bluuebunny/crossref_metadata_2025 huggingface dataset:
Real‐Options Water Supply Planning: Multistage Scenario Trees for Adaptive and Flexible Capacity Expansion Under Probabilistic Climate Change Uncertainty
Authors: Erfani Tohid , Pachos Kevis , Harou Julien J.
Published: June 2018

Planning water supply infrastructure includes identifying interventions that cost‐effectively secure an acceptably reliable water supply. Climate change is a source of uncertainty for water supply developments as its impact on source yields is uncertain. Adaptability to changing future conditions is increasingly viewed as a valuable design principle of strategic water planning. Because present decisions impact a system's ability to adapt to future needs, flexibility in activating, delaying, and replacing engineering projects should be considered in least‐cost water supply intervention scheduling. This is a principle of Real Options Analysis, which this paper applies to least‐cost capacity expansion scheduling via multistage stochastic mathematical programming. We apply the proposed model to a real‐world utility with many investment decision stages using a generalized scenario tree construction algorithm to efficiently approximate the probabilistic uncertainty. To evaluate the implementation of Real Options Analysis, the use of two metrics is proposed: the value of the stochastic solution and the expected value of perfect information that quantify the value of adopting adaptive and flexible plans, respectively. An application to London's water system demonstrates the generalized approach. The investment decisions results are a mixture of long‐term and contingency schemes that are optimally chosen considering different futures. The value of the stochastic solution shows that by considering uncertainty, adaptive investment decisions avoid £100 million net present value (NPV) cost, 15% of the total NPV. The expected value of perfect information demonstrates that optimal delay and early decisions have £50 million NPV, 6% of total NPV. Sensitivity of results to the characteristics of the scenario tree and uncertainty set is assessed.
Huge Spike in Quakes Badly Damages Kīlauea Observatory
Authors: Loomis Ilima
Published: June 2018

Meanwhile, some scientists say that the 35-year eruption from the Pu‘u Ō‘ō vent has ended and that the flows since 3 May are a new eruption. Others take issue with this view.
First demonstration of an all-solid-state optical cryocooler
Authors: Hehlen Markus P. , Meng Junwei , Albrecht Alexander R. , Lee Eric R. , Gragossian Aram , Love Steven P. , Hamilton Christopher E. , Epstein Richard I. , Sheik-Bahae Mansoor
Published: June 2018

Solid-state optical refrigeration uses anti-Stokes fluorescence to cool macroscopic objects to cryogenic temperatures without vibrations. Crystals such as Yb3+-doped YLiF4 (YLF:Yb) have previously been laser-cooled to 91 K. In this study, we show for the first time laser cooling of a payload connected to a cooling crystal. A YLF:Yb crystal was placed inside a Herriott cell and pumped with a 1020-nm laser (47 W) to cool a HgCdTe sensor that is part of a working Fourier Transform Infrared (FTIR) spectrometer to 135 K. This first demonstration of an all-solid-state optical cryocooler was enabled by careful control of the various desired and undesired heat flows. Fluorescence heating of the payload was minimized by using a single-kink YLF thermal link between the YLF:Yb cooling crystal and the copper coldfinger that held the HgCdTe sensor. The adhesive-free bond between YLF and YLF:Yb showed excellent thermal reliability. This laser-cooled assembly was then supported by silica aerogel cylinders inside a vacuum clamshell to minimize undesired conductive and radiative heat loads from the warm surroundings. Our structure can serve as a baseline for future optical cryocooler devices.
Networks of blood proteins in the neuroimmunology of schizophrenia
Authors: Jeffries Clark D. , Perkins Diana O. , Fournier Margot , Do Kim Q. , Cuenod Michel , Khadimallah Ines , Domenici Enrico , Addington Jean , Bearden Carrie E. , Cadenhead Kristin S. , Cannon Tyrone D. , Cornblatt Barbara A. , Mathalon Daniel H. , McGlashan Thomas H. , Seidman Larry J. , Tsuang Ming , Walker Elaine F. , Woods Scott W.
Published: June 2018

Levels of certain circulating cytokines and related immune system molecules are consistently altered in schizophrenia and related disorders. In addition to absolute analyte levels, we sought analytes in correlation networks that could be prognostic. We analyzed baseline blood plasma samples with a Luminex platform from 72 subjects meeting criteria for a psychosis clinical high-risk syndrome; 32 subjects converted to a diagnosis of psychotic disorder within two years while 40 other subjects did not. Another comparison group included 35 unaffected subjects. Assays of 141 analytes passed early quality control. We then used an unweighted co-expression network analysis to identify highly correlated modules in each group. Overall, there was a striking loss of network complexity going from unaffected subjects to nonconverters and thence to converters (applying standard, graph-theoretic metrics). Graph differences were largely driven by proteins regulating tissue remodeling (e.g. blood-brain barrier). In more detail, certain sets of antithetical proteins were highly correlated in unaffected subjects (e.g. SERPINE1 vs MMP9), as expected in homeostasis. However, for particular protein pairs this trend was reversed in converters (e.g. SERPINE1 vs TIMP1, being synthetical inhibitors of remodeling of extracellular matrix and vasculature). Thus, some correlation signals strongly predict impending conversion to a psychotic disorder and directly suggest pharmaceutical targets.
Reliance upon ancestral mutations is maintained in colorectal cancers that heterogeneously evolve during targeted therapies
Authors: Russo Mariangela , Lamba Simona , Lorenzato Annalisa , Sogari Alberto , Corti Giorgio , Rospo Giuseppe , Mussolin Benedetta , Montone Monica , Lazzari Luca , Arena Sabrina , Oddo Daniele , Linnebacher Michael , Sartore-Bianchi Andrea , Pietrantonio Filippo , Siena Salvatore , Di Nicolantonio Federica , Bardelli Alberto
Published: June 2018

Attempts at eradicating metastatic cancers with targeted therapies are limited by the emergence of resistant subclones bearing heterogeneous (epi)genetic changes. We used colorectal cancer (CRC) to test the hypothesis that interfering with an ancestral oncogenic event shared by all the malignant cells (such as WNT pathway alterations) could override heterogeneous mechanisms of acquired drug resistance. Here, we report that in CRC-resistant cell populations, phylogenetic analysis uncovers a complex subclonal architecture, indicating parallel evolution of multiple independent cellular lineages. Functional and pharmacological modulation of WNT signalling induces cell death in CRC preclinical models from patients that relapsed during the treatment, regardless of the drug type or resistance mechanisms. Concomitant blockade of WNT and MAPK signalling restrains the emergence of drug-resistant clones. Reliance upon the WNT–APC pathway is preserved throughout the branched genomic drift associated with emergence of treatment relapse, thus offering the possibility of a common therapeutic strategy to overcome secondary drug resistance.
Spatio-temporal relays control layer identity of direction-selective neuron subtypes in Drosophila
Authors: Apitz Holger , Salecker Iris
Published: June 2018

Visual motion detection in sighted animals is essential to guide behavioral actions ensuring their survival. In Drosophila, motion direction is first detected by T4/T5 neurons. Their axons innervate one of the four lobula plate layers. How T4/T5 neurons with layer-specific representation of motion-direction preferences are specified during development is unknown. We show that diffusible Wingless (Wg) between adjacent neuroepithelia induces its own expression to form secondary signaling centers. These activate Decapentaplegic (Dpp) signaling in adjacent lateral tertiary neuroepithelial domains dedicated to producing layer 3/4-specific T4/T5 neurons. T4/T5 neurons derived from the core domain devoid of Dpp signaling adopt the default layer 1/2 fate. Dpp signaling induces the expression of the T-box transcription factor Optomotor-blind (Omb), serving as a relay to postmitotic neurons. Omb-mediated repression of Dachshund transforms layer 1/2- into layer 3/4-specific neurons. Hence, spatio-temporal relay mechanisms, bridging the distances between neuroepithelial domains and their postmitotic progeny, implement T4/T5 neuron-subtype identity.
Oxidized phospholipids regulate amino acid metabolism through MTHFD2 to facilitate nucleotide release in endothelial cells
Authors: Hitzel Juliane , Lee Eunjee , Zhang Yi , Bibli Sofia Iris , Li Xiaogang , Zukunft Sven , Pflüger Beatrice , Hu Jiong , Schürmann Christoph , Vasconez Andrea Estefania , Oo James A. , Kratzer Adelheid , Kumar Sandeep , Rezende Flávia , Josipovic Ivana , Thomas Dominique , Giral Hector , Schreiber Yannick , Geisslinger Gerd , Fork Christian , Yang Xia , Sigala Fragiska , Romanoski Casey E. , Kroll Jens , Jo Hanjoong , Landmesser Ulf , Lusis Aldons J. , Namgaladze Dmitry , Fleming Ingrid , Leisegang Matthias S. , Zhu Jun , Brandes Ralf P.
Published: June 2018

Oxidized phospholipids (oxPAPC) induce endothelial dysfunction and atherosclerosis. Here we show that oxPAPC induce a gene network regulating serine-glycine metabolism with the mitochondrial methylenetetrahydrofolate dehydrogenase/cyclohydrolase (MTHFD2) as a causal regulator using integrative network modeling and Bayesian network analysis in human aortic endothelial cells. The cluster is activated in human plaque material and by atherogenic lipoproteins isolated from plasma of patients with coronary artery disease (CAD). Single nucleotide polymorphisms (SNPs) within the MTHFD2-controlled cluster associate with CAD. The MTHFD2-controlled cluster redirects metabolism to glycine synthesis to replenish purine nucleotides. Since endothelial cells secrete purines in response to oxPAPC, the MTHFD2-controlled response maintains endothelial ATP. Accordingly, MTHFD2-dependent glycine synthesis is a prerequisite for angiogenesis. Thus, we propose that endothelial cells undergo MTHFD2-mediated reprogramming toward serine-glycine and mitochondrial one-carbon metabolism to compensate for the loss of ATP in response to oxPAPC during atherosclerosis.
Computational design of high-performance ligand for enantioselective Markovnikov hydroboration of aliphatic terminal alkenes
Authors: Iwamoto Hiroaki , Imamoto Tsuneo , Ito Hajime
Published: June 2018

Finding optimal chiral ligands for transition-metal-catalyzed asymmetric reactions using trial-and-error methods is often time-consuming and costly, even if the details of the reaction mechanism are already known. Although modern computational analyses allow the prediction of the stereoselectivity, there are only very few examples for the attempted design of chiral ligands using a computational approach for the improvement of the stereoselectivity. Herein, we report a systematic method for the design of chiral ligands for the enantioselective Markovnikov hydroboration of aliphatic terminal alkenes based on a computational and experimental evaluation sequence. We developed a three-hindered-quadrant P-chirogenic bisphosphine ligand that was designed in accordance with the design guidelines derived from this method, which allowed the Markovnikov hydroboration to proceed with high enantioselectivity (up to 99% ee).
Thermally triggered polyrotaxane translational motion helps proton transfer
Authors: Ge Xiaolin , He Yubin , Liang Xian , Wu Liang , Zhu Yuan , Yang Zhengjin , Hu Min , Xu Tongwen
Published: June 2018

Synthetic polyelectrolytes, capable of fast transporting protons, represent a challenging target for membrane engineering in so many fields, for example, fuel cells, redox flow batteries, etc. Inspired by the fast advance in molecular machines, here we report a rotaxane based polymer entity assembled via host–guest interaction and prove that by exploiting the thermally triggered translational motion (although not in a controlled manner) of mechanically bonded rotaxane, exceptionally fast proton transfer can be fulfilled at an external thermal input. The relative motion of the sulfonated axle to the ring in rotaxane happens at ~60 °C in our cases and because of that a proton conductivity (indicating proton transfer rate) of 260.2 mS cm−1, which is much higher than that in the state-of-the-art Nafion, is obtained at a relatively low ion-exchange capacity (representing the amount of proton transfer groups) of 0.73 mmol g−1.
Author Correction: Ultrafast probes of electron–hole transitions between two atomic layers
Authors: Wen Xiewen , Chen Hailong , Wu Tianmin , Yu Zhihao , Yang Qirong , Deng Jingwen , Liu Zhengtang , Guo Xin , Guan Jianxin , Zhang Xiang , Gong Yongji , Yuan Jiangtan , Zhang Zhuhua , Yi Chongyue , Guo Xuefeng , Ajayan Pulickel M. , Zhuang Wei , Liu Zhirong , Lou Jun , Zheng Junrong
Published: June 2018

The original version of this Article omitted an affiliation of Xiewen Wen: ‘College of Chemistry and Molecular Engineering, Beijing National Laboratory for Molecular Sciences, Peking University, Beijing 100871, China’. This has been corrected in both the PDF and HTML versions of the Article.
Publisher Correction: Solvent-assisted programming of flat polymer sheets into reconfigurable and self-healing 3D structures
Authors: Yang Yang , Terentjev Eugene M. , Wei Yen , Ji Yan
Published: June 2018

The original version of this Article omitted the Received and Accepted dates; they should have been 21st January 2018 and 12th April 2018, respectively. This has been corrected in the PDF and HTML versions of the Article.
Large-scale variation in density of an aquatic ecosystem indicator species
Authors: Sutherland Chris , Fuller Angela K. , Royle J. Andrew , Hare Matthew P. , Madden Sean
Published: June 2018

Monitoring indicator species is a pragmatic approach to natural resource assessments, especially when the link between the indicator species and ecosystem state is well justified. However, conducting ecosystem assessments over representative spatial scales that are insensitive to local heterogeneity is challenging. We examine the link between polychlorinated biphenyl (PCB) contamination and population density of an aquatic habitat specialist over a large spatial scale using non-invasive genetic spatial capture-recapture. Using American mink (Neovison vison), a predatory mammal and an indicator of aquatic ecosystems, we compared estimates of density in two major river systems, one with extremely high levels of PCB contamination (Hudson River), and a hydrologically independent river with lower PCB levels (Mohawk River). Our work supports the hypothesis that mink densities are substantially (1.64–1.67 times) lower in the contaminated river system. We demonstrate the value of coupling the indicator species concept with well-conceived and spatially representative monitoring protocols. PCBs have demonstrable detrimental effects on aquatic ecosystems, including mink, and these effects are likely to be profound and long-lasting, manifesting as population-level impacts. Through integrating non-invasive data collection, genetic analysis, and spatial capture-recapture methods, we present a monitoring framework for generating robust density estimates across large spatial scales.
Europe-wide reassessment of Dictyocoela (Microsporidia) infecting native and invasive amphipods (Crustacea): molecular versus ultrastructural traits
Authors: Bacela-Spychalska Karolina , Wróblewski Piotr , Mamos Tomasz , Grabowski Michał , Rigaud Thierry , Wattier Remi , Rewicz Tomasz , Konopacka Alicja , Ovcharenko Mykola
Published: June 2018

Microsporidia are common parasites infecting animals and protists. They are specifically common pathogens of amphipods (Crustacea, Malacostraca), withDictyocoelaspp. being particularly frequent and highly prevalent, exhibiting a range of phenotypic and ecological effects. Until now, seven species ofDictyocoelawere defined, predominantly based on the genetic distance. However, neither the taxonomic status of this provisionally erected genus (based on eight novel sequences and one micrograph of the spore), nor its internal phylogenetic relationships have been clearly revealed. The formal description of the genus and of most of the putative species are still lacking. Here we aimed to fill this gap and performed both ultrastructural and molecular studies (based on SSU, ITS and partial LSU) using different species delimitation methods. As a consensus of these results and following conservative data interpretation, we propose to distinguish five species infecting gammarid hosts, and to keep the names introduced by the authors of the type sequences:Dictyocoela duebenum,D. muelleri,D. berillonumandD. roeselum. We provide full descriptions of these species. Moreover, thanks to our extensive sampling, we extend the known host and geographic range of these Microsporidia.
Publisher Correction: Upregulation of prefrontal metabotropic glutamate receptor 5 mediates neuropathic pain and negative mood symptoms after spinal nerve injury in rats
Authors: Chung Geehoon , Kim Chae Young , Yun Yeong-Chan , Yoon Sang Ho , Kim Myoung-Hwan , Kim Yu Kyeong , Kim Sang Jeong
Published: June 2018

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
The crystal structure of monoacylglycerol lipase from M. tuberculosis reveals the basis for specific inhibition
Authors: Aschauer Philipp , Zimmermann Robert , Breinbauer Rolf , Pavkov-Keller Tea , Oberer Monika
Published: June 2018

Monoacylglycerol lipases (MGLs) are enzymes that hydrolyze monoacylglycerol into a free fatty acid and glycerol. Fatty acids can be used for triacylglycerol synthesis, as energy source, as building blocks for energy storage, and as precursor for membrane phospholipids. In Mycobacterium tuberculosis, fatty acids also serve as precursor for polyketide lipids like mycolic acids, major components of the cellular envelope associated to resistance for drug. We present the crystal structure of the MGL Rv0183 from Mycobacterium tuberculosis (mtbMGL) in open conformation. The structure reveals remarkable similarities with MGL from humans (hMGL) in both, the cap region and the α/β core. Nevertheless, mtbMGL could not be inhibited with JZL-184, a known inhibitor of hMGL. Docking studies provide an explanation why the activity of mtbMGL was not affected by the inhibitor. Our findings suggest that specific inhibition of mtbMGL from Mycobacterium tuberculosis, one of the oldest recognized pathogens, is possible without influencing hMGL.
Comprehensive analysis of single molecule sequencing-derived complete genome and whole transcriptome of Hyposidra talaca nuclear polyhedrosis virus
Authors: Nguyen Thong T. , Suryamohan Kushal , Kuriakose Boney , Janakiraman Vasantharajan , Reichelt Mike , Chaudhuri Subhra , Guillory Joseph , Divakaran Neethu , Rabins P. E. , Goel Ridhi , Deka Bhabesh , Sarkar Suman , Ekka Preety , Tsai Yu-Chih , Vargas Derek , Santhosh Sam , Mohan Sangeetha , Chin Chen-Shan , Korlach Jonas , Thomas George , Babu Azariah , Seshagiri Somasekar
Published: June 2018

We sequenced the Hyposidra talaca NPV (HytaNPV) double stranded circular DNA genome using PacBio single molecule sequencing technology. We found that the HytaNPV genome is 139,089 bp long with a GC content of 39.6%. It encodes 141 open reading frames (ORFs) including the 37 baculovirus core genes, 25 genes conserved among lepidopteran baculoviruses, 72 genes known in baculovirus, and 7 genes unique to the HytaNPV genome. It is a group II alphabaculovirus that codes for the F protein and lacks the gp64 gene found in group I alphabaculovirus viruses. Using RNA-seq, we confirmed the expression of the ORFs identified in the HytaNPV genome. Phylogenetic analysis showed HytaNPV to be closest to BusuNPV, SujuNPV and EcobNPV that infect other tea pests, Buzura suppressaria, Sucra jujuba, and Ectropis oblique, respectively. We identified repeat elements and a conserved non-coding baculovirus element in the genome. Analysis of the putative promoter sequences identified motif consistent with the temporal expression of the genes observed in the RNA-seq data.
NCAM2 Fibronectin type-III domains form a rigid structure that binds and activates the Fibroblast Growth Factor Receptor
Authors: Rasmussen Kim Krighaar , Falkesgaard Maria Hansen , Winther Malene , Roed Nikolaj Kulahin , Quistgaard Christine Louise , Teisen Marie Nygaard , Edslev Sofie Marie , Petersen David Leander , Aljubouri Ali , Christensen Claus , Thulstrup Peter Waaben , Lo Leggio Leila , Teilum Kaare , Walmod Peter Schledermann
Published: June 2018

NCAM1 and NCAM2 have ectodomains consisting of 5 Ig domains followed by 2 membrane-proximal FnIII domains. In this study we investigate and compare the structures and functions of these FnIII domains. The NCAM1 and -2 FnIII2 domains both contain a Walker A motif. In NCAM1 binding of ATP to this motif interferes with NCAM1 binding to FGFR. We obtained a structural model of the NCAM2 FnIII2 domain by NMR spectroscopy, and by titration with an ATP analogue we show that the NCAM2 Walker A motif does not bind ATP. Small angle X-ray scattering (SAXS) data revealed that the NCAM2 FnIII1-2 double domain exhibits a very low degree of flexibility. Moreover, recombinant NCAM2 FnIII domains bind FGFRin vitro, and the FnIII1-2 double domain induces neurite outgrowth in a concentration-dependent manner through activation of FGFR. Several synthetic NCAM1-derived peptides induce neurite outgrowthviaFGFR. Only 2 of 5 peptides derived from similar regions in NCAM2 induce neurite outgrowth, but the most potent of these peptides stimulates neurite outgrowth through FGFR-dependent activation of the Ras-MAPK pathway. These results reveal that the NCAM2 FnIII domains form a rigid structure that binds and activates FGFR in a manner related to, but different from NCAM1.
Phenotypic Switching Can Speed up Microbial Evolution
Authors: Tadrowski Andrew C. , Evans Martin R. , Waclaw Bartlomiej
Published: June 2018

Stochastic phenotype switching has been suggested to play a beneficial role in microbial populations by leading to the division of labour among cells, or ensuring that at least some of the population survives an unexpected change in environmental conditions. Here we use a computational model to investigate an alternative possible function of stochastic phenotype switching: as a way to adapt more quickly even in a static environment. We show that when a genetic mutation causes a population to become less fit, switching to an alternative phenotype with higher fitness (growth rate) may give the population enough time to develop compensatory mutations that increase the fitness again. The possibility of switching phenotypes can reduce the time to adaptation by orders of magnitude if the “fitness valley” caused by the deleterious mutation is deep enough. Our work has important implications for the emergence of antibiotic-resistant bacteria. In line with recent experimental findings, we hypothesise that switching to a slower growing — but less sensitive — phenotype helps bacteria to develop resistance by providing alternative, faster evolutionary routes to resistance.
E-I balance emerges naturally from continuous Hebbian learning in autonomous neural networks
Authors: Trapp Philip , Echeveste Rodrigo , Gros Claudius
Published: June 2018

Spontaneous brain activity is characterized in part by a balanced asynchronous chaotic state. Cortical recordings show that excitatory (E) and inhibitory (I) drivings in the E-I balanced state are substantially larger than the overall input. We show that such a state arises naturally in fully adapting networks which are deterministic, autonomously active and not subject to stochastic external or internal drivings. Temporary imbalances between excitatory and inhibitory inputs lead to large but short-lived activity bursts that stabilize irregular dynamics. We simulate autonomous networks of rate-encoding neurons for which all synaptic weights are plastic and subject to a Hebbian plasticity rule, the flux rule, that can be derived from the stationarity principle of statistical learning. Moreover, the average firing rate is regulated individually via a standard homeostatic adaption of the bias of each neuron’s input-output non-linear function. Additionally, networks with and without short-term plasticity are considered. E-I balance may arise only when the mean excitatory and inhibitory weights are themselves balanced, modulo the overall activity level. We show that synaptic weight balance, which has been considered hitherto as given, naturally arises in autonomous neural networks when the here considered self-limiting Hebbian synaptic plasticity rule is continuously active.
Human trophoblast stem cell self-renewal and differentiation: Role of decorin
Authors: Nandi Pinki , Lim Hyobin , Torres-Garcia Eloy Jose , Lala Peeyush K.
Published: June 2018

The origin and regulation of stem cells sustaining trophoblast renewal in the human placenta remain unclear. Decorin, a leucine-rich proteoglycan restrains trophoblast proliferation, migration/invasiveness and endovascular differentiation, and local decorin overproduction is associated with preeclampsia (PE). Here, we tested the role of decorin in human trophoblast stem cell self-renewal and differentiation, using two models: an immortalized first trimester trophoblast cell line HTR-8/SVneo (HTR) and freshly isolated primary trophoblast (p-trophoblast) from early first trimester (6–9 weeks) placentas. Self-renewal capacity was measured by spheroid forming ability of single cells on ultra-low attachment plates for multiple generations. Markers of embryonic stem (ES) cells, trophoblast stem (TS) cells and trophoblast were used to identify stem cell hierarchy. Differentiation markers for syncytial and extravillous (EVT) pathways were employed to identify differentiated cells. Bewo cells were additionally used to explore DCN effects on syncytialization. Results reveal that the incidence of spheroid forming stem-like cells was 13–15% in HTR and 0.1–0.4%, in early first trimester p-trophoblast, including a stem cell hierarchy of two populations of ES and TS-like cells. DCN restrained ES cell self-renewal, promoted ES to TS transition and maintenance of TS cell stem-ness, but inhibited TS cell differentiation into both syncytial and EVT pathways.
Dual Therapy with Liraglutide and Ghrelin Promotes Brain and Peripheral Energy Metabolism in the R6/2 Mouse Model of Huntington’s Disease
Authors: Duarte Ana I. , Sjögren Marie , Santos Maria S. , Oliveira Catarina R. , Moreira Paula I. , Björkqvist Maria
Published: June 2018

Neuronal loss alongside altered energy metabolism, are key features of Huntington’s disease (HD) pathology. The orexigenic gut-peptide hormone ghrelin is known to stimulate appetite and affect whole body energy metabolism. