Journal Articles

[Report] Quantum squeezing of motion in a mechanical resonator

Science - Thu, 08/27/2015 - 23:00
According to quantum mechanics, a harmonic oscillator can never be completely at rest. Even in the ground state, its position will always have fluctuations, called the zero-point motion. Although the zero-point fluctuations are unavoidable, they can be manipulated. Using microwave frequency radiation pressure, we have manipulated the thermal fluctuations of a micrometer-scale mechanical resonator to produce a stationary quadrature-squeezed state with a minimum variance of 0.80 times that of the ground state. We also performed phase-sensitive, back-action evading measurements of a thermal state squeezed to 1.09 times the zero-point level. Our results are relevant to the quantum engineering of states of matter at large length scales, the study of decoherence of large quantum systems, and for the realization of ultrasensitive sensing of force and motion. Authors: E. E. Wollman, C. U. Lei, A. J. Weinstein, J. Suh, A. Kronwald, F. Marquardt, A. A. Clerk, K. C. Schwab
Categories: Journal Articles

[Report] Production of amorphous nanoparticles by supersonic spray-drying with a microfluidic nebulator

Science - Thu, 08/27/2015 - 23:00
Amorphous nanoparticles (a-NPs) have physicochemical properties distinctly different from those of the corresponding bulk crystals; for example, their solubility is much higher. However, many materials have a high propensity to crystallize and are difficult to formulate in an amorphous structure without stabilizers. We fabricated a microfluidic nebulator that can produce amorphous NPs from a wide range of materials, even including pure table salt (NaCl). By using supersonic air flow, the nebulator produces drops that are so small that they dry before crystal nuclei can form. The small size of the resulting spray-dried a-NPs limits the probability of crystal nucleation in any given particle during storage. The kinetic stability of the a-NPs—on the order of months—is advantageous for hydrophobic drug molecules. Authors: Esther Amstad, Manesh Gopinadhan, Christian Holtze, Chinedum O. Osuji, Michael P. Brenner, Frans Spaepen, David A. Weitz
Categories: Journal Articles

[Report] Iron-catalyzed intermolecular [2+2] cycloadditions of unactivated alkenes

Science - Thu, 08/27/2015 - 23:00
Cycloadditions, such as the [4+2] Diels-Alder reaction to form six-membered rings, are among the most powerful and widely used methods in synthetic chemistry. The analogous [2+2] alkene cycloaddition to synthesize cyclobutanes is kinetically accessible by photochemical methods, but the substrate scope and functional group tolerance are limited. Here, we report iron-catalyzed intermolecular [2+2] cycloaddition of unactivated alkenes and cross cycloaddition of alkenes and dienes as regio- and stereoselective routes to cyclobutanes. Through rational ligand design, development of this base metal–catalyzed method expands the chemical space accessible from abundant hydrocarbon feedstocks. Authors: Jordan M. Hoyt, Valerie A. Schmidt, Aaron M. Tondreau, Paul J. Chirik
Categories: Journal Articles

[Report] Irrationality in mate choice revealed by túngara frogs

Science - Thu, 08/27/2015 - 23:00
Mate choice models derive from traditional microeconomic decision theory and assume that individuals maximize their Darwinian fitness by making economically rational decisions. Rational choices exhibit regularity, whereby the relative strength of preferences between options remains stable when additional options are presented. We tested female frogs with three simulated males who differed in relative call attractiveness and call rate. In binary choice tests, females’ preferences favored stimulus caller B over caller A; however, with the addition of an inferior “decoy” C, females reversed their preferences and chose A over B. These results show that the relative valuation of mates is not independent of inferior alternatives in the choice set and therefore cannot be explained with the rational choice models currently used in sexual selection theory. Authors: Amanda M. Lea, Michael J. Ryan
Categories: Journal Articles

[Report] Age-related mortality explains life history strategies of tropical and temperate songbirds

Science - Thu, 08/27/2015 - 23:00
Life history theory attempts to explain why species differ in offspring number and quality, growth rate, and parental effort. I show that unappreciated interactions of these traits in response to age-related mortality risk challenge traditional perspectives and explain life history evolution in songbirds. Counter to a long-standing paradigm, tropical songbirds grow at similar overall rates to temperate species but grow wings relatively faster. These growth tactics are favored by predation risk, both in and after leaving the nest, and are facilitated by greater provisioning of individual offspring by parents. Increased provisioning of individual offspring depends on partitioning effort among fewer young because of constraints on effort from adult and nest mortality. These growth and provisioning responses to mortality risk finally explain the conundrum of small clutch sizes of tropical birds. Author: Thomas E. Martin
Categories: Journal Articles

[Report] Global assessment of arbuscular mycorrhizal fungus diversity reveals very low endemism

Science - Thu, 08/27/2015 - 23:00
The global biogeography of microorganisms remains largely unknown, in contrast to the well-studied diversity patterns of macroorganisms. We used arbuscular mycorrhizal (AM) fungus DNA from 1014 plant-root samples collected worldwide to determine the global distribution of these plant symbionts. We found that AM fungal communities reflected local environmental conditions and the spatial distance between sites. However, despite AM fungi apparently possessing limited dispersal ability, we found 93% of taxa on multiple continents and 34% on all six continents surveyed. This contrasts with the high spatial turnover of other fungal taxa and with the endemism displayed by plants at the global scale. We suggest that the biogeography of AM fungi is driven by unexpectedly efficient dispersal, probably via both abiotic and biotic vectors, including humans. Authors: J. Davison, M. Moora, M. Öpik, A. Adholeya, L. Ainsaar, A. Bâ, S. Burla, A. G. Diedhiou, I. Hiiesalu, T. Jairus, N. C. Johnson, A. Kane, K. Koorem, M. Kochar, C. Ndiaye, M. Pärtel, Ü. Reier, Ü. Saks, R. Singh, M. Vasar, M. Zobel
Categories: Journal Articles

[Report] Glycerophospholipid regulation of modality-specific sensory axon guidance in the spinal cord

Science - Thu, 08/27/2015 - 23:00
Glycerophospholipids, the structural components of cell membranes, have not been considered to be spatial cues for intercellular signaling because of their ubiquitous distribution. We identified lyso-phosphatidyl-β-d-glucoside (LysoPtdGlc), a hydrophilic glycerophospholipid, and demonstrated its role in modality-specific repulsive guidance of spinal cord sensory axons. LysoPtdGlc is locally synthesized and released by radial glia in a patterned spatial distribution to regulate the targeting of nociceptive but not proprioceptive central axon projections. Library screening identified the G protein–coupled receptor GPR55 as a high-affinity receptor for LysoPtdGlc, and GPR55 deletion or LysoPtdGlc loss of function in vivo caused the misallocation of nociceptive axons into proprioceptive zones. These findings show that LysoPtdGlc/GPR55 is a lipid-based signaling system in glia-neuron communication for neural development. Authors: Adam T. Guy, Yasuko Nagatsuka, Noriko Ooashi, Mariko Inoue, Asuka Nakata, Peter Greimel, Asuka Inoue, Takuji Nabetani, Akiho Murayama, Kunihiro Ohta, Yukishige Ito, Junken Aoki, Yoshio Hirabayashi, Hiroyuki Kamiguchi
Categories: Journal Articles

[Report] Base triplet stepping by the Rad51/RecA family of recombinases

Science - Thu, 08/27/2015 - 23:00
DNA strand exchange plays a central role in genetic recombination across all kingdoms of life, but the physical basis for these reactions remains poorly defined. Using single-molecule imaging, we found that bacterial RecA and eukaryotic Rad51 and Dmc1 all stabilize strand exchange intermediates in precise three-nucleotide steps. Each step coincides with an energetic signature (0.3 kBT) that is conserved from bacteria to humans. Triplet recognition is strictly dependent on correct Watson-Crick pairing. Rad51, RecA, and Dmc1 can all step over mismatches, but only Dmc1 can stabilize mismatched triplets. This finding provides insight into why eukaryotes have evolved a meiosis-specific recombinase. We propose that canonical Watson-Crick base triplets serve as the fundamental unit of pairing interactions during DNA recombination. Authors: Ja Yil Lee, Tsuyoshi Terakawa, Zhi Qi, Justin B. Steinfeld, Sy Redding, YoungHo Kwon, William A. Gaines, Weixing Zhao, Patrick Sung, Eric C. Greene
Categories: Journal Articles

[Report] Titin mutations in iPS cells define sarcomere insufficiency as a cause of dilated cardiomyopathy

Science - Thu, 08/27/2015 - 23:00
Human mutations that truncate the massive sarcomere protein titin [TTN-truncating variants (TTNtvs)] are the most common genetic cause for dilated cardiomyopathy (DCM), a major cause of heart failure and premature death. Here we show that cardiac microtissues engineered from human induced pluripotent stem (iPS) cells are a powerful system for evaluating the pathogenicity of titin gene variants. We found that certain missense mutations, like TTNtvs, diminish contractile performance and are pathogenic. By combining functional analyses with RNA sequencing, we explain why truncations in the A-band domain of TTN cause DCM, whereas truncations in the I band are better tolerated. Finally, we demonstrate that mutant titin protein in iPS cell–derived cardiomyocytes results in sarcomere insufficiency, impaired responses to mechanical and β-adrenergic stress, and attenuated growth factor and cell signaling activation. Our findings indicate that titin mutations cause DCM by disrupting critical linkages between sarcomerogenesis and adaptive remodeling. Authors: John T. Hinson, Anant Chopra, Navid Nafissi, William J. Polacheck, Craig C. Benson, Sandra Swist, Joshua Gorham, Luhan Yang, Sebastian Schafer, Calvin C. Sheng, Alireza Haghighi, Jason Homsy, Norbert Hubner, George Church, Stuart A. Cook, Wolfgang A. Linke, Christopher S. Chen, J. G. Seidman, Christine E. Seidman
Categories: Journal Articles

[Report] Emergent genetic oscillations in a synthetic microbial consortium

Science - Thu, 08/27/2015 - 23:00
A challenge of synthetic biology is the creation of cooperative microbial systems that exhibit population-level behaviors. Such systems use cellular signaling mechanisms to regulate gene expression across multiple cell types. We describe the construction of a synthetic microbial consortium consisting of two distinct cell types—an “activator” strain and a “repressor” strain. These strains produced two orthogonal cell-signaling molecules that regulate gene expression within a synthetic circuit spanning both strains. The two strains generated emergent, population-level oscillations only when cultured together. Certain network topologies of the two-strain circuit were better at maintaining robust oscillations than others. The ability to program population-level dynamics through the genetic engineering of multiple cooperative strains points the way toward engineering complex synthetic tissues and organs with multiple cell types. Authors: Ye Chen, Jae Kyoung Kim, Andrew J. Hirning, Krešimir Josić, Matthew R. Bennett
Categories: Journal Articles

[Report] The microbiota regulates type 2 immunity through RORγt+ T cells

Science - Thu, 08/27/2015 - 23:00
Changes to the symbiotic microbiota early in life, or the absence of it, can lead to exacerbated type 2 immunity and allergic inflammations. Although it is unclear how the microbiota regulates type 2 immunity, it is a strong inducer of proinflammatory T helper 17 (TH17) cells and regulatory T cells (Tregs) in the intestine. Here, we report that microbiota-induced Tregs express the nuclear hormone receptor RORγt and differentiate along a pathway that also leads to TH17 cells. In the absence of RORγt+ Tregs, TH2-driven defense against helminths is more efficient, whereas TH2-associated pathology is exacerbated. Thus, the microbiota regulates type 2 responses through the induction of type 3 RORγt+ Tregs and TH17 cells and acts as a key factor in balancing immune responses at mucosal surfaces. Authors: Caspar Ohnmacht, Joo-Hong Park, Sascha Cording, James B. Wing, Koji Atarashi, Yuuki Obata, Valérie Gaboriau-Routhiau, Rute Marques, Sophie Dulauroy, Maria Fedoseeva, Meinrad Busslinger, Nadine Cerf-Bensussan, Ivo G. Boneca, David Voehringer, Koji Hase, Kenya Honda, Shimon Sakaguchi, Gérard Eberl
Categories: Journal Articles

[Report] Individual intestinal symbionts induce a distinct population of RORγ+ regulatory T cells

Science - Thu, 08/27/2015 - 23:00
T regulatory cells that express the transcription factor Foxp3 (Foxp3+ Tregs) promote tissue homeostasis in several settings. We now report that symbiotic members of the human gut microbiota induce a distinct Treg population in the mouse colon, which constrains immuno-inflammatory responses. This induction—which we find to map to a broad, but specific, array of individual bacterial species—requires the transcription factor Rorγ, paradoxically, in that Rorγ is thought to antagonize FoxP3 and to promote T helper 17 (TH17) cell differentiation. Rorγ’s transcriptional footprint differs in colonic Tregs and TH17 cells and controls important effector molecules. Rorγ, and the Tregs that express it, contribute substantially to regulating colonic TH1/TH17 inflammation. Thus, the marked context-specificity of Rorγ results in very different outcomes even in closely related cell types. Authors: Esen Sefik, Naama Geva-Zatorsky, Sungwhan Oh, Liza Konnikova, David Zemmour, Abigail Manson McGuire, Dalia Burzyn, Adriana Ortiz-Lopez, Mercedes Lobera, Jianfei Yang, Shomir Ghosh, Ashlee Earl, Scott B. Snapper, Ray Jupp, Dennis Kasper, Diane Mathis, Christophe Benoist
Categories: Journal Articles

[New Products] New Products

Science - Thu, 08/27/2015 - 23:00
A weekly roundup of information on newly offered instrumentation, apparatus, and laboratory materials of potential interest to researchers.
Categories: Journal Articles

[Podcast] Science Podcast: 28 August Show

Science - Thu, 08/27/2015 - 23:00
On this week's show: The origin of moralizing gods, replicating 100 psychology experiments, and a roundup of daily news stories.
Categories: Journal Articles

[Business Office Feature] Characterizing cell morphology using imaging flow cytometry

Science - Thu, 08/27/2015 - 23:00
Defining the morphological characteristics—such as the size, shape, or structure—of different cell types has played a key role in assessing the progression and status of various diseases. Imaging flow cytometry combines the visual analysis capabilities of microscopy with flow cytometry to provide researchers with a powerful tool to study cell morphology and the potential effects of therapeutic interventions. In this webinar, we will explore ways to characterize cell morphology and how this information can be applied to better understand blood disorders, including how erythrocyte morphology is used in the analysis of sickle cell disease and to identify functional intermediates in erythropoiesis.View the Webinar Authors: Kathleen E. McGrath, David Archer
Categories: Journal Articles

[Working Life] The fungi that ate my house

Science - Thu, 08/27/2015 - 23:00
Author: Joan W. Bennett
Categories: Journal Articles

The structure of the Caenorhabditis elegans manganese superoxide dismutase MnSOD-3-azide complex

Protein Science - Thu, 08/27/2015 - 21:30
Abstract

C. elegans MnSOD-3 has been implicated in the longevity pathway and its mechanism of catalysis is relevant to the aging process and carcinogenesis. The structures of MnSOD-3 provide unique crystallographic evidence of a dynamic region of the tetrameric interface (residues 41–54). We have determined the structure of the MnSOD-3-azide complex to 1.77-Å resolution. Analysis of this complex shows that the substrate analog, azide, binds end-on to the manganese center as a sixth ligand and that it ligates directly to a third and new solvent molecule also positioned within interacting distance to the His30 and Tyr34 residues of the substrate access funnel. This is the first structure of a eukaryotic MnSOD-azide complex that demonstrates the extended, uninterrupted hydrogen-bonded network that forms a proton relay incorporating three outer sphere solvent molecules, the substrate analog, the gateway residues, Gln142, and the solvent ligand. This configuration supports the formation and release of the hydrogen peroxide product in agreement with the 5-6-5 catalytic mechanism for MnSOD. The high product dissociation constant k4 of MnSOD-3 reflects low product inhibition making this enzyme efficient even at high levels of superoxide.

Categories: Journal Articles

Conformational stability of the RNP domain controls fibril formation of PABPN1

Protein Science - Thu, 08/27/2015 - 21:29
Abstract

The disease oculopharyngeal muscular dystrophy is caused by alanine codon trinucleotide expansions in the N-terminal segment of the nuclear poly(A) binding protein PABPN1. As histochemical features of the disease, intranuclear inclusions of PABPN1 have been reported. Whereas the purified N-terminal domain of PABPN1 forms fibrils in an alanine-dependent way, fibril formation of the full-length protein occurs also in the absence of alanines. Here, we addressed the question whether the stability of the RNP domain or domain swapping within the RNP domain may add to fibril formation. A variant of full-length PABPN1 with a stabilizing disulfide bond at position 185/201 in the RNP domain fibrillized in a redox-sensitive manner suggesting that the integrity of the RNP domain may contribute to fibril formation. Thermodynamic analysis of the isolated wild-type and the disulfide-linked RNP domain showed two state unfolding/refolding characteristics without detectable intermediates. Quantification of the thermodynamic stability of the mutant RNP domain pointed to an inverse correlation between fibril formation of full-length PABPN1 and the stability of the RNP domain.

Categories: Journal Articles

Large-scale identification of membrane proteins with properties favorable for crystallization

Protein Science - Thu, 08/27/2015 - 21:29
Abstract

Membrane protein crystallography is notoriously difficult due to challenges in protein expression and issues of degradation and structural stability. We have developed a novel method for large-scale screening of native sources for integral membrane proteins that have intrinsic biochemical properties favorable for crystallization. Highly expressed membrane proteins that are thermally stable and nonaggregating in detergent solutions were identified by mass spectrometry from Escherichia coli, Saccharomyces cerevisiae, and Sus scrofa cerebrum. Many of the membrane proteins identified had been crystallized previously, supporting the promise of the approach. Most identified proteins have known functions and include high-value targets such as transporters and ATPases. To validate the method, we recombinantly expressed and purified the yeast protein, Yop1, which is responsible for endoplasmic reticulum curvature. We demonstrate that Yop1 can be purified with the detergent dodecylmaltoside without aggregating.

Categories: Journal Articles

Escher: A Web Application for Building, Sharing, and Embedding Data-Rich Visualizations of Biological Pathways

PLoS Computational Biology - Thu, 08/27/2015 - 16:00

by Zachary A. King, Andreas Dräger, Ali Ebrahim, Nikolaus Sonnenschein, Nathan E. Lewis, Bernhard O. Palsson

Escher is a web application for visualizing data on biological pathways. Three key features make Escher a uniquely effective tool for pathway visualization. First, users can rapidly design new pathway maps. Escher provides pathway suggestions based on user data and genome-scale models, so users can draw pathways in a semi-automated way. Second, users can visualize data related to genes or proteins on the associated reactions and pathways, using rules that define which enzymes catalyze each reaction. Thus, users can identify trends in common genomic data types (e.g. RNA-Seq, proteomics, ChIP)—in conjunction with metabolite- and reaction-oriented data types (e.g. metabolomics, fluxomics). Third, Escher harnesses the strengths of web technologies (SVG, D3, developer tools) so that visualizations can be rapidly adapted, extended, shared, and embedded. This paper provides examples of each of these features and explains how the development approach used for Escher can be used to guide the development of future visualization tools.
Categories: Journal Articles
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