Targeted delivery of antisense oligonucleotides to pancreatic β-cells Sci. Adv. (IF 11.511) Pub Date : 2018-10-01 C. Ämmälä, W. J. Drury, L. Knerr, I. Ahlstedt, P. Stillemark-Billton, C. Wennberg-Huldt, E.-M. Andersson, E. Valeur, R. Jansson-Löfmark, D. Janzén, L. Sundström, J. Meuller, J. Claesson, P. Andersson, C. Johansson, R. G. Lee, T. P. Prakash, P. P. Seth, B. P. Monia, S. Andersson
Antisense oligonucleotide (ASO) silencing of the expression of disease-associated genes is an attractive novel therapeutic approach, but treatments are limited by the ability to deliver ASOs to cells and tissues. Following systemic administration, ASOs preferentially accumulate in liver and kidney. Among the cell types refractory to ASO uptake is the pancreatic insulin-secreting β-cell. Here, we show that conjugation of ASOs to a ligand of the glucagon-like peptide-1 receptor (GLP1R) can productively deliver ASO cargo to pancreatic β-cells both in vitro and in vivo. Ligand-conjugated ASOs silenced target genes in pancreatic islets at doses that did not affect target gene expression in liver or other tissues, indicating enhanced tissue and cell type specificity. This finding has potential to broaden the use of ASO technology, opening up novel therapeutic opportunities, and presents an innovative approach for targeted delivery of ASOs to additional cell types.
An enzymatic approach reverses nicotine dependence, decreases compulsive-like intake, and prevents relapse Sci. Adv. (IF 11.511) Pub Date : 2018-10-01 Marsida Kallupi, Song Xue, Bin Zhou, Kim D. Janda, Olivier George
Tobacco use disorder is the leading cause of disease and preventable death worldwide, but current medications that are based on pharmacodynamics have low efficacy. Novel pharmacokinetic approaches to prevent nicotine from reaching the brain have been tested using vaccines, but these efforts have failed because antibody affinity and concentration are not sufficient to completely prevent nicotine from reaching the brain. We provide preclinical evidence of the efficacy of an enzymatic approach to reverse nicotine dependence, reduce compulsive-like nicotine intake, and prevent relapse in rats with a history of nicotine dependence. Chronic administration of NicA2-J1, an engineered nicotine-degrading enzyme that was originally isolated from Pseudomonas putida S16, completely prevented nicotine from reaching the brain and reversed somatic signs of withdrawal, hyperalgesia, and irritability-like behavior in nicotine-dependent rats with a history of escalation of nicotine self-administration. NicA2-J1 also decreased compulsive-like nicotine intake, reflected by responding despite the adverse consequences of contingent footshocks, and prevented nicotine- and stress (yohimbine)–induced relapse. These results demonstrate the efficacy of enzymatic therapy in treating nicotine addiction in advanced animal models and provide a strong foundation for the development of biological therapies for smoking cessation in humans.
Global expansion of Mycobacterium tuberculosis lineage 4 shaped by colonial migration and local adaptation Sci. Adv. (IF 11.511) Pub Date : 2018-10-01 Ola B. Brynildsrud, Caitlin S. Pepperell, Philip Suffys, Louis Grandjean, Johana Monteserin, Nadia Debech, Jon Bohlin, Kristian Alfsnes, John O.-H. Pettersson, Ingerid Kirkeleite, Fatima Fandinho, Marcia Aparecida da Silva, Joao Perdigao, Isabel Portugal, Miguel Viveiros, Taane Clark, Maxine Caws, Sarah Dunstan, Phan Vuong Khac Thai, Beatriz Lopez, Viviana Ritacco, Andrew Kitchen, Tyler S. Brown, Dick van Soolingen, Mary B. O’Neill, Kathryn E. Holt, Edward J. Feil, Barun Mathema, Francois Balloux, Vegard Eldholm
On the basis of population genomic and phylogeographic analyses of 1669 Mycobacterium tuberculosis lineage 4 (L4) genomes, we find that dispersal of L4 has been completely dominated by historical migrations out of Europe. We demonstrate an intimate temporal relationship between European colonial expansion into Africa and the Americas and the spread of L4 tuberculosis (TB). Markedly, in the age of antibiotics, mutations conferring antimicrobial resistance overwhelmingly emerged locally (at the level of nations), with minimal cross-border transmission of resistance. The latter finding was found to reflect the relatively recent emergence of these mutations, as a similar degree of local restriction was observed for susceptible variants emerging on comparable time scales. The restricted international transmission of drug-resistant TB suggests that containment efforts at the level of individual countries could be successful.
New generation of U.S. satellite microwave sounder achieves high radiometric stability performance for reliable climate change detection Sci. Adv. (IF 11.511) Pub Date : 2018-10-01 Cheng-Zhi Zou, Mitchell D. Goldberg, Xianjun Hao
Observations from the satellite microwave sounders play a vital role in measuring the long-term temperature trends for climate change monitoring. Changes in diurnal sampling over time and calibration drift have been the main sources of uncertainties in the satellite-measured temperature trends. We examine observations from the first of a series of U.S. new generation of microwave sounder, the Advanced Technology Microwave Sounder (ATMS), which has been flying onboard the National Oceanic and Atmospheric Administration (NOAA)/NASA Suomi National Polar-orbiting Partnership (SNPP) environmental satellite since late 2011. The SNPP satellite has a stable afternoon orbit that has close to the same local observation time as NASA’s Aqua satellite that has been carrying the heritage microwave sounder, the Advanced Microwave Sounding Unit-A (AMSU-A), from 2002 until the present. The similar overpass timing naturally removes most of their diurnal differences. In addition, direct comparison of temperature anomalies between the two instruments shows little or no relative calibration drift for most channels. Our results suggest that both SNPP/ATMS and Aqua/AMSU-A instruments have achieved absolute stability in the measured atmospheric temperatures within 0.04 K per decade. This uncertainty is small enough to allow reliable detection of the temperature climate trends and help to resolve debate on relevant issues. We also analyze AMSU-A observations onboard the European MetOp-A satellite that has a stable morning orbit 8 hours apart from the SNPP overpass time. Their comparison reveals large asymmetric trends between day and night in the lower- and mid-tropospheric temperatures over land. This information could help to improve climate data records for temperature trend detection with improved accuracy. The SNPP satellite will be followed by four NOAA operational Joint Polar Satellite System (JPSS) satellites, providing accurate and stable measurement for decades to come. The primary mission of JPSS is for weather forecasting. Now, with the added feature of stable orbits, JPSS observations can also be used to monitor changes in climate with much lower uncertainty than the previous generation of NOAA operational satellites.
Prevention of pesticide-induced neuronal dysfunction and mortality with nucleophilic poly-Oxime topical gel Sci. Adv. (IF 11.511) Pub Date : 2018-10-01 Ketan Thorat, Subhashini Pandey, Sandeep Chandrashekharappa, Nikitha Vavilthota, Ankita A. Hiwale, Purna Shah, Sneha Sreekumar, Shubhangi Upadhyay, Tenzin Phuntsok, Manohar Mahato, Kiran K. Mudnakudu-Nagaraju, Omprakash Sunnapu, Praveen K. Vemula
Organophosphate-based pesticides inhibit acetylcholinesterase (AChE), which plays a pivotal role in neuromuscular function. While spraying in the field, farmworkers get exposed to pesticides through the dermal route. Internalized pesticide inhibits AChE, which leads to neurotoxicity, cardiotoxicity, cognitive dysfunction, loss of endurance, and death in severe cases. Here, we present a nucleophilic pyridine-2-aldoxime–functionalized chitosan-based topical gel (poly-Oxime gel) that rapidly deactivates organophosphates, methyl parathion (MPT), on the skin of rats, which leads to reduced AChE inhibition in the blood and tissues. Testing the robustness of poly-Oxime gel, we report reduction in AChE inhibition following repeated dermal administration of MPT in the presence of poly-Oxime gel. Furthermore, poly-Oxime gel prevented MPT-induced neuromuscular dysfunction, loss of endurance, and locomotor coordination. We observe a 100% survival in rats following topical MPT administration in the presence of poly-Oxime gel. This prophylactic gel may therefore help farmworkers by limiting pesticide-induced toxicity and mortality.
GPR40 modulates epileptic seizure and NMDA receptor function Sci. Adv. (IF 11.511) Pub Date : 2018-10-01 Yong Yang, Xin Tian, Demei Xu, Fangshuo Zheng, Xi Lu, Yanke Zhang, Yuanlin Ma, Yun Li, Xin Xu, Binglin Zhu, Xuefeng Wang
Epilepsy is a common neurological disease, and approximately 30% of patients do not respond adequately to antiepileptic drug treatment. Recent studies suggest that G protein–coupled receptor 40 (GPR40) is expressed in the central nervous system and is involved in the regulation of neurological function. However, the impact of GPR40 on epileptic seizures remains unclear. In this study, we first reported that GPR40 expression was increased in epileptic brains. In the kainic acid–induced epilepsy model, GPR40 activation after status epilepticus alleviated epileptic activity, whereas GPR40 inhibition showed the opposite effect. In the pentylenetetrazole-induced kindling model, susceptibility to epilepsy was reduced with GPR40 activation and increased with GPR40 inhibition. Whole-cell patch-clamp recordings demonstrated that GPR40 affected N-methyl-d-aspartate (NMDA) receptor–mediated synaptic transmission. Moreover, GPR40 regulated NR2A and NR2B expression on the surface of neurons. In addition, endocytosis of NMDA receptors and binding of GPR40 with NR2A and NR2B can be regulated by GPR40. Together, our findings indicate that GPR40 modulates epileptic seizures, providing a novel antiepileptic target.
