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NEWS FOCUS: Vigil at North Korea's Mount Doom
Historical records and ash layers indicate that Mount Paektu, a volcano that straddles the border between North Korea and China, explodes to life every 100 years or so, the last time in 1903. (Two-thirds of the mountain is in China, where it is called Changbai.) Around 1000 years ago, the volcano rained tephra—pumice and ash—across 33,000 square kilometers of northeast China and Korea, dumping 5 centimeters of ash as far away as Japan. Scientists are keeping a wary vigil. Because Changbai's silica-rich magma is viscous and gassy, allowing pressure to build, the next eruption should be explosive, researchers say. In recent months, Chinese researchers have observed geophysical anomalies, including elevated temperatures of hot springs and deflation of the caldera rim. But most concur that there is no evidence of magma rising toward the surface, which would signal an imminent eruption. Podcast Interview
REPORT: Neural Mechanisms for the Coordination of Duet Singing in Wrens
Plain-tailed wrens (Pheugopedius euophrys
) cooperate to produce a duet song in which males and females rapidly alternate singing syllables. We examined how sensory information from each wren is used to coordinate singing between individuals for the production of this cooperative behavior. Previous findings in nonduetting songbird species suggest that premotor circuits should encode each bird’s own contribution to the duet. In contrast, we find that both male and female wrens encode the combined cooperative output of the pair of birds. Further, behavior and neurophysiology show that both sexes coordinate the timing of their singing based on feedback from the partner and suggest that females may lead the duet.
Supporting online material
EDITORIAL: Understanding the Human Brain
Like most fields in biology, neuroscience is succumbing to an "epidomic" of data collecting. There are major projects under way to completely characterize the proteomic, metabolomic, genomic, and methylomic signatures for all of the different types of neurons and glial cells in the human brain. In addition, "connectomics" plans to provide the complete network structure of brains, and "synaptomics" aims to uncover all molecules and their interactions at synapses. This is a good time to pause and ask ourselves what we expect to find at the end of this immense omic brainbow.
REPORT: Recent Synchronous Radiation of a Living Fossil
Modern survivors of previously more diverse lineages are regarded as living fossils, particularly when characterized by morphological stasis. Cycads are often cited as a classic example, reaching their greatest diversity during the Jurassic—Cretaceous (199.6 to 65.5 million years ago) then dwindling to their present diversity of ~300 species as flowering plants rose to dominance. Using fossil-calibrated molecular phylogenies, we show that cycads underwent a near synchronous global rediversification beginning in the late Miocene, followed by a slowdown toward the Recent. Although the cycad lineage is ancient, our timetrees indicate that living cycad species are not much older than ~12 million years. These data reject the hypothesized role of dinosaurs in generating extant diversity and the designation of today’s cycad species as living fossils.
Supporting online material
NEWS FOCUS: Fewer Dollars, Forced Choices
With Congress committed to reducing the $1.5 trillion federal deficit, research agency budgets will likely be flat or declining for the foreseeable future, meaning the loss of thousands of jobs and grants and the delay or cancellation of numerous high-profile projects. But will Congress actually abide by the Budget Control Act of 2011, which caps discretionary spending at $1.043 trillion for the 2012 fiscal year and requires reducing the deficit by at least $1.2 trillion over 10 years? The so-called Super Committee was formed to break the political gridlock: Republicans typically object to any tax hikes, and Democrats want to avoid cutting social programs. On other hand, nobody likes the idea of mandatory cuts, and there is talk of rewriting the rules. So far the panel has been unable to reach agreement on any plan, and time is running out. Podcast Interview
EDITORIAL: Rethinking the Science System
As the U.S. budget environment for science and technology (S&T) threatens to get worse, it is essential for the scientific community to go beyond just advocating for special consideration. There is a strong case for maintaining investments in S&T as a foundation for long-term economic growth and social well-being. But when resources are constrained, it is essential that they be used effectively and efficiently to avoid losing scientific momentum and to ensure that society will benefit maximally from S&T's potential. The scientific community cannot afford to simply adapt passively to reduced budgets. The impact of impending cuts can be at least partially mitigated by some fundamental rethinking of the ways in which S&T are both funded and conducted. Although the United States is used as the example here, the same issues will apply in many other parts of the world.
REPORT: Ultralight Metallic Microlattices
Ultralight (<10 milligrams per cubic centimeter) cellular materials are desirable for thermal insulation; battery electrodes; catalyst supports; and acoustic, vibration, or shock energy damping. We present ultralight materials based on periodic hollow-tube microlattices. These materials are fabricated by starting with a template formed by self-propagating photopolymer waveguide prototyping, coating the template by electroless nickel plating, and subsequently etching away the template. The resulting metallic microlattices exhibit densities ? ≥ 0.9 milligram per cubic centimeter, complete recovery after compression exceeding 50% strain, and energy absorption similar to elastomers. Young’s modulus E
scales with density as E
, in contrast to the E
scaling observed for ultralight aerogels and carbon nanotube foams with stochastic architecture. We attribute these properties to structural hierarchy at the nanometer, micrometer, and millimeter scales. Supporting online material
RESEARCH ARTICLE: Crystal Structure of the Eukaryotic 60S Ribosomal Subunit in Complex with Initiation Factor 6
Protein synthesis in all organisms is catalyzed by ribosomes. In comparison to their prokaryotic counterparts, eukaryotic ribosomes are considerably larger and are subject to more complex regulation. The large ribosomal subunit (60S) catalyzes peptide bond formation and contains the nascent polypeptide exit tunnel. We present the structure of the 60S ribosomal subunit from Tetrahymena thermophila
in complex with eukaryotic initiation factor 6 (eIF6), cocrystallized with the antibiotic cycloheximide (a eukaryotic-specific inhibitor of protein synthesis), at a resolution of 3.5 angstroms. The structure illustrates the complex functional architecture of the eukaryotic 60S subunit, which comprises an intricate network of interactions between eukaryotic-specific ribosomal protein features and RNA expansion segments. It reveals the roles of eukaryotic ribosomal protein elements in the stabilization of the active site and the extent of eukaryotic-specific differences in other functional regions of the subunit. Furthermore, it elucidates the molecular basis of the interaction with eIF6 and provides a structural framework for further studies of ribosome-associated diseases and the role of the 60S subunit in the initiation of protein synthesis.
Supporting online material
EDITORIAL: The Energy Research Imperative
As someone now working full time in global health and development, I see firsthand how the U.S. government's support for scientific research has improved people's lives. That support is vital in another area—affordable, clean energy. I believe it is imperative that the government commit to clean energy innovation at a level similar to its research investments in health and defense.
NEWS FOCUS: Mysteries of the Cell
We live in the golden age of genetics, but the fundamental unit of biology is still arguably the cell. The scientists gathering next week in Denver for the American Society for Cell Biology's annual meeting need little reminding of that, but as they detail their latest insights and data, it's useful to reflect on how much of the cell remains unexplained or unknown.
NEWS FOCUS: Do Lipid Rafts Exist?
Many scientists argue that the molecular platforms that sail on the cell's outer, or plasma, membrane, known as lipid rafts, either don't exist or have no biological relevance, but their supporters insist the idea remains afloat. Cell biologists say it's important to resolve the lipid raft debate eventually because the plasma membrane controls what enters and exits cells and how they send and receive signals. Although researchers have proposed several alternatives for how the plasma membrane organizes itself, none of them has caught on. But if a better explanation rises to the surface, cell biologists will have to give some of the credit to rafts.
REPORT: Climate Change, Keystone Predation, and Biodiversity Loss
Climate change can affect organisms both directly via physiological stress and indirectly via changing relationships among species. However, we do not fully understand how changing interspecific relationships contribute to community- and ecosystem-level responses to environmental forcing. I used experiments and spatial and temporal comparisons to demonstrate that warming substantially reduces predator-free space on rocky shores. The vertical extent of mussel beds decreased by 51% in 52 years, and reproductive populations of mussels disappeared at several sites. Prey species were able to occupy a hot, extralimital site if predation pressure was experimentally reduced, and local species richness more than doubled as a result. These results suggest that anthropogenic climate change can alter interspecific interactions and produce unexpected changes in species distributions, community structure, and diversity.
Supporting online material
In Science Signaling
p53 and MicroRNA-34 Are Suppressors of Canonical Wnt Signaling
Abstract: Although loss of p53 function and activation of canonical Wnt signaling cascades are frequently coupled in cancer, the links between these two pathways remain unclear. We report that p53 transactivated microRNA-34 (miR-34), which consequently suppressed the transcriptional activity of ß-catenin–T cell factor and lymphoid enhancer factor (TCF/LEF) complexes by targeting the untranslated regions (UTRs) of a set of conserved targets in a network of genes encoding elements of the Wnt pathway. Loss of p53 function increased canonical Wnt signaling by alleviating miR-34–specific interactions with target UTRs, and miR-34 depletion relieved p53-mediated Wnt repression. Gene expression signatures reflecting the status of ß-catenin–TCF/LEF transcriptional activity in breast cancer and pediatric neuroblastoma patients were correlated with p53 and miR-34 functional status. Loss of p53 or miR-34 contributed to neoplastic progression by triggering the Wnt-dependent, tissue-invasive activity of colorectal cancer cells. Further, during development, miR-34 interactions with the β-catenin UTR affected Xenopus body axis polarity and the expression of Wnt-dependent patterning genes. These data provide insight into the mechanisms by which a p53–miR-34 network restrains canonical Wnt signaling cascades in developing organisms and human cancer.
PRESPECTIVES: Setting the Clock for Recirculating Lymphocytes
Abstract: In their search for antigens, lymphocytes continuously shuttle among blood vessels, lymph vessels, and lymphatic tissues. Chemokines mediate entry of lymphocytes into lymphatic tissues, and sphingosine 1-phosphate (S1P) promotes localization of lymphocytes to the vasculature. Both signals are sensed through G protein—oupled receptors (GPCRs). Most GPCRs undergo ligand-dependent homologous receptor desensitization, a process that decreases their signaling output after previous exposure to high ligand concentration. Such desensitization can explain why lymphocytes do not take an intermediate position between two signals but rather oscillate between them. The desensitization of S1P receptor 1 (S1PR1) is mediated by GPCR kinase 2 (GRK2). Deletion of GRK2 in lymphocytes compromises desensitization by high vascular S1P concentrations, thereby reducing responsiveness to the chemokine signal and trapping the cells in the vascular compartment. The desensitization kinetics of S1PR1 allows lymphocytes to dynamically shuttle between vasculature and lymphatic tissue, although the positional information in both compartments is static.
RESEARCH ARTICLE: Local Application of Neurotrophins Specifies Axons Through Inositol 1,4,5-Trisphosphate, Calcium, and Ca2+/Calmodulin–Dependent Protein Kinases
Abstract: Neurons are highly polarized cells that have structurally distinct processes—the axons and dendrites—that differentiate from common immature neurites. In cultured hippocampal neurons, one of these immature neurites stochastically initiates rapid extension and becomes an axon, whereas the others become dendrites. Various extracellular and intracellular signals contribute to axon specification; however, the specific intracellular pathways whereby particular extracellular stimuli lead to axon specification remain to be delineated. Here, we found that the neurotrophins brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) were required for axon specification in an autocrine or a paracrine fashion. Using local application with a micropipette to selectively stimulate individual neurites, we found that stimulation of a selected neurite by BDNF or NT-3 induced neurite outgrowth and subsequent axon formation. NT-3 induced a rapid increase in calcium ions (Ca2+) in an inositol 1,4,5-trisphosphate (IP3)–dependent fashion as well as local activation of the Ca2+effector Ca2+/calmodulin-dependent protein kinase kinase (CaMKK) in the growth cone. Inhibition of neurotrophin receptors or CaMKK attenuated NT-3–induced axon specification in cultured neurons and axon formation in cortical neurons in vivo. These results identify a role for IP3-Ca2+-CaMKK signaling in axon specification.
Agonist-Driven Maturation and Plasma Membrane Insertion of Calcium-Sensing Receptors Dynamically Control Signal Amplitude
Abstract: Calcium-sensing receptors (CaSRs) regulate systemic calcium homeostasis in the parathyroid gland, kidney, intestine, and bone and translate fluctuations in serum calcium into peptide hormone secretion, cell signaling, and regulation of gene expression. The CaSR is a G protein (heterotrimeric guanosine triphosphate–binding protein)–coupled receptor that operates in the constant presence of agonist, sensing small changes with high cooperativity and minimal functional desensitization. Here, we used multiwavelength total internal reflection fluorescence microscopy to demonstrate that the signaling properties of the CaSR result from agonist-driven maturation and insertion of CaSRs into the plasma membrane. Plasma membrane CaSRs underwent constitutive endocytosis without substantial recycling, indicating that signaling was determined by the rate of insertion of CaSRs into the plasma membrane. Intracellular CaSRs colocalized with calnexin in the perinuclear endoplasmic reticulum and formed complexes with 14-3-3 proteins. Ongoing CaSR signaling resulted from agonist-driven trafficking of CaSR through the secretory pathway. The intracellular reservoir of CaSRs that were mobilized by agonist was depleted when glycosylation of newly synthesized receptors was blocked, suggesting that receptor biosynthesis was coupled to signaling. The continuous, signaling-dependent insertion of CaSRs into the plasma membrane ensured a rapid response to alterations in the concentrations of extracellular calcium or allosteric agonist despite ongoing desensitization and endocytosis. Regulation of CaSR plasma membrane abundance represents a previously unknown mechanism of regulation that may be relevant to other receptors that operate in the chronic presence of agonist.
In Science Translational Medicine
RESEARCH ARTICLE: ALDH2 Activator Inhibits Increased Myocardial Infarction Injury by Nitroglycerin Tolerance
Abstract: Nitroglycerin, which treats impaired cardiac function through vasodilation as it is converted to nitric oxide, is used worldwide for patients with various ischemic and congestive cardiac diseases, including angina pectoris. Nevertheless, after continuous treatment, the benefits of nitroglycerin are limited by the development of tolerance to the drug. Nitroglycerin tolerance is a result of inactivation of aldehyde dehydrogenase 2 (ALDH2), an enzyme essential for cardioprotection in animals subjected to myocardial infarction. Here, we tested the hypothesis that the tolerance that develops as a result of sustained nitroglycerin treatment increases cardiac injury by subsequent myocardial infarction. In a rat model of myocardial infarction, 16 hours of prior, sustained nitroglycerin treatment resulted in infarcts that were twice as large as those in untreated control animals and in diminished cardiac function at 3 days and 2 weeks after the myocardial infarction. We also sought to identify a potential treatment to protect against this increased cardiac damage. Nitroglycerin inhibited ALDH2 activity in vitro, an effect that was blocked by Alda-1, an activator of ALDH2. Co-administration of Alda-1 with the nitroglycerin prevented the nitroglycerin-induced increase in cardiac dysfunction after myocardial infarction in rats, at least in part by enhancing metabolism of reactive aldehyde adducts that impair normal protein functions. If our animal studies showing that nitroglycerin tolerance increases cardiac injury upon ischemic insult are corroborated in humans, activators of ALDH2 such as Alda-1 may help to protect patients with myocardial infarction from this nitroglycerin-induced increase in cardiac injury while maintaining the cardiac benefits of the increased nitric oxide concentrations produced by nitroglycerin.
RESEARCH ARTICLE: A Peptidomimetic Targeting White Fat Causes Weight Loss and Improved Insulin Resistance in Obese Monkeys
Abstract: Obesity, defined as body mass index greater than 30, is a leading cause of morbidity and mortality and a financial burden worldwide. Despite significant efforts in the past decade, very few drugs have been successfully developed for the treatment of obese patients. Biological differences between rodents and primates are a major hurdle for translation of anti-obesity strategies either discovered or developed in rodents into effective human therapeutics. Here, we evaluate the ligand-directed peptidomimetic CKGGRAKDC-GG-D(KLAKLAK)2 (henceforth termed adipotide) in obese Old World monkeys. Treatment with adipotide induced targeted apoptosis within blood vessels of white adipose tissue and resulted in rapid weight loss and improved insulin resistance in obese monkeys. Magnetic resonance imaging and dual-energy x-ray absorptiometry confirmed a marked reduction in white adipose tissue. At experimentally determined optimal doses, monkeys from three different species displayed predictable and reversible changes in renal proximal tubule function. Together, these data in primates establish adipotide as a prototype in a new class of candidate drugs that may be useful for treating obesity in humans.
RESEARCH ARTICLE: Mathematical Model Identifies Blood Biomarker–Based Early Cancer Detection Strategies and Limitations
Abstract: Most clinical blood biomarkers lack the necessary sensitivity and specificity to reliably detect cancer at an early stage, when it is best treatable. It is not yet clear how early a clinical blood assay can be used to detect cancer or how biomarker-based strategies can be improved to enable earlier detection of smaller tumors. To address these issues, we developed a mathematical model describing dynamic plasma biomarker kinetics in relation to the growth of a tumor, beginning with a single cancer cell. To exemplify a realistic scenario in which biomarker is shed by both cancerous and noncancerous cells, we primed the model on ovarian tumor growth and CA125 shedding data, for which tumor growth parameters and shedding rates are readily available in published literature. We found that a tumor could grow unnoticed for more than 10.1 years and reach a volume of about π/6(25.36 mm)3, corresponding to a spherical diameter of about 25.36 mm, before becoming detectable by current clinical blood assays. Model parameters were perturbed over log orders of magnitude to quantify ideal shedding rates and identify other blood-based strategies required for early submillimeter tumor detectability. The detection times we estimated are consistent with recently published tumor progression time lines based on clinical genomic sequencing data for several cancers. Here, we rigorously showed that shedding rates of current clinical blood biomarkers are likely 104-fold too low to enable detection of a developing tumor within the first decade of tumor growth. The model presented here can be extended to virtually any solid cancer and associated biomarkers.
RESEARCH ARTICLE: Rapid Cancer Detection by Topically Spraying a γ-Glutamyltranspeptidase–Activated Fluorescent Probe
Abstract: The ability of the unaided human eye to detect small cancer foci or accurate borders between cancer and normal tissue during surgery or endoscopy is limited. Fluorescent probes are useful for enhancing visualization of small tumors but are typically limited by either high background signal or the requirement for administration hours to days before use. We synthesized a rapidly activatable, cancer-selective fluorescence imaging probe, γ-glutamyl hydroxymethyl rhodamine green (gGlu-HMRG), with intramolecular spirocyclic caging for complete quenching. Activation occurs by rapid one-step cleavage of glutamate with γ-glutamyltranspeptidase (GGT), which is not expressed in normal tissue, but is overexpressed on the cell membrane of various cancer cells, thus leading to complete uncaging and dequenching of the fluorescence probe. In vitro activation of gGlu-HMRG was evident in 11 human ovarian cancer cell lines tested. In vivo in mouse models of disseminated human peritoneal ovarian cancer, activation of gGlu-HMRG occurred within 1 min of topically spraying the tumor, creating high signal contrast between the tumor and the background. The gGlu-HMRG probe is practical for clinical application during surgical or endoscopic procedures because of its rapid and strong activation upon contact with GGT on the surface of cancer cells.
IMAGE CREDITS (In order of appearance): CLIVE OPPENHEIMER, ISTOCKPHOTO, BGC3