The origins of these polyploidization events and their consequences for tumor progression are explored in this review.
Dynamin: Functional Design of a Membrane Fission Catalyst
Authors: Schmid Sandra L. , Frolov Vadim A.
Published: March 2011

Dynamin, best studied for its role in clathrin-mediated endocytosis, is the prototypical member of a family of multidomain GTPases involved in fission and remodeling of multiple organelles. Recent studies have shown that dynamin alone can catalyze fission of membrane tubules and vesicle formation from planar lipid templates. Thus, dynamin appears to be a self-sufficient fission machine. Here we review the biochemical activities and structural features of dynamin required for fission activity. As all changes in membrane topology require energetically unfavorable rearrangements of the lipid bilayer, we discuss the interplay between dynamin and its lipid substrates that are critical to defining a nonleaky pathway to membrane fission. We propose a two-stage model for dynamin-catalyzed fission. In stage one, dynamin's mechanochemical activities induce localized curvature stress and position its lipid-interacting pleckstrin homology domains to create a catalytic center that, in stage two, guides lipid remodeling through hemifission intermediates to drive membrane fission.
Optogenetic Control of Cells and Circuits
Authors: Miesenböck Gero
Published: March 2011

The absorption of light by bound or diffusible chromophores causes conformational rearrangements in natural and artificial photoreceptor proteins. These rearrangements are coupled to the opening or closing of ion transport pathways, the association or dissociation of binding partners, the enhancement or suppression of catalytic activity, or the transcription or repression of genetic information. Illumination of cells, tissues, or organisms engineered genetically to express photoreceptor proteins can thus be used to perturb biochemical and electrical signaling with exquisite cellular and molecular specificity. First demonstrated in 2002, this principle of optogenetic control has had a profound impact on neuroscience, where it provides a direct and stringent means of probing the organization of neural circuits and of identifying the neural substrates of behavior. The impact of optogenetic control is also beginning to be felt in other areas of cell and organismal biology.
Biology and Management of Palm Dynastid Beetles: Recent Advances
Authors: Bedford Geoffrey O.
Published: March 2011

Coconut, oil, and date palms are important crops in the tropics and are attacked by dynastids that cause loss of production or death of hosts. Knowledge of their breeding sites has been extended since a previous review in 1980. The fungus Metarhizium anisopliae has potential as a biopesticide against immature stages in friable breeding sites. The molecular biology and ultrastructure of Oryctes rhinoceros Nudivirus (OrNV), disseminated by adults, have been studied, and this pathogen can reduce O. rhinoceros populations and damage when introduced into new locations, especially where damage had been high. New PCR techniques may enable reliable quantification of dosages ingested and hence virulence of different isolates. Male-produced aggregation pheromones have been identified in several species, for which they may have management potential, having been used commercially for trapping O. rhinoceros in oil palm plantations in Southeast Asia, and tested against O. monoceros in Africa.
Essential Oils in Insect Control: Low-Risk Products in a High-Stakes World
Authors: Regnault-Roger Catherine , Vincent Charles , Arnason John Thor
Published: March 2011

In recent years, the use of essential oils (EOs) derived from aromatic plants as low-risk insecticides has increased considerably owing to their popularity with organic growers and environmentally conscious consumers. EOs are easily produced by steam distillation of plant material and contain many volatile, low-molecular-weight terpenes and phenolics. The major plant families from which EOs are extracted include Myrtaceae, Lauraceae, Lamiaceae, and Asteraceae. EOs have repellent, insecticidal, and growth-reducing effects on a variety of insects. They have been used effectively to control preharvest and postharvest phytophagous insects and as insect repellents for biting flies and for home and garden insects. The compounds exert their activities on insects through neurotoxic effects involving several mechanisms, notably through GABA, octopamine synapses, and the inhibition of acetylcholinesterase. With a few exceptions, their mammalian toxicity is low and environmental persistence is short. Registration has been the main bottleneck in putting new products on the market, but more EOs have been approved for use in the United States than elsewhere owing to reduced-risk processes for these materials.
Insect Nuclear Receptors
Authors: Fahrbach Susan E. , Smagghe Guy , Velarde Rodrigo A.
Published: March 2011

The nuclear receptors (NRs) of metazoans are an ancient family of transcription factors defined by conserved DNA- and ligand-binding domains (DBDs and LBDs, respectively). The Drosophila melanogaster genome project revealed 18 canonical NRs (with DBDs and LBDs both present) and 3 receptors with the DBD only. Annotation of subsequently sequenced insect genomes revealed only minor deviations from this pattern. A renewed focus on functional analysis of the isoforms of insect NRs is therefore required to understand the diverse roles of these transcription factors in embryogenesis, metamorphosis, reproduction, and homeostasis. One insect NR, ecdysone receptor (EcR), functions as a receptor for the ecdysteroid molting hormones of insects. Researchers have developed nonsteroidal ecdysteroid agonists for EcR that disrupt molting and can be used as safe pesticides. An exciting new technology allows EcR to be used in chimeric, ligand-inducible gene-switch systems with applications in pest management and medicine.
Insect Speciation Rules: Unifying Concepts in Speciation Research
Authors: Mullen Sean P. , Shaw Kerry L.
Published: March 2011

The study of speciation is concerned with understanding the connection between causes of divergent evolution and the origin and maintenance of barriers to gene exchange between incipient species. Although the field has historically focused either on examples of recent divergence and its causes or on the genetic basis of reproductive isolation between already divergent species, current efforts seek to unify these two approaches. Here we integrate these perspectives through a discussion of recent progress in several insect speciation model systems. We focus on the evolution of speciation phenotypes in each system (i.e., those phenotypes causally involved in reducing gene flow between incipient species), drawing an explicit connection between cause and effect (process and pattern). We emphasize emerging insights into the genomic architecture of speciation as well as timely areas for future research.
Managing Social Insects of Urban Importance
Authors: Rust Michael K. , Su Nan-Yao
Published: March 2011

Social insects have a tremendous economic and social impact on urban communities. The rapid urbanization of the world has dramatically increased the incidence of urban pests. Human commerce has resulted in the spread of urban invasive species worldwide such that various species are now common to many major urban centers. We aim to highlight those social behaviors that can be exploited to control these pests with the minimal use of pesticides. Their cryptic behavior often prohibits the direct treatment of colonies. However, foraging and recruitment are essential aspects of their social behavior and expose workers to traps, baits, and pesticide applications. The advent of new chemistries has revolutionized the pest management strategies used to control them. In recent years, there has been an increased environmental awareness, especially in the urban community. Advances in molecular and microbial agents promise additional tools in developing integrated pest management programs against social insects.
Reevaluating the Arthropod Tree of Life
Authors: Giribet Gonzalo , Edgecombe Gregory D.
Published: March 2011

Arthropods are the most diverse group of animals and have been so since the Cambrian radiation. They belong to the protostome clade Ecdysozoa, with Onychophora (velvet worms) as their most likely sister group and tardigrades (water bears) the next closest relative. The arthropod tree of life can be interpreted as a five-taxon network, containing Pycnogonida, Euchelicerata, Myriapoda, Crustacea, and Hexapoda, the last two forming the clade Tetraconata or Pancrustacea. The unrooted relationship of Tetraconata to the three other lineages is well established, but of three possible rooting positions the Mandibulata hypothesis receives the most support. Novel approaches to studying anatomy with noninvasive three-dimensional reconstruction techniques, the application of these techniques to new and old fossils, and the so-called next-generation sequencing techniques are at the forefront of understanding arthropod relationships. Cambrian fossils assigned to the arthropod stem group inform on the origin of arthropod characters from a lobopodian ancestry. Monophyly of Pycnogonida, Euchelicerata, Myriapoda, Tetraconata, and Hexapoda is well supported, but the interrelationships of arachnid orders and the details of crustacean paraphyly with respect to Hexapoda remain the major unsolved phylogenetic problems.
The Ecology of Nest Movement in Social Insects
Authors: McGlynn Terrence P.
Published: March 2011

Social insect colonies are typically mobile entities, moving nests from one location to another throughout the life of a colony. The majority of social insect species—ants, bees, wasps, and termites—have likely adopted the habit of relocating nests periodically. The syndromes of nest relocation include legionary nomadism, unstable nesting, intrinsic nest relocation, and adventitious nest relocation. The emergence of nest movement is a functional response to a broad range of potential selective forces, including colony growth, competition, foraging efficiency, microclimate, nest deterioration, nest quality, parasitism, predation, and seasonality. Considering the great taxonomic and geographic distribution of nest movements, assumptions regarding the nesting biology of social insects should be reevaluated, including our understanding of population genetics, life-history evolution, and the role of competition in structuring communities.
Systematics, Biodiversity, Biogeography, and Host Associations of the Miridae (Insecta: Hemiptera: Heteroptera: Cimicomorpha)
Authors: Cassis G. , Schuh R.T.
Published: March 2011

The Miridae, a hyperdiverse family containing more than 11,020 valid described species, are discussed and the pertinent literature is reviewed. Diagnoses for the family and subfamilies are given. Color habitus photos are presented for representatives of most of the 35 currently recognized tribes. Key morphological character systems are discussed and illustrated, including pretarsal structures, femoral trichobothria, external efferent system of the metathoracic glands, male and female genitalia, and molecular markers. A historical comparison of tribal classifications and the most up-to-date classification are presented in tabular form. A brief history of the classification of each of the eight recognized subfamilies is presented. Distributional patterns and relative generic diversity across biogeographic regions are discussed; generic diversity by biogeographic region is presented in tabular form. Taxonomic accumulation graphs are presented by biogeographic region, indicating an ongoing need for taxonomic work in the Southern Hemisphere, and most particularly in Australia. Host plant associations are evaluated graphically, showing high specificity for many taxa and a preference among phytophagous taxa for the Asteridae and Rosidae.
Plasmodium knowlesi: A Malaria Parasite of Monkeys and Humans
Authors: Collins William E.
Published: March 2011

Plasmodium knowlesi is a malaria parasite of monkeys of Southeast Asia that is transmitted by mosquitoes of the Anopheles leucosphyrus group. Humans are frequently infected with this parasite and misdiagnosed as being infected with Plasmodium malariae. The parasite was a major monkey animal model for developing antimalarial vaccines and investigations of the biology of parasite invasion. P. knowlesi is the first monkey malaria parasite genome to be sequenced and annotated.
Understanding Continental Margin Biodiversity: A New Imperative
Authors: Levin Lisa A. , Sibuet Myriam
Published: March 2011

Until recently, the deep continental margins (200–4,000 m) were perceived as monotonous mud slopes of limited ecological or environmental concern. Progress in seafloor mapping and direct observation now reveals unexpected heterogeneity, with a mosaic of habitats and ecosystems linked to geomorphological, geochemical, and hydrographic features that influence biotic diversity. Interactions among water masses, terrestrial inputs, sediment diagenesis, and tectonic activity create a multitude of ecological settings supporting distinct communities that populate canyons and seamounts, high-stress oxygen minimum zones, and methane seeps, as well as vast reefs of cold corals and sponges. This high regional biodiversity is fundamental to the production of valuable fisheries, energy, and mineral resources, and performs critical ecological services (nutrient cycling, carbon sequestration, nursery and habitat support). It is under significant threat from climate change and human resource extraction activities. Serious actions are required to preserve the functions and services provided by the deep-sea settings we are just now getting to know.
The Wind- and Wave-Driven Inner-Shelf Circulation
Authors: Lentz Steven J. , Fewings Melanie R.
Published: March 2011

The inner continental shelf, which spans water depths of a few meters to tens of meters, is a dynamically defined region that lies between the surf zone (where waves break) and the middle continental shelf (where the along-shelf circulation is usually in geostrophic balance). Many types of forcing that are often neglected over the deeper shelf—such as tides, buoyant plumes, surface gravity waves, and cross-shelf wind stress—drive substantial circulations over the inner shelf. Cross-shelf circulation over the inner shelf has ecological and geophysical consequences: It connects the shore to the open ocean by transporting pollutants, larvae, phytoplankton, nutrients, and sediment. This review of circulation and momentum balances over the inner continental shelf contrasts prior studies, which focused mainly on the roles of along-shelf wind and pressure gradients, with recent understanding of the dominant roles of cross-shelf wind and surface gravity waves.
Jellyfish and Ctenophore Blooms Coincide with Human Proliferations and Environmental Perturbations
Authors: Purcell Jennifer E.
Published: March 2011

Human populations have been concentrated along and exploiting the coastal zones for millennia. Of regions with the highest human impacts on the oceans ( Halpern et al. 2008 ), 6 of the top 10 have recently experienced blooms or problems with jellies. I review the time lines of human population growth and their effects on the coastal environment. I explore evidence suggesting that human activities—specifically, seafood harvest, eutrophication, hard substrate additions, transport of nonindigenous species, aquaculture, and climate change—may benefit jelly populations. Direct evidence is lacking for most of these factors; however, numerous correlations show abundant jellies in areas with warm temperatures and low forage fish populations. Jelly populations fluctuate in ∼10- and ∼20-year cycles in concert with solar and climate cycles. Global warming will provide a rising baseline against which climate cycles will cause fluctuations in jelly populations. The probable acceleration of anthropogenic effects may lead to further problems with jellies.
Marine Microgels
Authors: Verdugo Pedro
Published: March 2011

The ocean plays a critical role in global carbon cycling: it handles half of the global primary production, yielding the world's largest stock of reduced organic carbon (ROC) that supports one of the world's largest biomasses. However, the mechanisms whereby ROC becomes mineralized remain unresolved. This review focuses on laboratory and field observations that dissolved organic carbon (DOC) self-assembles, forming self-assembled microgels (SAGs). Self-assembly has ∼10% yield, generating an estimated global seawater SAG budget of ∼1016 g C. Transects at depths of 10–4,000 m reveal concentrations of ∼106 to ∼3 × 1012 SAG L−1, respectively, forming an estimated ROC stock larger than the global marine biomass. Because hydrogels have ∼1% solids (10 g L−1), whereas seawater DOC reaches ∼10−3 g L−1, SAGs contain ∼104 more bacterial substrate than seawater. Thus, microgels represent an unsuspected and huge micron-level ocean patchiness that could profoundly influence the passage of DOC through the microbial loop, with ramifications that may scale to global cycles of bioactive elements.
Marine Protistan Diversity
Authors: Caron David A. , Countway Peter D. , Jones Adriane C. , Kim Diane Y. , Schnetzer Astrid
Published: March 2011

Protists have fascinated microbiologists since their discovery nearly 350 years ago. These single-celled, eukaryotic species span an incredible range of sizes, forms, and functions and, despite their generally diminutive size, constitute much of the genetic diversity within the domain Eukarya. Protists in marine ecosystems play fundamental ecological roles as primary producers, consumers, decomposers, and trophic links in aquatic food webs. Much of our knowledge regarding the diversity and ecological activities of these species has been obtained during the past half century, and only within the past few decades have hypotheses depicting the evolutionary relationships among the major clades of protists attained some degree of consensus. This recent progress is attributable to the development of genetic approaches, which have revealed an unexpectedly large diversity of protists, including cryptic species and previously undescribed clades of protists. New genetic tools now exist for identifying protistan species of interest and for reexamining long-standing debates regarding the biogeography of protists. Studies of protistan diversity provide insight regarding how species richness and community composition contribute to ecosystem function. These activities support the development of predictive models that describe how microbial communities will respond to natural or anthropogenically mediated changes in environmental conditions.
Nutrient Ratios as a Tracer and Driver of Ocean Biogeochemistry
Authors: Deutsch Curtis , Weber Thomas
Published: March 2011

Microbial life in the ocean contains immense taxonomic and physiological diversity, yet its collective activity yields global cycles of the major biolimiting elements N and P that are tightly linked. Moreover, the availability of N and P in seawater is closely matched to the metabolic demands of “average” plankton, as if plankton composition and the oceanic nutrient reservoirs were mutually influenced. These simple observations have broad implications for the function of nutrient cycles within the Earth system, which can operate either as a biological homeostat that buffers ocean fertility against large changes or as an amplifier of climate perturbations, by alleviating or exacerbating the nutrient limitation of biological productivity and ocean C storage. A mechanistic understanding of these observations and dynamics must draw upon diverse fields, from physiology and evolution to physical oceanography and paleoceanography, and must account for processes spanning a wide range of spatial and temporal scales. Here we summarize this understanding from the perspective of the nutrient distributions themselves and their changes over time. We offer a synthesis view in which ocean circulation communicates the resource constraints of stoichiometrically distinct planktonic biomes across large spatial scales, allowing geochemical constancy to emerge from rich biological diversity.
The Global Distribution and Dynamics of Chromophoric Dissolved Organic Matter
Authors: Nelson Norman B. , Siegel David A.
Published: March 2011

Chromophoric dissolved organic matter (CDOM) is a ubiquitous component of the open ocean dissolved matter pool, and is important owing to its influence on the optical properties of the water column, its role in photochemistry and photobiology, and its utility as a tracer of deep ocean biogeochemical processes and circulation. In this review, we discuss the global distribution and dynamics of CDOM in the ocean, concentrating on developments in the past 10 years and restricting our discussion to open ocean and deep ocean (below the main thermocline) environments. CDOM has been demonstrated to exert primary control on ocean color by its absorption of light energy, which matches or exceeds that of phytoplankton pigments in most cases. This has important implications for assessing the ocean biosphere via ocean color–based remote sensing and the evaluation of ocean photochemical and photobiological processes. The general distribution of CDOM in the global ocean is controlled by a balance between production (primarily microbial remineralization of organic matter) and photolysis, with vertical ventilation circulation playing an important role in transporting CDOM to and from intermediate water masses. Significant decadal-scale fluctuations in the abundance of global surface ocean CDOM have been observed using remote sensing, indicating a potentially important role for CDOM in ocean-climate connections through its impact on photochemistry and photobiology.
Marine Fungi: Their Ecology and Molecular Diversity
Authors: Richards Thomas A. , Jones Meredith D.M. , Leonard Guy , Bass David
Published: March 2011

Fungi appear to be rare in marine environments. There are relatively few marine isolates in culture, and fungal small subunit ribosomal DNA (SSU rDNA) sequences are rarely recovered in marine clone library experiments (i.e., culture-independent sequence surveys of eukaryotic microbial diversity from environmental DNA samples). To explore the diversity of marine fungi, we took a broad selection of SSU rDNA data sets and calculated a summary phylogeny. Bringing these data together identified a diverse collection of marine fungi, including sequences branching close to chytrids (flagellated fungi), filamentous hypha-forming fungi, and multicellular fungi. However, the majority of the sequences branched with ascomycete and basidiomycete yeasts. We discuss evidence for 36 novel marine lineages, the majority and most divergent of which branch with the chytrids. We then investigate what these data mean for the evolutionary history of the Fungi and specifically marine-terrestrial transitions. Finally, we discuss the roles of fungi in marine ecosystems.
Genomic Insights into Bacterial DMSP Transformations
Authors: Moran Mary Ann , Reisch Chris R. , Kiene Ronald P. , Whitman William B.
Published: March 2011

Genomic and functional genomic methods applied to both model organisms and natural communities have rapidly advanced understanding of bacterial dimethylsulfoniopropionate (DMSP) degradation in the ocean. The genes for the two main pathways in bacterial degradation, routing DMSP to distinctly different biogeochemical fates, have recently been identified. The genes dmdA, -B, -C, and -D mediate the demethylation of DMSP and facilitate retention of carbon and sulfur in the marine microbial food web. The genes dddD, -L, -P, -Q, -W, and -Y mediate the cleavage of DMSP to dimethylsulfide (DMS), with important consequences for ocean-atmosphere sulfur flux. In ocean metagenomes, sufficient copies of these genes are present for ∼60% of surface ocean bacterial cells to directly participate in DMSP degradation. The factors that regulate these two competing pathways remain elusive, but gene transcription analyses of natural bacterioplankton communities are making headway in unraveling the intricacies of bacterial DMSP processing in the ocean.
The Role of B Vitamins in Marine Biogeochemistry
Authors: Sañudo-Wilhelmy Sergio A. , Gómez-Consarnau Laura , Suffridge Christopher , Webb Eric A.
Published: March 2011

The soluble B vitamins (B1, B7, and B12) have long been recognized as playing a central metabolic role in marine phytoplankton and bacteria; however, the importance of these organic external metabolites in marine ecology has been largely disregarded, as most research has focused on inorganic nutrients and trace metals. Using recently available genomic data combined with culture-based surveys of vitamin auxotrophy (i.e., vitamin requirements), we show that this auxotrophy is widespread in the marine environment and occurs in both autotrophs and heterotrophs residing in oligotrophic and eutrophic environments. Our analysis shows that vitamins originate from the activities of some bacteria and algae and that taxonomic changes observed in marine phytoplankton communities could be the result of their specific vitamin requirements and/or vitamin availability. Dissolved vitamin concentration measurements show that large areas of the world ocean are devoid of B vitamins, suggesting that vitamin limitation could be important for the efficiency of carbon and nitrogen fixation in those regions.
The Physiology of Global Change: Linking Patterns to Mechanisms
Authors: Somero George N.
Published: March 2011

Global change includes alterations in ocean temperature, oxygen availability, salinity, and pH, abiotic variables with strong and interacting influences on the physiology of all taxa. Physiological stresses resulting from changes in these four variables may cause broad biogeographic shifts as well as localized changes in distribution in mosaic habitats. To elucidate these causal linkages, I address the following questions: What types of physiological limitations can alter species' distributions and, in cases of extreme stress, cause extinctions? Which species are most threatened by these physiological challenges—and why? How do contents of genomes establish capacities to respond to global change, notably in the case of species that have evolved in highly stable habitats? How fully can phenotypic acclimatization offset abiotic stress? Can physiological measurements, including new molecular (“-omic”) approaches, provide indices of the degree of sublethal stress an organism experiences? And can physiological evolution keep pace with global change?
Thin Phytoplankton Layers: Characteristics, Mechanisms, and Consequences
Authors: Durham William M. , Stocker Roman
Published: March 2011

For over four decades, aggregations of phytoplankton known as thin layers have been observed to harbor large amounts of photosynthetic cells within narrow horizontal bands. Field observations have revealed complex linkages among thin phytoplankton layers, the physical environment, cell behavior, and higher trophic levels. Several mechanisms have been proposed to explain layer formation and persistence, in the face of the homogenizing effect of turbulent dispersion. The challenge ahead is to connect mechanistic hypotheses with field observations to gain better insight on the phenomena that shape layer dynamics. Only through a mechanistic understanding of the relevant biological and physical processes can we begin to predict the effect of thin layers on the ecology of phytoplankton and higher organisms.
Eosinophilic Esophagitis: Rapidly Advancing Insights
Authors: Abonia J. Pablo , Rothenberg Marc E.
Published: March 2011

Eosinophilic esophagitis (EoE) now represents a commonly recognized disorder among both pediatric and adult patients presenting to allergy and gastroenterology clinics throughout the world. The consequences of this localized and eosinophil-predominant inflammation of the esophagus can have an outsized and profound systemic and emotional impact for patients and their families. Unlike gastroesophageal reflux disease (GERD), whose symptoms closely overlap with those of EoE, EoE represents a primarily antigen-driven disorder whose symptoms and pathology are therapeutically mitigated with either long-term dietary control or chronic steroid therapies, rather than the acid-suppressive medications that are the mainstay of GERD treatment. Beyond the dissimilarities in their responses to treatment, these disorders are distinct in their gene expression profiles, heredity, genetic underpinning, and linkage with atopy. The antigen-driven nature of EoE has been reinforced by the remarkable impact of therapies utilizing elemental formulas to control the disease as well as a number of reports linking aeroallergens to seasonal worsening of disease.
Familial and Acquired Hemophagocytic Lymphohistiocytosis
Authors: Janka G.E.
Published: March 2011

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome in which an uncontrolled and ineffective immune response, triggered in most cases by infectious agents, leads to severe hyperinflammation. Familial forms of HLH (FHL), which are increasingly found also in adolescents and adults, are due to genetic defects leading to impaired function of natural killer cells and cytotoxic T cells. These mutations occur either in the perforin gene or in genes important for the exocytosis of cytotoxic granules. Cytotoxic granules contain perforin and granzymes, which induce apoptosis upon entering (infected) target cells. Additionally, perforin is important for the downregulation of the immune response. Acquired forms of HLH are encountered in association with (usually) viral infections, autoinflammatory/autoimmune diseases, malignant diseases, and acquired immune deficiency states (e.g., after organ transplantation). Treatment of HLH includes immune-suppressive and immune-modulatory agents, cytostatic drugs, and biological response modifiers. For patients with FHL, stem cell transplantation is indicated and can be curative.
Role of Fructose-Containing Sugars in the Epidemics of Obesity and Metabolic Syndrome
Authors: Stanhope Kimber L.
Published: March 2011

There is controversy concerning the role of sugar in the epidemics of obesity and metabolic syndrome. There is less controversy concerning the effects of fructose on components of metabolic syndrome; consumption of fructose has been shown to increase visceral adipose deposition and de novo lipogenesis (DNL), produce dyslipidemia, and decrease insulin sensitivity in older, overweight/obese subjects. This review examines the potential mechanisms of these effects of fructose and considers whether these mechanisms are relevant to the effects of consuming sucrose or high-fructose corn syrup. Evidence demonstrating that the commonly consumed sugars increase visceral adipose deposition, DNL, and insulin insensitivity is limited or inconclusive. Evidence that sugar consumption promotes development of an unfavorable lipid profile is strong and suggests that the upper added sugar consumption limit of 25% of energy or less, suggested in the Report of the Dietary Guidelines Advisory Committee on the Dietary Guidelines for Americans 2010, may merit re-evaluation.
The Management of Gastrointestinal Stromal Tumors: A Model for Targeted and Multidisciplinary Therapy of Malignancy
Authors: Joensuu Heikki , DeMatteo Ronald P.
Published: March 2011

Gastrointestinal stromal tumor (GIST) has become a model for targeted therapy in cancer. The vast majority of GISTs contain an activating mutation in either the KIT or platelet-derived growth factor A (PDGFRA) gene. GIST is highly responsive to several selective tyrosine kinase inhibitors. In fact, this cancer has been converted to a chronic disease in some patients. Considerable progress has been made recently in our understanding of the natural history and molecular biology of GIST, risk stratification, and drug resistance. Despite the efficacy of targeted therapy, though, surgery remains the only curative primary treatment and cures >50% of GIST patients who present with localized disease. Adjuvant therapy with imatinib prolongs recurrence-free survival and may improve overall survival. Combined or sequential use of tyrosine kinase inhibitors with other agents following tumor molecular subtyping is an attractive next step in the management of GIST.
Emerging Concepts on the Role of Innate Immunity in the Prevention and Control of HIV Infection
Authors: Ackerman Margaret E. , Dugast Anne-Sophie , Alter Galit
Published: March 2011

While neutralizing antibodies can provide sterilizing protection from HIV infection via their variable domains, the antibody constant domain provides a functional link between innate and adaptive immunity and offers a means to harness the potent antiviral properties of a wide spectrum of innate immune effector cells. There has been a growing appreciation of the role of these effector mechanisms across fields from cancer immunotherapy to autoimmunity and infectious disease, as well as speculation that this mechanism may be responsible for the protection observed in the RV144 HIV vaccine trial. This review summarizes these extraneutralizing humoral immune activities, progress in defining the importance of these effector mechanisms during progression in HIV infection, and the potential impact that such vaccine-induced immune responses may have on protection from infection.
Screening for Prostate Cancer: Early Detection or Overdetection?
Authors: Vickers Andrew J. , Roobol Monique J. , Lilja Hans
Published: March 2011

A sophisticated reading of the randomized trial evidence suggests that, although screening for prostate cancer with prostate-specific antigen (PSA) can reduce cancer-specific mortality, it does so at considerable cost in terms of the number of men who need to be screened, biopsied, and treated to prevent one death. The challenge is to design screening programs that maximize benefits (reducing prostate cancer mortality) and minimize costs (overtreatment). Recent research has suggested that this can be achieved by risk-stratifying screening and biopsy; increasing reliance on active surveillance for low-risk cancer; restricting radical prostatectomy to high-volume surgeons; and using appropriately high-dose radiotherapy. In current U.S. practice, however, many men who are screened are unlikely to benefit, most men found to have low-risk cancers are referred for unnecessary curative treatment, and much treatment is given at low-volume centers.
Huntington's Disease: Advocacy Driving Science
Authors: Wexler Nancy S.
Published: March 2011

My mother, Leonore, was diagnosed with Huntington's disease (HD) in 1968 at age 53. I was 23, my sister Alice 26, and our father, Milton Wexler, 60 years old. The same year, our father created the Hereditary Disease Foundation (HDF), dedicated to finding treatments and cures for HD. HD is an autosomal dominant, neurodegenerative disorder. Alice and I each have a 50% chance of inheriting and dying from the disorder. Over the past 43 years, we have been proud to change the face of science. Through Milton Wexler Interdisciplinary Workshops, judicious funding, and focusing on innovation and creativity, the HDF is an integral partner in key discoveries. The HDF recruited and supported >100 scientists worldwide who worked together as the Huntington's Disease Collaborative Research Group in a successful ten-year search for the HD gene. We found a DNA marker for the HD gene in 1983—the first marker to be found when the chromosomal location was unknown. We isolated the HD gene itself a decade later. These breakthroughs helped launch the Human Genome Project. We supported creating the first mouse model of HD and many other model systems. Currently, we focus on gene silencing, among other approaches, to create new treatments and cures.