The demise of Angkor: Systemic vulnerability of urban infrastructure to climatic variations Sci. Adv. (IF 11.511) Pub Date : 2018-10-01 Dan Penny, Cameron Zachreson, Roland Fletcher, David Lau, Joseph T. Lizier, Nicholas Fischer, Damian Evans, Christophe Pottier, Mikhail Prokopenko
Complex infrastructural networks provide critical services to cities but can be vulnerable to external stresses, including climatic variability. This vulnerability has also challenged past urban settlements, but its role in cases of historic urban demise has not been precisely documented. We transform archeological data from the medieval Cambodian city of Angkor into a numerical model that allows us to quantify topological damage to critical urban infrastructure resulting from climatic variability. Our model reveals unstable behavior in which extensive and cascading damage to infrastructure occurs in response to flooding within Angkor’s urban water management system. The likelihood and extent of the cascading failure abruptly grow with the magnitude of flooding relative to normal flows in the system. Our results support the hypothesis that systemic infrastructural vulnerability, coupled with abrupt climatic variation, contributed to the demise of the city. The factors behind Angkor’s demise are analogous to challenges faced by modern urban communities struggling with complex critical infrastructure.
Tracking time with ricequakes in partially soaked brittle porous media Sci. Adv. (IF 11.511) Pub Date : 2018-10-01 Itai Einav, François Guillard
When brittle porous media interact with chemically active fluids, they may suddenly crumble. This has reportedly triggered the collapse of rockfill dams, sinkholes, and ice shelves. To study this problem, we use a surrogate experiment for the effect of fluid on rocks and ice involving a column of puffed rice partially soaked in a reservoir of liquid under constant pressure. We disclose localized crushing collapse in the unsaturated region that produces incremental global compaction and loud audible beats. These “ricequakes” repeat perpetually during the experiments and propagate upward through the material. The delay time between consecutive quakes grows linearly with time and is accompanied by creep motion. All those new observations can be explained using a simple chemomechanical model of capillary-driven crushing steps progressing through the micropores.
Unraveling the long-pursued Au144 structure by x-ray crystallography Sci. Adv. (IF 11.511) Pub Date : 2018-10-01 Nan Yan, Nan Xia, Lingwen Liao, Min Zhu, Fengming Jin, Rongchao Jin, Zhikun Wu
The transition from nanocluster to nanocrystal is a central issue in nanoscience. The atomic structure determination of metal nanoparticles in the transition size range is challenging and particularly important in understanding the quantum size effect at the atomic level. On the basis of the rationale that the intra- and interparticle weak interactions play critical roles in growing high-quality single crystals of metal nanoparticles, we have reproducibly obtained ideal crystals of Au144(SR)60 and successfully solved its structure by x-ray crystallography (XRC); this structure was theoretically predicted a decade ago and has long been pursued experimentally but without success until now. Here, XRC reveals an interesting Au12 hollow icosahedron in thiolated gold nanoclusters for the first time. The Au–Au bond length, close to that of bulk gold, shows better thermal extensibility than the other Au–Au bond lengths in Au144(SR)60, providing an atomic-level perspective because metal generally shows better thermal extensibility than nonmetal materials. Thus, our work not only reveals the mysterious, long experimentally pursued structure of a transition-sized nanoparticle but also has important implications for the growth of high-quality, single-crystal nanoparticles, as well as for the understanding of the thermal extensibility of metals from the perspective of chemical bonding.
Optically transparent, high-toughness elastomer using a polyrotaxane cross-linker as a molecular pulley Sci. Adv. (IF 11.511) Pub Date : 2018-10-01 Hiroaki Gotoh, Chang Liu, Abu Bin Imran, Mitsuo Hara, Takahiro Seki, Koichi Mayumi, Kohzo Ito, Yukikazu Takeoka
An elastomer is a three-dimensional network with a cross-linked polymer chain that undergoes large deformation with a small external force and returns to its original state when the external force is removed. Because of this hyperelasticity, elastomers are regarded as one of the best candidates for the matrix material of soft robots. However, the comprehensive performance required of matrix materials is a special challenge because improvement of some matrix properties often causes the deterioration of others. For example, an improvement in toughness can be realized by adding a large amount of filler to an elastomer, but to the impairment of optical transparency. Therefore, to produce an elastomer exhibiting optimum properties suitable for the desired purpose, very elaborate, complicated materials are often devised. Here, we have succeeded in creating an optically transparent, easily fabricated elastomer with good extensibility and high toughness by using a polyrotaxane (PR) composed of cyclic molecules and a linear polymer as a cross-linking agent. In general, elastomers having conventional cross-linked structures are susceptible to breakage as a result of loss of extensibility at high cross-linking density. We found that the toughness of the transparent elastomer prepared using the PR cross-linking agent is enhanced along with its Young’s modulus as cross-linking density is increased.
Tunable structure and dynamics of active liquid crystals Sci. Adv. (IF 11.511) Pub Date : 2018-10-01 Nitin Kumar, Rui Zhang, Juan J. de Pablo, Margaret L. Gardel
Active materials are capable of converting free energy into directional motion, giving rise to notable dynamical phenomena. Developing a general understanding of their structure in relation to the underlying nonequilibrium physics would provide a route toward control of their dynamic behavior and pave the way for potential applications. The active system considered here consists of a quasi–two-dimensional sheet of short (≈1 μm) actin filaments driven by myosin II motors. By adopting a concerted theoretical and experimental strategy, new insights are gained into the nonequilibrium properties of active nematics over a wide range of internal activity levels. In particular, it is shown that topological defect interactions can be led to transition from attractive to repulsive as a function of initial defect separation and relative orientation. Furthermore, by examining the +1/2 defect morphology as a function of activity, we found that the apparent elastic properties of the system (the ratio of bend-to-splay elastic moduli) are altered considerably by increased activity, leading to an effectively lower bend elasticity. At high levels of activity, the topological defects that decorate the material exhibit a liquid-like structure and adopt preferred orientations depending on their topological charge. Together, these results suggest that it should be possible to tune internal stresses in active nematic systems with the goal of designing out-of-equilibrium structures with engineered dynamic responses.
Quantum interference mediated vertical molecular tunneling transistors Sci. Adv. (IF 11.511) Pub Date : 2018-10-01 Chuancheng Jia, Marjan Famili, Marco Carlotti, Yuan Liu, Peiqi Wang, Iain M. Grace, Ziying Feng, Yiliu Wang, Zipeng Zhao, Mengning Ding, Xiang Xu, Chen Wang, Sung-Joon Lee, Yu Huang, Ryan C. Chiechi, Colin J. Lambert, Xiangfeng Duan
Molecular transistors operating in the quantum tunneling regime represent potential electronic building blocks for future integrated circuits. However, due to their complex fabrication processes and poor stability, traditional molecular transistors can only operate stably at cryogenic temperatures. Here, through a combined experimental and theoretical investigation, we demonstrate a new design of vertical molecular tunneling transistors, with stable switching operations up to room temperature, formed from cross-plane graphene/self-assembled monolayer (SAM)/gold heterostructures. We show that vertical molecular junctions formed from pseudo-p-bis((4-(acetylthio)phenyl)ethynyl)-p-[2,2]cyclophane (PCP) SAMs exhibit destructive quantum interference (QI) effects, which are absent in 1,4-bis(((4-acetylthio)phenyl)ethynyl)benzene (OPE3) SAMs. Consequently, the zero-bias differential conductance of the former is only about 2% of the latter, resulting in an enhanced on-off current ratio for (PCP) SAMs. Field-effect control is achieved using an ionic liquid gate, whose strong vertical electric field penetrates through the graphene layer and tunes the energy levels of the SAMs. The resulting on-off current ratio achieved in PCP SAMs can reach up to ~330, about one order of magnitude higher than that of OPE3 SAMs. The demonstration of molecular junctions with combined QI effect and gate tunability represents a critical step toward functional devices in future molecular-scale electronics.
Shaping nanoparticle fingerprints at the interface of cholesteric droplets Sci. Adv. (IF 11.511) Pub Date : 2018-10-01 Lisa Tran, Hye-Na Kim, Ningwei Li, Shu Yang, Kathleen J. Stebe, Randall D. Kamien, Martin F. Haase
The ordering of nanoparticles into predetermined configurations is of importance to the design of advanced technologies. Here, we balance the interfacial energy of nanoparticles against the elastic energy of cholesteric liquid crystals to dynamically shape nanoparticle assemblies at a fluid interface. By adjusting the concentration of surfactant that plays the dual role of tuning the degree of nanoparticle hydrophobicity and altering the molecular anchoring of liquid crystals, we pattern nanoparticles at the interface of cholesteric liquid crystal emulsions. In this system, interfacial assembly is tempered by elastic patterns that arise from the geometric frustration of confined cholesterics. Patterns are tunable by varying both surfactant and chiral dopant concentrations. Adjusting the particle hydrophobicity more finely by regulating the surfactant concentration and solution pH further modifies the rigidity of assemblies, giving rise to surprising assembly dynamics dictated by the underlying elasticity of the cholesteric. Because particle assembly occurs at the interface with the desired structures exposed to the surrounding water solution, we demonstrate that particles can be readily cross-linked and manipulated, forming structures that retain their shape under external perturbations. This study serves as a foundation for better understanding inter-nanoparticle interactions at interfaces by tempering their assembly with elasticity and for creating materials with chemical heterogeneity and linear, periodic structures, essential for optical and energy applications.
A high-entropy alloy with hierarchical nanoprecipitates and ultrahigh strength Sci. Adv. (IF 11.511) Pub Date : 2018-10-01 Zhiqiang Fu, Lin Jiang, Jenna L. Wardini, Benjamin E. MacDonald, Haiming Wen, Wei Xiong, Dalong Zhang, Yizhang Zhou, Timothy J. Rupert, Weiping Chen, Enrique J. Lavernia
High-entropy alloys (HEAs) are a class of metallic materials that have revolutionized alloy design. They are known for their high compressive strengths, often greater than 1 GPa; however, the tensile strengths of most reported HEAs are limited. Here, we report a strategy for the design and fabrication of HEAs that can achieve ultrahigh tensile strengths. The proposed strategy involves the introduction of a high density of hierarchical intragranular nanoprecipitates. To establish the validity of this strategy, we designed and fabricated a bulk Fe25Co25Ni25Al10Ti15 HEA to consist of a principal face-centered cubic (fcc) phase containing hierarchical intragranular nanoprecipitates. Our results show that precipitation strengthening, as one of the main strengthening mechanisms, contributes to a tensile yield strength (σ0.2) of ~1.86 GPa and an ultimate tensile strength of ~2.52 GPa at room temperature, which heretofore represents the highest strength reported for an HEA with an appreciable failure strain of ~5.2%.
Uranium polyhydrides at moderate pressures: Prediction, synthesis, and expected superconductivity Sci. Adv. (IF 11.511) Pub Date : 2018-10-01 Ivan A. Kruglov, Alexander G. Kvashnin, Alexander F. Goncharov, Artem R. Oganov, Sergey S. Lobanov, Nicholas Holtgrewe, Shuqing Jiang, Vitali B. Prakapenka, Eran Greenberg, Alexey V. Yanilkin
Hydrogen-rich hydrides attract great attention due to recent theoretical (1) and then experimental discovery of record high-temperature superconductivity in H3S [Tc = 203 K at 155 GPa (2)]. Here we search for stable uranium hydrides at pressures up to 500 GPa using ab initio evolutionary crystal structure prediction. Chemistry of the U-H system turned out to be extremely rich, with 14 new compounds, including hydrogen-rich UH5, UH6, U2H13, UH7, UH8, U2H17, and UH9. Their crystal structures are based on either common face-centered cubic or hexagonal close-packed uranium sublattice and unusual H8 cubic clusters. Our high-pressure experiments at 1 to 103 GPa confirm the predicted UH7, UH8, and three different phases of UH5, raising confidence about predictions of the other phases. Many of the newly predicted phases are expected to be high-temperature superconductors. The highest-Tc superconductor is UH7, predicted to be thermodynamically stable at pressures above 22 GPa (with Tc = 44 to 54 K), and this phase remains dynamically stable upon decompression to zero pressure (where it has Tc = 57 to 66 K).
Wide-field multiphoton imaging through scattering media without correction Sci. Adv. (IF 11.511) Pub Date : 2018-10-01 Adrià Escobet-Montalbán, Roman Spesyvtsev, Mingzhou Chen, Wardiya Afshar Saber, Melissa Andrews, C. Simon Herrington, Michael Mazilu, Kishan Dholakia
Optical approaches to fluorescent, spectroscopic, and morphological imaging have made exceptional advances in the last decade. Super-resolution imaging and wide-field multiphoton imaging are now underpinning major advances across the biomedical sciences. While the advances have been startling, the key unmet challenge to date in all forms of optical imaging is to penetrate deeper. A number of schemes implement aberration correction or the use of complex photonics to address this need. In contrast, we approach this challenge by implementing a scheme that requires no a priori information about the medium nor its properties. Exploiting temporal focusing and single-pixel detection in our innovative scheme, we obtain wide-field two-photon images through various turbid media including a scattering phantom and tissue reaching a depth of up to seven scattering mean free path lengths. Our results show that it competes favorably with standard point-scanning two-photon imaging, with up to a fivefold improvement in signal-to-background ratio while showing significantly lower photobleaching.
Synthesis of stable and low-CO2 selective ε-iron carbide Fischer-Tropsch catalysts Sci. Adv. (IF 11.511) Pub Date : 2018-10-01 Peng Wang, Wei Chen, Fu-Kuo Chiang, A. Iulian Dugulan, Yuanjun Song, Robert Pestman, Kui Zhang, Jinsong Yao, Bo Feng, Ping Miao, Wayne Xu, Emiel J. M. Hensen
The Fe-catalyzed Fischer-Tropsch (FT) reaction constitutes the core of the coal-to-liquids (CTL) process, which converts coal into liquid fuels. Conventional Fe-based catalysts typically convert 30% of the CO feed to CO2 in the FT unit. Decreasing the CO2 release in the FT step will reduce costs and enhance productivity of the overall process. In this context, we synthesize phase-pure ε(′)-Fe2C catalysts exhibiting low CO2 selectivity by carefully controlling the pretreatment and carburization conditions. Kinetic data reveal that liquid fuels can be obtained free from primary CO2. These catalysts displayed stable FT performance at 23 bar and 235°C for at least 150 hours. Notably, in situ characterization emphasizes the high durability of pure ε(′)-Fe2C in an industrial pilot test. These findings contribute to the development of new Fe-based FT catalysts for next-generation CTL processes.
Switchable counterion gradients around charged metallic nanoparticles enable reception of radio waves Sci. Adv. (IF 11.511) Pub Date : 2018-10-01 Xing Zhao, Bin Tu, Mengyao Li, Xiaojing Feng, Yuchun Zhang, Qiaojun Fang, Tiehu Li, Bartosz A. Grzybowski, Yong Yan
Mechanically flexible, easy-to-process, and environmentally benign materials capable of current rectification are interesting alternatives to “hard” silicon-based devices. Among these materials are metallic/charged-organic nanoparticles in which electronic currents though metal cores are modulated by the gradients of counterions surrounding the organic ligands. Although layers of oppositely charged particles can respond to both electronic and chemical signals and can function even under significant mechanical deformation, the rectification ratios of these “chemoelectronic” elements have been, so far, low. This work shows that significantly steeper counterion gradients and significantly higher rectification ratios can be achieved with nanoparticles of only one polarity but in contact with a porous electrode serving as a counterion “sink.” These composite structures act as rectifiers even at radio frequencies, providing a new means of interfacing counterions’ dynamics with high-frequency electronic currents.
Climbing the crustal ladder: Magma storage-depth evolution during a volcanic flare-up Sci. Adv. (IF 11.511) Pub Date : 2018-10-01 Guilherme A. R. Gualda, Darren M. Gravley, Michelle Connor, Brooke Hollmann, Ayla S. Pamukcu, Florence Bégué, Mark S. Ghiorso, Chad D. Deering
Very large eruptions (>50 km3) and supereruptions (>450 km3) reveal Earth’s capacity to produce and store enormous quantities (>1000 km3) of crystal-poor, eruptible magma in the shallow crust. We explore the interplay between crustal evolution and volcanism during a volcanic flare-up in the Taupo Volcanic Zone (TVZ, New Zealand) using a combination of quartz-feldspar-melt equilibration pressures and time scales of quartz crystallization. Over the course of the flare-up, crystallization depths became progressively shallower, showing the gradual conditioning of the crust. Yet, quartz crystallization times were invariably very short (<100 years), demonstrating that very large reservoirs of eruptible magma were transient crustal features. We conclude that the dynamic nature of the TVZ crust favored magma eruption over storage. Episodic tapping of eruptible magmas likely prevented a supereruption. Instead, multiple very large bodies of eruptible magma were assembled and erupted in decadal time scales.
Mitochondrial oxidation of the carbohydrate fuel is required for neural precursor/stem cell function and postnatal cerebellar development Sci. Adv. (IF 11.511) Pub Date : 2018-10-01 Hong Zheng, Wen-Mei Yu, Jinhua Shen, Sumin Kang, Dolores Hambardzumyan, James Y. Li, Yuxian Shen, Anna M. Kenney, Jing Chen, Cheng-Kui Qu
While deregulation of mitochondrial metabolism and cytosolic glycolysis has been well recognized in tumor cells, the role of coordinated mitochondrial oxidation and cytosolic fermentation of pyruvate, a key metabolite derived from glucose, in physiological processes is not well understood. Here, we report that knockout of PTPMT1, a mitochondrial phosphoinositide phosphatase, completely blocked postnatal cerebellar development. Proliferation of granule cell progenitors, the most actively replicating cells in the developing cerebellum, was only moderately decreased, and proliferation of Purkinje cell progenitors did not seem to be affected in knockout mice. In contrast, generation of functional Bergmann glia from multipotent precursor cells (radial glia), which is essential for cerebellar corticogenesis, was totally disrupted. Moreover, despite a low turnover rate, neural stem cells were impaired in self-renewal in knockout mice. Mechanistically, loss of PTPMT1 decreased mitochondrial aerobic metabolism by limiting utilization of pyruvate, which resulted in bioenergetic stress in neural precursor/stem cells but not in progenitor or mature cells, leading to cell cycle arrest through activation of the AMPK-p19/p21 pathway. This study suggests that mitochondrial oxidation of the carbohydrate fuel is required for postnatal cerebellar development, and identifies a bioenergetic stress–induced cell cycle checkpoint in neural precursor/stem cells.
Decoupled taxonomic and ecological recoveries from the Permo-Triassic extinction Sci. Adv. (IF 11.511) Pub Date : 2018-10-01 Haijun Song, Paul B. Wignall, Alexander M. Dunhill
The Permian-Triassic mass extinction was the worst crisis faced by life; it killed >90% of marine species in less than 0.1 million years (Ma). However, knowledge of its macroecological impact over prolonged time scales is limited. We show that marine ecosystems dominated by non-motile animals shifted to ones dominated by nektonic groups after the extinction. In Triassic oceans, animals at high trophic levels recovered faster than those at lower levels. The top-down rebuilding of marine ecosystems was still underway in the latest Triassic, ~50 Ma after the extinction, and contrasts with the ~5-Ma recovery required for taxonomic diversity. The decoupling between taxonomic and ecological recoveries suggests that a process of vacant niche filling before reaching the maximum environmental carrying capacity is independent of ecosystem structure building.
Microphysiological 3D model of amyotrophic lateral sclerosis (ALS) from human iPS-derived muscle cells and optogenetic motor neurons Sci. Adv. (IF 11.511) Pub Date : 2018-10-01 Tatsuya Osaki, Sebastien G. M. Uzel, Roger D. Kamm
Amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease involving loss of motor neurons (MNs) and muscle atrophy, still has no effective treatment, despite much research effort. To provide a platform for testing drug candidates and investigating the pathogenesis of ALS, we developed an ALS-on-a-chip technology (i.e., an ALS motor unit) using three-dimensional skeletal muscle bundles along with induced pluripotent stem cell (iPSC)–derived and light-sensitive channelrhodopsin-2–induced MN spheroids from a patient with sporadic ALS. Each tissue was cultured in a different compartment of a microfluidic device. Axon outgrowth formed neuromuscular junctions on the muscle fiber bundles. Light was used to activate muscle contraction, which was measured on the basis of pillar deflections. Compared to a non-ALS motor unit, the ALS motor unit generated fewer muscle contractions, there was MN degradation, and apoptosis increased in the muscle. Furthermore, the muscle contractions were recovered by single treatments and cotreatment with rapamycin (a mechanistic target of rapamycin inhibitor) and bosutinib (an Src/c-Abl inhibitor). This recovery was associated with up-regulation of autophagy and degradation of TAR DNA binding protein–43 in the MNs. Moreover, administering the drugs via an endothelial cell barrier decreased the expression of P-glycoprotein (an efflux pump that transports bosutinib) in the endothelial cells, indicating that rapamycin and bosutinib cotreatment has considerable potential for ALS treatment. This ALS-on-a-chip and optogenetics technology could help to elucidate the pathogenesis of ALS and to screen for drug candidates.
Gravitational collapse of Mount Etna’s southeastern flank Sci. Adv. (IF 11.511) Pub Date : 2018-10-01 Morelia Urlaub, Florian Petersen, Felix Gross, Alessandro Bonforte, Giuseppe Puglisi, Francesco Guglielmino, Sebastian Krastel, Dietrich Lange, Heidrun Kopp
The southeastern flank of Etna volcano slides into the Ionian Sea at rates of centimeters per year. The prevailing understanding is that pressurization of the magmatic system, and not gravitational forces, controls flank movement, although this has also been proposed. So far, it has not been possible to separate between these processes, because no data on offshore deformation were available until we conducted the first long-term seafloor displacement monitoring campaign from April 2016 until July 2017. Unprecedented seafloor geodetic data reveal a >4-cm slip along the offshore extension of a fault related to flank kinematics during one 8-day-long event in May 2017, while displacement on land peaked at ~4 cm at the coast. As deformation increases away from the magmatic system, the bulk of Mount Etna’s present continuous deformation must be driven by gravity while being further destabilized by magma dynamics. We cannot exclude flank movement to evolve into catastrophic collapse, implying that Etna’s flank movement poses a much greater hazard than previously thought. The hazard of flank collapse might be underestimated at other coastal and ocean island volcanoes, where the dynamics of submerged flanks are unknown.
The IgM pentamer is an asymmetric pentagon with an open groove that binds the AIM protein Sci. Adv. (IF 11.511) Pub Date : 2018-10-01 Emiri Hiramoto, Akihisa Tsutsumi, Risa Suzuki, Shigeru Matsuoka, Satoko Arai, Masahide Kikkawa, Toru Miyazaki
Soluble immunoglobulin M (IgM) forms a pentamer containing a joining (J) chain polypeptide. While IgM pentamer has various immune functions, it also behaves as a carrier of circulating apoptosis inhibitor of macrophage (AIM; also called CD5L) protein that facilitates repair during different diseases. AIM binds to the IgM pentamer solely in the presence of the J chain. Here, using a single-particle negative-stain electron microscopy, we found that the IgM pentamer exhibits an asymmetric pentagon containing one large gap, which is markedly different from the textbook symmetric pentagon model. A single AIM molecule specifically fits into the gap, cross-bridging two IgM-Fc that form the edges of the gap through a disulfide bond at one side and a charge-based interaction at the other side. The discovery of the bona fide shape of the IgM pentamer advances our structural understanding of the pentameric IgM and its binding mode with AIM.
Cryo-EM structure of P. falciparum circumsporozoite protein with a vaccine-elicited antibody is stabilized by somatically mutated inter-Fab contacts Sci. Adv. (IF 11.511) Pub Date : 2018-10-01 David Oyen, Jonathan L. Torres, Christopher A. Cottrell, C. Richter King, Ian A. Wilson, Andrew B. Ward
The circumsporozoite protein (CSP) on the surface of Plasmodium falciparum sporozoites is important for parasite development, motility, and host hepatocyte invasion. However, intrinsic disorder of the NANP repeat sequence in the central region of CSP has hindered its structural and functional characterization. Here, the cryo–electron microscopy structure at ~3.4-Å resolution of a recombinant shortened CSP construct with the variable domains (Fabs) of a highly protective monoclonal antibody reveals an extended spiral conformation of the central NANP repeat region surrounded by antibodies. This unusual structure appears to be stabilized and/or induced by interaction with an antibody where contacts between adjacent Fabs are somatically mutated and enhance the interaction. This maturation in non-antigen contact residues may be an effective mechanism for antibodies to target tandem repeat sequences and provide novel insights into malaria vaccine design.
Observation of long-range dipole-dipole interactions in hyperbolic metamaterials Sci. Adv. (IF 11.511) Pub Date : 2018-10-01 Ward D. Newman, Cristian L. Cortes, Amir Afshar, Ken Cadien, Al Meldrum, Robert Fedosejevs, Zubin Jacob
Dipole-dipole interactions (Vdd) between closely spaced atoms and molecules are related to real photon and virtual photon exchange between them and decrease in the near field connected with the characteristic Coulombic dipole field law. The control and modification of this marked scaling with distance have become a long-standing theme in quantum engineering since dipole-dipole interactions govern Van der Waals forces, collective Lamb shifts, atom blockade effects, and Förster resonance energy transfer. We show that metamaterials can fundamentally modify these interactions despite large physical separation between interacting quantum emitters. We demonstrate a two orders of magnitude increase in the near-field resonant dipole-dipole interactions at intermediate field distances (10 times the near field) and observe the distance scaling law consistent with a super-Coulombic interaction theory curtailed only by absorption and finite size effects of the metamaterial constituents. We develop a first-principles numerical approach of many-body dipole-dipole interactions in metamaterials to confirm our theoretical predictions and experimental observations. In marked distinction to existing approaches of engineering radiative interactions, our work paves the way for controlling long-range dipole-dipole interactions using hyperbolic metamaterials and natural hyperbolic two-dimensional materials.
Transformation of alcohols to esters promoted by hydrogen bonds using oxygen as the oxidant under metal-free conditions Sci. Adv. (IF 11.511) Pub Date : 2018-10-01 Mingyang Liu, Zhanrong Zhang, Huizhen Liu, Zhenbing Xie, Qingqing Mei, Buxing Han
One-pot oxidative transformation of alcohols into esters is very attractive, but metal-based catalysts are used in the reported routes. We discovered that the basic ionic liquid 1-ethyl-3-methylimidazolium acetate ([EMIM] OAc) could effectively catalyze this kind of reaction using O2 as an oxidant without any other catalysts or additives. The oxidative self-esterification of benzylic alcohols or aliphatic alcohols and cross-esterification between benzyl alcohols and aliphatic alcohols could all be achieved with high yields. Detailed study revealed that the cation with acidic proton and basic acetate anion could simultaneously form multiple hydrogen bonds with the hydroxyl groups of the alcohols, which catalyzed the reaction very effectively. As far as we know, this is the first work to carry out this kind of reaction under metal-free conditions.
Upgrading traditional liquid electrolyte via in situ gelation for future lithium metal batteries Sci. Adv. (IF 11.511) Pub Date : 2018-10-01 Feng-Quan Liu, Wen-Peng Wang, Ya-Xia Yin, Shuai-Feng Zhang, Ji-Lei Shi, Lu Wang, Xu-Dong Zhang, Yue Zheng, Jian-Jun Zhou, Lin Li, Yu-Guo Guo
High-energy lithium metal batteries (LMBs) are expected to play important roles in the next-generation energy storage systems. However, the uncontrolled Li dendrite growth in liquid electrolytes still impedes LMBs from authentic commercialization. Upgrading the traditional electrolyte system from liquid to solid and quasi-solid has therefore become a key issue for prospective LMBs. From this premise, it is particularly urgent to exploit facile strategies to accomplish this goal. We report that commercialized liquid electrolyte can be easily converted into a novel quasi-solid gel polymer electrolyte (GPE) via a simple and efficient in situ gelation strategy, which, in essence, is to use LiPF6 to induce the cationic polymerization of the ether-based 1,3-dioxolane and 1,2-dimethoxyethane liquid electrolyte under ambient temperature. The newly developed GPE exhibits elevated protective effects on Li anodes and has universality for diversified cathodes including but not restricted to sulfur, olivine-type LiFePO4, and layered LiNi0.6Co0.2Mn0.2O2, revealing tremendous potential in promoting the large-scale application of future LMBs.
Secondary building units as the turning point in the development of the reticular chemistry of MOFs Sci. Adv. (IF 11.511) Pub Date : 2018-10-01 Markus J. Kalmutzki, Nikita Hanikel, Omar M. Yaghi
The secondary building unit (SBU) approach was a turning point in the discovery of permanently porous metal-organic frameworks (MOFs) and in launching the field of reticular chemistry. In contrast to the single-metal nodes known in coordination networks, the polynuclear nature of SBUs allows these structures to serve as rigid, directional, and stable building units in the design of robust crystalline materials with predetermined structures and properties. This concept has also enabled the development of MOFs with ultra-high porosity and structural complexity. The architectural, mechanical, and chemical stability of MOFs imparted by their SBUs also gives rise to unique framework chemistry. All of this chemistry –including ligand, linker, metal exchange, and metallation reactions, as well as precisely controlled formation of ordered vacancies– is carried out with full retention of the MOF structure, crystallinity, and porosity. The unique chemical nature of SBUs makes MOFs useful in many applications including gas and vapor adsorption, separation processes, and SBU-mediated catalysis. In essence, the SBU approach realizes a long-standing dream of scientists by bringing molecular chemistry (both organic and inorganic) to extended solid-state structures. This contribution highlights the importance of the SBUs in the development of MOFs and points to the tremendous potential still to be harnessed.
Approaching the forbidden fruit of reaction dynamics: Aiming reagent at selected impact parameters Sci. Adv. (IF 11.511) Pub Date : 2018-10-01 Kelvin Anggara, Lydie Leung, Matthew J. Timm, Zhixin Hu, John C. Polanyi
Collision geometry is central to reaction dynamics. An important variable in collision geometry is the miss-distance between molecules, known as the “impact parameter.” This is averaged in gas-phase molecular beam studies. By aligning molecules on a surface prior to electron-induced dissociation, we select impact parameters in subsequent inelastic collisions. Surface-collimated “projectile” molecules, difluorocarbene (CF2), were aimed at stationary “target” molecules characterized by scanning tunneling microscopy (STM), with the observed scattering interpreted by computational molecular dynamics. Selection of impact parameters showed that head-on collisions favored bimolecular reaction, whereas glancing collisions led only to momentum transfer. These collimated projectiles could be aimed at the wide variety of adsorbed targets identifiable by STM, with the selected impact parameter assisting in the identification of the collision geometry required for reaction.
Kinetic approach to superconductivity hidden behind a competing order Sci. Adv. (IF 11.511) Pub Date : 2018-10-01 Hiroshi Oike, Manabu Kamitani, Yoshinori Tokura, Fumitaka Kagawa
Exploration for superconductivity is one of the research frontiers in condensed matter physics. In strongly correlated electron systems, the emergence of superconductivity is often inhibited by the formation of a thermodynamically more stable magnetic/charge order. Thus, to develop the superconductivity as the thermodynamically most stable state, the free-energy balance between the superconductivity and the competing order has been controlled mainly by changing thermodynamic parameters, such as the physical/chemical pressure and carrier density. However, such a thermodynamic approach may not be the only way to materialize the superconductivity. We present a new kinetic approach to avoiding the competing order and thereby inducing persistent superconductivity. In the transition-metal dichalcogenide IrTe2 as an example, by using current pulse–based rapid cooling of up to ~107 K s−1, we successfully kinetically avoid a first-order phase transition to a competing charge order and uncover metastable superconductivity hidden behind. Because the electronic states at low temperatures depend on the history of thermal quenching, electric pulse applications enable nonvolatile and reversible switching of the metastable superconductivity, a unique advantage of the kinetic approach. Thus, our findings provide a new approach to developing and manipulating superconductivity beyond the framework of thermodynamics.
The benefits of grouping as a main driver of social evolution in a halictine bee Sci. Adv. (IF 11.511) Pub Date : 2018-10-01 Yusaku Ohkubo, Tatsuhiro Yamamoto, Natsuki Ogusu, Saori Watanabe, Yuuka Murakami, Norihiro Yagi, Eisuke Hasegawa
Over the past decade, the cause of sociality has been much debated. Inclusive fitness [br in Hamilton’s rule (br − c > 0)] has been criticized but is still useful in the organization of a framework by elucidating mechanisms through which br (benefit × relatedness) becomes larger than c (cost). The bee Lasioglossum baleicum is suitable for investigation of this issue because of the sympatric occurrence of both social and solitary nesting in its populations. We show that a large part (approximately 92%) of the inclusive fitness of a eusocial worker can be attributed to the benefits of grouping. A 1.5-fold relatedness asymmetry benefit in singly mated haplo-diploids explains a small part (approximately 8.5%) of the observed inclusive fitness. Sociality enables this species to conduct foraging and nest defense simultaneously, which is not the case in solitary nests. Our results indicate that this benefit of grouping is the main source of the increased inclusive fitness of eusocial workers.
Opening the window to the Southern Ocean: The role of jet dynamics Sci. Adv. (IF 11.511) Pub Date : 2018-10-01 Andreas Klocker
The surface waters of the Southern Ocean act as a control valve through which climatically important tracers such as heat, freshwater, and CO2 are transferred between the atmosphere and the ocean. The process that transports these tracers through the surface mixed layer into the ocean interior is known as ocean ventilation. Changes in ocean ventilation are thought to be important for both rapid transitions of the ocean’s global overturning circulation during the last deglaciation and the uptake and storage of excess heat and CO2 as a consequence of anthropogenic climate change. I show how the interaction between Southern Ocean jets, topographic features, and ocean stratification can lead to rapid changes in Southern Ocean ventilation as a function of wind stress. For increasing winds, this interaction leads from a state in which tracers are confined to the surface mixed layer to a state in which tracers fill the ocean interior. For sufficiently high winds, the jet dynamics abruptly change, allowing the tracer to ventilate a water mass known as Antarctic Intermediate Water in the mid-depth Southern Ocean. Abrupt changes in Antarctic Intermediate Water ventilation have played a major role in rapid climate transitions in Earth’s past, and combined with the results presented here, this would suggest that jet dynamics could play a prominent role in contributing to, or even triggering, rapid transitions of the global climate system.
Cross-talk among writers, readers, and erasers of m6A regulates cancer growth and progression Sci. Adv. (IF 11.511) Pub Date : 2018-10-01 Subbarayalu Panneerdoss, Vijay K. Eedunuri, Pooja Yadav, Santosh Timilsina, Subapriya Rajamanickam, Suryavathi Viswanadhapalli, Nourhan Abdelfattah, Benjamin C. Onyeagucha, Xiadong Cui, Zhao Lai, Tabrez A. Mohammad, Yogesh K. Gupta, Tim Hui-Ming Huang, Yufei Huang, Yidong Chen, Manjeet K. Rao
The importance of RNA methylation in biological processes is an emerging focus of investigation. We report that altering m6A levels by silencing either N6-adenosine methyltransferase METTL14 (methyltransferase-like 14) or demethylase ALKBH5 (ALKB homolog 5) inhibits cancer growth and invasion. METTL14/ALKBH5 mediate their protumorigenic function by regulating m6A levels of key epithelial-mesenchymal transition and angiogenesis-associated transcripts, including transforming growth factor–β signaling pathway genes. Using MeRIP-seq (methylated RNA immunoprecipitation sequencing) analysis and functional studies, we find that these target genes are particularly sensitive to changes in m6A modifications, as altered m6A status leads to aberrant expression of these genes, resulting in inappropriate cell cycle progression and evasion of apoptosis. Our results reveal that METTL14 and ALKBH5 determine the m6A status of target genes by controlling each other’s expression and by inhibiting m6A reader YTHDF3 (YTH N6-methyladenosine RNA binding protein 3), which blocks RNA demethylase activity. Furthermore, we show that ALKBH5/METTL14 constitute a positive feedback loop with RNA stability factor HuR to regulate the stability of target transcripts. We discover that hypoxia alters the level/activity of writers, erasers, and readers, leading to decreased m6A and consequently increased expression of target transcripts in cancer cells. This study unveils a previously undefined role for m6A in cancer and shows that the collaboration among writers-erasers-readers sets up the m6A threshold to ensure the stability of progrowth/proliferation-specific genes, and protumorigenic stimulus, such as hypoxia, perturbs that m6A threshold, leading to uncontrolled expression/activity of those genes, resulting in tumor growth, angiogenesis, and progression.
Impact of parallel fiber to Purkinje cell long-term depression is unmasked in absence of inhibitory input Sci. Adv. (IF 11.511) Pub Date : 2018-10-01 Henk-Jan Boele, Saša Peter, Michiel M. Ten Brinke, Lucas Verdonschot, Anna C. H. IJpelaar, Dimitris Rizopoulos, Zhenyu Gao, Sebastiaan K. E. Koekkoek, Chris I. De Zeeuw
Pavlovian eyeblink conditioning has been used extensively to study the neural mechanisms underlying associative and motor learning. During this simple learning task, memory formation takes place at Purkinje cells in defined areas of the cerebellar cortex, which acquire a strong temporary suppression of their activity during conditioning. Yet, it is unknown which neuronal plasticity mechanisms mediate this suppression. Two potential mechanisms include long-term depression of parallel fiber to Purkinje cell synapses and feed-forward inhibition by molecular layer interneurons. We show, using a triple transgenic approach, that only concurrent disruption of both these suppression mechanisms can severely impair conditioning, highlighting that both processes can compensate for each other’s deficits.
Assessing bimanual motor skills with optical neuroimaging Sci. Adv. (IF 11.511) Pub Date : 2018-10-01 Arun Nemani, Meryem A. Yücel, Uwe Kruger, Denise W. Gee, Clairice Cooper, Steven D. Schwaitzberg, Suvranu De, Xavier Intes
Measuring motor skill proficiency is critical for the certification of highly skilled individuals in numerous fields. However, conventional measures use subjective metrics that often cannot distinguish between expertise levels. We present an advanced optical neuroimaging methodology that can objectively and successfully classify subjects with different expertise levels associated with bimanual motor dexterity. The methodology was tested by assessing laparoscopic surgery skills within the framework of the fundamentals of a laparoscopic surgery program, which is a prerequisite for certification in general surgery. We demonstrate that optical-based metrics outperformed current metrics for surgical certification in classifying subjects with varying surgical expertise. Moreover, we report that optical neuroimaging allows for the successful classification of subjects during the acquisition of these skills.
Ancient genomes suggest the eastern Pontic-Caspian steppe as the source of western Iron Age nomads Sci. Adv. (IF 11.511) Pub Date : 2018-10-01 Maja Krzewińska, Gülşah Merve Kılınç, Anna Juras, Dilek Koptekin, Maciej Chyleński, Alexey G. Nikitin, Nikolai Shcherbakov, Iia Shuteleva, Tatiana Leonova, Liudmila Kraeva, Flarit A. Sungatov, Alfija N. Sultanova, Inna Potekhina, Sylwia Łukasik, Marta Krenz-Niedbała, Love Dalén, Vitaly Sinika, Mattias Jakobsson, Jan Storå, Anders Götherström
For millennia, the Pontic-Caspian steppe was a connector between the Eurasian steppe and Europe. In this scene, multidirectional and sequential movements of different populations may have occurred, including those of the Eurasian steppe nomads. We sequenced 35 genomes (low to medium coverage) of Bronze Age individuals (Srubnaya-Alakulskaya) and Iron Age nomads (Cimmerians, Scythians, and Sarmatians) that represent four distinct cultural entities corresponding to the chronological sequence of cultural complexes in the region. Our results suggest that, despite genetic links among these peoples, no group can be considered a direct ancestor of the subsequent group. The nomadic populations were heterogeneous and carried genetic affinities with populations from several other regions including the Far East and the southern Urals. We found evidence of a stable shared genetic signature, making the eastern Pontic-Caspian steppe a likely source of western nomadic groups.
Couples showing off: Audience promotes both male and female multimodal courtship display in a songbird Sci. Adv. (IF 11.511) Pub Date : 2018-10-01 Nao Ota, Manfred Gahr, Masayo Soma
Social environments can shape animal communication. Although mutual courtship displays are generally thought to function in private communication between a male and a female, we provide experimental evidence that they work in a broader social context than previously thought. We examined the audience effect on mutual courtship in blue-capped cordon-bleus, a socially monogamous songbird. This species is characterized by conspicuous courtship shared between sexes: Both sexes sing songs and sometimes add a unique dance display that looks like human tap dancing. We found that in both sexes, multimodal courtship displays (song accompanied by dance) were promoted in the presence of an audience, especially if it was the opposite sex. In contrast, unimodal displays (song without dance) were suppressed by audiences. Because birds directed the courtship dancing toward their partners (but not the audience), multimodal courtship displays are likely meant to advertise their current mating status to other cordon-bleus.
Fruit scent as an evolved signal to primate seed dispersal Sci. Adv. (IF 11.511) Pub Date : 2018-10-01 Omer Nevo, Diary Razafimandimby, Juan Antonio James Jeffrey, Stefan Schulz, Manfred Ayasse
The tremendous diversity of floral and fruit traits is, to a large extent, a set of adaptations that promote plant reproduction through animal pollinators and seed dispersers. Yet, it is still unknown whether fruit scent is a by-product of fruit maturation or an evolved communication channel with animal mutualists. We show that in species that specialize on seed dispersal by lemurs—an olfactorily oriented primate—fruits increase scent production and change their chemical composition significantly more than sympatric species whose seeds are largely dispersed by birds. We further show that lemurs use these shifts in fruit scent to identify ripe fruits. These results show that fruit scent is an evolved communication system that facilitates animal-plant mutualism.
Artelle et al. (2018) miss the science underlying North American wildlife management Sci. Adv. (IF 11.511) Pub Date : 2018-10-01 Jonathan R. Mawdsley, John F. Organ, Daniel J. Decker, Ann B. Forstchen, Ronald J. Regan, Shawn J. Riley, Mark S. Boyce, John E. McDonald, Chris Dwyer, Shane P. Mahoney
Artelle et al. (2018) conclude that “hallmarks of science” are largely missing from North American wildlife management based on a desk review of selected hunting management plans and related documents found through Internet searches and email requests to state and provincial wildlife agencies. We highlight three fundamental problems that compromise the validity of the conclusions posited: missing information to support selection of “hallmarks of science,” confusion about the roles and nature of science and management, and failure to engage effectively with the scientists and managers actively managing wildlife populations in North America.
Genomic and functional evidence reveals molecular insights into the origin of echolocation in whales Sci. Adv. (IF 11.511) Pub Date : 2018-10-01 Zhen Liu, Fei-Yan Qi, Dong-Ming Xu, Xin Zhou, Peng Shi
Echolocation allows toothed whales to adapt to underwater habitats where vision is ineffective. Because echolocation requires the ability to detect exceptional high-frequency sounds, fossils related to the auditory system can help to pinpoint the origin of echolocation in whales. However, because of conflicting interpretations of archaeocete fossils, when and how whales evolved the high-frequency hearing correlated with echolocation remain unclear. We address these questions at the molecular level by systematically investigating the convergent evolution of 7206 orthologs across 16 mammals and find that convergent genes between the last common ancestor of all whales (LCAW) and echolocating bats are not significantly enriched in functional categories related to hearing, and that convergence in hearing-related proteins between them is not stronger than that between nonecholocating mammalian lineages and echolocating bats. However, these results contrast with those of parallel analyses between the LCA of toothed whales (LCATW) and echolocating bats. Furthermore, we reconstruct the ancestral genes for the hearing protein prestin for the LCAW and LCATW; we show that the LCAW prestin exhibits the same function as that of nonecholocating mammals, but the LCATW prestin shows functional convergence with that of extant echolocating mammals. Mutagenesis shows that functional convergence of prestin is driven by convergent changes in the prestins S392A and L497M in the LCATW and echolocating bats. Our results provide genomic and functional evidence supporting the origin of high-frequency hearing in the LCAW, not the LCATW, and reveal molecular insights into the origin and evolutionary trajectories of echolocation in whales.
Evidence for a large exomoon orbiting Kepler-1625b Sci. Adv. (IF 11.511) Pub Date : 2018-10-01 Alex Teachey, David M. Kipping
Exomoons are the natural satellites of planets orbiting stars outside our solar system, of which there are currently no confirmed examples. We present new observations of a candidate exomoon associated with Kepler-1625b using the Hubble Space Telescope to validate or refute the moon’s presence. We find evidence in favor of the moon hypothesis, based on timing deviations and a flux decrement from the star consistent with a large transiting exomoon. Self-consistent photodynamical modeling suggests that the planet is likely several Jupiter masses, while the exomoon has a mass and radius similar to Neptune. Since our inference is dominated by a single but highly precise Hubble epoch, we advocate for future monitoring of the system to check model predictions and confirm repetition of the moon-like signal.
Working constructively toward an improved North American approach to wildlife management Sci. Adv. (IF 11.511) Pub Date : 2018-10-01 Kyle A. Artelle, John D. Reynolds, Adrian Treves, Jessica C. Walsh, Paul C. Paquet, Chris T. Darimont
Mawdsley et al. (2018) respond disapprovingly to our 2018 review of 667 wildlife management systems across Canada and the United States, which found that many of these systems lacked the scientific hallmarks of clear objectives, evidence, transparency, and independent review. Although we strongly agree with several of Mawdsley et al.’s points about the role of science in management, their response suggests confusion about three elements of our approach that we clarify herein: (i) the selection of hallmarks, (ii) the role of science in wildlife management, and (iii) our engagement with wildlife agencies. We contend that both critics and defenders of the current approach to wildlife management in Canada and the United States similarly desire rigorous management that achieves social and ecological benefits. Our original study—which used a clear approach to define hallmarks of science-based management, employed a reasonable set of indicator criteria to test for them, and was based on data available to the general public on whose behalf management is conducted—found evidence that the current approach falls short. However, it also provided a framework for addressing shortcomings moving forward. We suggest that advancing discussion on the operational role of science in management, including clarifying what “science-based management” actually means, could curtail practitioners and critics of the status quo talking over each other’s heads and encourage all parties to work constructively to improve the governance of wildlife at a continental scale.
Evidence of a low-temperature dynamical transition in concentrated microgels Sci. Adv. (IF 11.511) Pub Date : 2018-09-01 Marco Zanatta, Letizia Tavagnacco, Elena Buratti, Monica Bertoldo, Francesca Natali, Ester Chiessi, Andrea Orecchini, Emanuela Zaccarelli
A low-temperature dynamical transition has been reported in several proteins. We provide the first observation of a “protein-like” dynamical transition in nonbiological aqueous environments. To this aim, we exploit the popular colloidal system of poly-N-isopropylacrylamide (PNIPAM) microgels, extending their investigation to unprecedentedly high concentrations. Owing to the heterogeneous architecture of the microgels, water crystallization is avoided in concentrated samples, allowing us to monitor atomic dynamics at low temperatures. By elastic incoherent neutron scattering and molecular dynamics simulations, we find that a dynamical transition occurs at a temperature Td ~ 250 K, independently from PNIPAM mass fraction. However, the transition is smeared out on approaching dry conditions. The quantitative agreement between experiments and simulations provides evidence that the transition occurs simultaneously for PNIPAM and water dynamics. The similarity of these results with hydrated protein powders suggests that the dynamical transition is a generic feature in complex macromolecular systems, independently from their biological function.
Unprecedented high irreversibility line in the nontoxic cuprate superconductor (Cu,C)Ba2Ca3Cu4O11+δ Sci. Adv. (IF 11.511) Pub Date : 2018-09-01 Yue Zhang, Wenhao Liu, Xiyu Zhu, Haonan Zhao, Zheng Hu, Chengping He, Hai-Hu Wen
One of the key factors that limit the high-power applications for a type II superconductor is the irreversibility line Hirr(T), which reflects the very boundary of resistive dissipation in the phase diagram of magnetic field versus temperature. In cuprate family, the Y-, Bi-, Hg-, and Tl-based systems have superconducting transition temperatures exceeding the liquid nitrogen boiling temperature (~77 K). However, the toxic elements Hg and Tl in the latter two systems strongly constrain the applications. The best perspective so far is relying on the YBa2Cu3O7−δ (Tc ≈ 90 K) system, which is nontoxic and has a relatively high irreversibility magnetic field. We report the study of a nontoxic superconductor (Cu,C)Ba2Ca3Cu4O11+δ with Tc = 116 K. We found that the irreversibility magnetic field is extremely high, and it thus provides great potential for applications above the liquid nitrogen temperature.
Enhanced transport in transistor by tuning transition-metal oxide electronic states interfaced with diamond Sci. Adv. (IF 11.511) Pub Date : 2018-09-01 Zongyou Yin, Moshe Tordjman, Youngtack Lee, Alon Vardi, Rafi Kalish, Jesús A. del Alamo
High electron affinity transition-metal oxides (TMOs) have gained a central role in two-dimensional (2D) electronics by enabling unprecedented surface charge doping efficiency in numerous exotic 2D solid-state semiconductors. Among them, diamond-based 2D electronics are entering a new era by using TMOs as surface acceptors instead of previous molecular-like unstable acceptors. Similarly, surface-doped diamond with TMOs has recently yielded record sheet hole concentrations (2 × 1014 cm−2) and launched the quest for its implementation in microelectronic devices. Regrettably, field-effect transistor operation based on this surface doping has been so far disappointing due to fundamental material obstacles such as (i) carrier scattering induced by nonhomogeneous morphology of TMO surface acceptor layer, (ii) stoichiometry changes caused by typical transistor fabrication process, and (iii) carrier transport loss due to electronic band energy misalignment. This work proposes and demonstrates a general strategy that synergistically surmounts these three barriers by developing an atomic layer deposition of a hydrogenated MoO3 layer as a novel efficient surface charge acceptor for transistors. It shows high surface uniformity, enhanced immunity to harsh fabrication conditions, and benefits from tunable electronic gap states for improving carrier transfer at interfaces. These breakthroughs permit crucial integration of TMO surface doping into transistor fabrication flows and allow outperforming electronic devices to be reached.
An “ideal lignin” facilitates full biomass utilization Sci. Adv. (IF 11.511) Pub Date : 2018-09-01 Yanding Li, Li Shuai, Hoon Kim, Ali Hussain Motagamwala, Justin K. Mobley, Fengxia Yue, Yuki Tobimatsu, Daphna Havkin-Frenkel, Fang Chen, Richard A. Dixon, Jeremy S. Luterbacher, James A. Dumesic, John Ralph
Lignin, a major component of lignocellulosic biomass, is crucial to plant growth and development but is a major impediment to efficient biomass utilization in various processes. Valorizing lignin is increasingly realized as being essential. However, rapid condensation of lignin during acidic extraction leads to the formation of recalcitrant condensed units that, along with similar units and structural heterogeneity in native lignin, drastically limits product yield and selectivity. Catechyl lignin (C-lignin), which is essentially a benzodioxane homopolymer without condensed units, might represent an ideal lignin for valorization, as it circumvents these issues. We discovered that C-lignin is highly acid-resistant. Hydrogenolysis of C-lignin resulted in the cleavage of all benzodioxane structures to produce catechyl-type monomers in near-quantitative yield with a selectivity of 90% to a single monomer.
Multidimensional spectroscopy with attosecond extreme ultraviolet and shaped near-infrared pulses Sci. Adv. (IF 11.511) Pub Date : 2018-09-01 Hugo J. B. Marroux, Ashley P. Fidler, Daniel M. Neumark, Stephen R. Leone
Dynamics following excitation with attosecond extreme ultraviolet (XUV) pulses arise from enormous numbers of accessible excited states, complicating the retrieval of state-specific time evolutions. We develop attosecond XUV multidimensional spectroscopy here to separate interfering pathways on a near-infrared (NIR) energy axis, retrieving single state dynamics in argon atoms in a two-dimensional (2D) XUV-NIR spectrum. In this experiment, we measure four-wave mixing signal arising from the interaction of XUV attosecond pulses centered around 15 eV with two few-cycle NIR pulses. The 2D spectrum is created by measuring the emitted XUV signal field spectrum while applying narrowband amplitude and phase modulations to one of the NIR pulses. Application of such a technique to systems of high dimensionality will provide for the observation of state-resolved pure electronic dynamics, in direct analogy to phenomena unraveled by multidimensional spectroscopies at optical frequencies.
Evaluating biological activity of compounds by transcription factor activity profiling Sci. Adv. (IF 11.511) Pub Date : 2018-09-01 Alexander Medvedev, Matt Moeser, Liubov Medvedeva, Elena Martsen, Alexander Granick, Lydia Raines, Ming Zeng, Sergei Makarov, Keith A. Houck, Sergei S. Makarov
Assessing the biological activity of compounds is an essential objective of biomedical research. We show that one can infer the bioactivity of compounds by assessing the activity of transcription factors (TFs) that regulate gene expression. Using a multiplex reporter system, the FACTORIAL, we characterized cell response to a compound by a quantitative signature, the TF activity profile (TFAP). We found that perturbagens of biological pathways elicited distinct TFAP signatures in human cells. Unexpectedly, perturbagens of the same pathway all produced identical TFAPs, regardless of where or how they interfered. We found invariant TFAPs for mitochondrial, histone deacetylase, and ubiquitin/proteasome pathway inhibitors; cytoskeleton disruptors; and DNA-damaging agents. Using these invariant signatures permitted straightforward identification of compounds with specified bioactivities among uncharacterized chemicals. Furthermore, this approach allowed us to assess the multiple bioactivities of polypharmacological drugs. Thus, TF activity profiling affords straightforward assessment of the bioactivity of compounds through the identification of perturbed biological pathways.
Flagellar number governs bacterial spreading and transport efficiency Sci. Adv. (IF 11.511) Pub Date : 2018-09-01 Javad Najafi, Mohammad Reza Shaebani, Thomas John, Florian Altegoer, Gert Bange, Christian Wagner
Peritrichous bacteria synchronize and bundle their flagella to actively swim, while disruption of the bundle leads to a slow motility phase with a weak propulsion. It is still not known whether the number of flagella represents an evolutionary adaptation toward optimizing bacterial navigation. We study the swimming dynamics of differentially flagellated Bacillus subtilis strains in a quasi–two-dimensional system. We find that decreasing the number of flagella Nf reduces the average turning angle between two successive run phases and enhances the run time and the directional persistence of the run phase. As a result, having fewer flagella is beneficial for long-distance transport and fast spreading, while having a lot of flagella is advantageous for the processes that require a slower spreading, such as biofilm formation. We develop a two-state random walk model that incorporates spontaneous switchings between the states and yields exact analytical expressions for transport properties, in remarkable agreement with experiments. The results of numerical simulations based on our two-state model suggest that the efficiency of searching and exploring the environment is optimized at intermediate values of Nf. The optimal choice of Nf, for which the search time is minimized, decreases with increasing the size of the environment in which the bacteria swim.
A new fossil assemblage shows that large angiosperm trees grew in North America by the Turonian (Late Cretaceous) Sci. Adv. (IF 11.511) Pub Date : 2018-09-01 Nathan A. Jud, Michael D. D’Emic, Scott A. Williams, Josh C. Mathews, Katie M. Tremaine, Janok Bhattacharya
The diversification of flowering plants and marked turnover in vertebrate faunas during the mid-Cretaceous transformed terrestrial communities, but the transition is obscured by reduced terrestrial deposition attributable to high sea levels. We report a new fossil assemblage from multiple localities in the Upper Cretaceous Ferron Sandstone Member of the Mancos Shale Formation in Utah. The fossils date to the Turonian, a severely underrepresented interval in the terrestrial fossil record of North America. A large silicified log (maximum preserved diameter, 1.8 m; estimated height, ca. 50 m) is assigned to the genus Paraphyllanthoxylon; it is the largest known pre-Campanian angiosperm and the earliest documented occurrence of an angiosperm tree more than 1.0 m in diameter. Foliage and palynomorphs of ferns, conifers, and angiosperms confirm the presence of mixed forest or woodland vegetation. Previously known terrestrial vertebrate remains from the Ferron Sandstone Member include fish teeth, two short dinosaur trackways, and a pterosaur; we report the first turtle and crocodilian remains and an ornithopod sacrum. Previous studies indicate that angiosperm trees were present by the Cenomanian, but this discovery demonstrates that angiosperm trees approaching 2 m in diameter were part of the forest canopies across southern North America by the Turonian (~92 million years ago), nearly 15 million years earlier than previously thought.
Large regional shortwave forcing by anthropogenic methane informed by Jovian observations Sci. Adv. (IF 11.511) Pub Date : 2018-09-01 William D. Collins, Daniel R. Feldman, Chaincy Kuo, Newton H. Nguyen
Recently, it was recognized that widely used calculations of methane radiative forcing systematically underestimated its global value by 15% by omitting its shortwave effects. We show that shortwave forcing by methane can be accurately calculated despite considerable uncertainty and large gaps in its shortwave spectroscopy. We demonstrate that the forcing is insensitive, even when confronted with much more complete methane absorption spectra extending to violet light wavelengths derived from observations of methane-rich Jovian planets. We undertake the first spatially resolved global calculations of this forcing and find that it is dependent on bright surface features and clouds. Localized annual mean forcing from preindustrial to present-day methane increases approaches +0.25 W/m2, 10 times the global annualized shortwave forcing and 43% of the total direct CH4 forcing. Shortwave forcing by anthropogenic methane is sufficiently large and accurate to warrant its inclusion in historical analyses, projections, and mitigation strategies for climate change.
Evidence for precision grasping in Neandertal daily activities Sci. Adv. (IF 11.511) Pub Date : 2018-09-01 Fotios Alexandros Karakostis, Gerhard Hotz, Vangelis Tourloukis, Katerina Harvati
Neandertal manual activities, as previously reconstructed from their robust hand skeletons, are thought to involve systematic power grasping rather than precise hand movements. However, this interpretation is at odds with increasing archeological evidence for sophisticated cultural behavior. We reevaluate the manipulative behaviors of Neandertals and early modern humans using a historical reference sample with extensive genealogical and lifelong occupational documentation, in combination with a new and precise three-dimensional multivariate analysis of hand muscle attachments. Results show that Neandertal muscle marking patterns overlap exclusively with documented lifelong precision workers, reflecting systematic precision grasping consistent with the use of their associated cultural remains. Our findings challenge the established interpretation of Neandertal behavior and establish a solid link between biological and cultural remains in the fossil record.
Biomechanics of hover performance in Neotropical hummingbirds versus bats Sci. Adv. (IF 11.511) Pub Date : 2018-09-01 Rivers Ingersoll, Lukas Haizmann, David Lentink
Hummingbirds and nectar bats are the only vertebrates that are specialized for hovering in front of flowers to forage nectar. How their aerodynamic performance compares is, however, unclear. To hover, hummingbirds consistently generate about a quarter of the vertical aerodynamic force required to support their body weight during the upstroke. In contrast, generalist birds in slow hovering flight generate little upstroke weight support. We report that nectar bats also generate elevated weight support during the upstroke compared to generalist bats. Comparing 20 Neotropical species, we show how nectarivorous birds and bats converged on this ability by inverting their respective feathered and membrane wings more than species with other diets. However, while hummingbirds converged on an efficient horizontal wingbeat to mostly generate lift, bats rely on lift and drag during the downstroke to fully support their body weight. Furthermore, whereas the ability of nectar bats to aerodynamically support their body weight during the upstroke is elevated, it is much smaller than that of hummingbirds. Bats compensate by generating more aerodynamic weight support during their extended downstroke. Although, in principle, it requires more aerodynamic power to hover using this method, bats have adapted by evolving much larger wings for their body weight. Therefore, the net aerodynamic induced power required to hover is similar among hummingbirds and bats per unit body mass. This mechanistic insight into how feathered wings and membrane wings ultimately require similar aerodynamic power to hover may inform analogous design trade-offs in aerial robots.
Facile profiling of molecular heterogeneity by microfluidic digital melt Sci. Adv. (IF 11.511) Pub Date : 2018-09-01 Christine M. O’Keefe, Thomas R. Pisanic, Helena Zec, Michael J. Overman, James G. Herman, Tza-Huei Wang
This work presents a digital microfluidic platform called HYPER-Melt (high-density profiling and enumeration by melt) for highly parallelized copy-by-copy DNA molecular profiling. HYPER-Melt provides a facile means of detecting and assessing sequence variations of thousands of individual DNA molecules through digitization in a nanowell microchip array, allowing amplification and interrogation of individual template molecules by detecting HRM fluorescence changes due to sequence-dependent denaturation. As a model application, HYPER-Melt is used here for the detection and assessment of intermolecular heterogeneity of DNA methylation within the promoters of classical tumor suppressor genes. The capabilities of this platform are validated through serial dilutions of mixed epialleles, with demonstrated detection limits as low as 1 methylated variant in 2 million unmethylated templates (0.00005%) of a classic tumor suppressor gene, CDKN2A (p14ARF). The clinical potential of the platform is demonstrated using a digital assay for NDRG4, a tumor suppressor gene that is commonly methylated in colorectal cancer, in liquid biopsies of healthy and colorectal cancer patients. Overall, the platform provides the depth of information, simplicity of use, and single-molecule sensitivity necessary for rapid assessment of intermolecular variation contributing to genetic and epigenetic heterogeneity for challenging applications in embryogenesis, carcinogenesis, and rare biomarker detection.
Manta rays feed using ricochet separation, a novel nonclogging filtration mechanism Sci. Adv. (IF 11.511) Pub Date : 2018-09-01 Raj V. Divi, James A. Strother, E. W. Misty Paig-Tran
Solid-liquid filtration is a ubiquitous process found in industrial and biological systems. Although implementations vary widely, almost all filtration systems are based on a small set of fundamental separation mechanisms, including sieve, cross-flow, hydrosol, and cyclonic separation. Anatomical studies showed that manta rays have a highly specialized filter-feeding apparatus that does not resemble previously described filtration systems. We examined the fluid flow around the manta filter-feeding apparatus using a combination of physical modeling and computational fluid dynamics. Our results indicate that manta rays use a unique solid-fluid separation mechanism in which direct interception of particles with wing-like structures causes particles to “ricochet” away from the filter pores. This filtration mechanism separates particles smaller than the pore size, allows high flow rates, and resists clogging.
Molecular parallelism in fast-twitch muscle proteins in echolocating mammals Sci. Adv. (IF 11.511) Pub Date : 2018-09-01 Jun-Hoe Lee, Kevin M. Lewis, Timothy W. Moural, Bogdan Kirilenko, Barbara Borgonovo, Gisa Prange, Manfred Koessl, Stefan Huggenberger, ChulHee Kang, Michael Hiller
Detecting associations between genomic changes and phenotypic differences is fundamental to understanding how phenotypes evolved. By systematically screening for parallel amino acid substitutions, we detected known as well as novel cases (Strc, Tecta, and Cabp2) of parallelism between echolocating bats and toothed whales in proteins that could contribute to high-frequency hearing adaptations. Our screen also showed that echolocating mammals exhibit an unusually high number of parallel substitutions in fast-twitch muscle fiber proteins. Both echolocating bats and toothed whales produce an extremely rapid call rate when homing in on their prey, which was shown in bats to be powered by specialized superfast muscles. We show that these genes with parallel substitutions (Casq1, Atp2a1, Myh2, and Myl1) are expressed in the superfast sound-producing muscle of bats. Furthermore, we found that the calcium storage protein calsequestrin 1 of the little brown bat and the bottlenose dolphin functionally converged in its ability to form calcium-sequestering polymers at lower calcium concentrations, which may contribute to rapid calcium transients required for superfast muscle physiology. The proteins that our genomic screen detected could be involved in the convergent evolution of vocalization in echolocating mammals by potentially contributing to both rapid Ca2+ transients and increased shortening velocities in superfast muscles.
Niche partitioning of a pathogenic microbiome driven by chemical gradients Sci. Adv. (IF 11.511) Pub Date : 2018-09-01 Robert A. Quinn, William Comstock, Tianyu Zhang, James T. Morton, Ricardo da Silva, Alda Tran, Alexander Aksenov, Louis-Felix Nothias, Daniel Wangpraseurt, Alexey V. Melnik, Gail Ackermann, Douglas Conrad, Isaac Klapper, Rob Knight, Pieter C. Dorrestein
Environmental microbial communities are stratified by chemical gradients that shape the structure and function of these systems. Similar chemical gradients exist in the human body, but how they influence these microbial systems is more poorly understood. Understanding these effects can be particularly important for dysbiotic shifts in microbiome structure that are often associated with disease. We show that pH and oxygen strongly partition the microbial community from a diseased human lung into two mutually exclusive communities of pathogens and anaerobes. Antimicrobial treatment disrupted this chemical partitioning, causing complex death, survival, and resistance outcomes that were highly dependent on the individual microorganism and on community stratification. These effects were mathematically modeled, enabling a predictive understanding of this complex polymicrobial system. Harnessing the power of these chemical gradients could be a drug-free method of shaping microbial communities in the human body from undesirable dysbiotic states.
The CCT chaperonin is a novel regulator of Ca2+ signaling through modulation of Orai1 trafficking Sci. Adv. (IF 11.511) Pub Date : 2018-09-01 Rawad Hodeify, Manjula Nandakumar, Maryam Own, Raphael J. Courjaret, Johannes Graumann, Satanay Z. Hubrack, Khaled Machaca
Store-operated Ca2+ entry (SOCE) encodes a range of cellular responses downstream of Ca2+ influx through the SOCE channel Orai1. Orai1 recycles at the plasma membrane (PM), with ~40% of the total Orai1 pool residing at the PM at steady state. The mechanisms regulating Orai1 recycling remain poorly understood. We map the domains in Orai1 that are required for its trafficking to and recycling at the PM. We further identify, using biochemical and proteomic approaches, the CCT [chaperonin-containing TCP-1 (T-complex protein 1)] chaperonin complex as a novel regulator of Orai1 recycling by primarily regulating Orai1 endocytosis. We show that Orai1 interacts with CCT through its intracellular loop and that inhibition of CCT-Orai1 interaction increases Orai1 PM residence. This increased residence is functionally significant as it results in prolonged Ca2+ signaling, early formation of STIM1-Orai1 puncta, and more rapid activation of NFAT (nuclear factor of activated T cells) downstream of SOCE. Therefore, the CCT chaperonin is a novel regulator of Orai1 trafficking and, as such, a modulator of Ca2+ signaling and effector activation kinetics.
A unique role for DNA (hydroxy)methylation in epigenetic regulation of human inhibitory neurons Sci. Adv. (IF 11.511) Pub Date : 2018-09-01 Alexey Kozlenkov, Junhao Li, Pasha Apontes, Yasmin L. Hurd, William M. Byne, Eugene V. Koonin, Michael Wegner, Eran A. Mukamel, Stella Dracheva
Brain function depends on interaction of diverse cell types whose gene expression and identity are defined, in part, by epigenetic mechanisms. Neuronal DNA contains two major epigenetic modifications, methylcytosine (mC) and hydroxymethylcytosine (hmC), yet their cell type–specific landscapes and relationship with gene expression are poorly understood. We report high-resolution (h)mC analyses, together with transcriptome and histone modification profiling, in three major cell types in human prefrontal cortex: glutamatergic excitatory neurons, medial ganglionic eminence–derived γ-aminobutyric acid (GABA)ergic inhibitory neurons, and oligodendrocytes. We detected a unique association between hmC and gene expression in inhibitory neurons that differed significantly from the pattern in excitatory neurons and oligodendrocytes. We also found that risk loci associated with neuropsychiatric diseases were enriched near regions of reduced hmC in excitatory neurons and reduced mC in inhibitory neurons. Our findings indicate differential roles for mC and hmC in regulation of gene expression in different brain cell types, with implications for the etiology of human brain diseases.
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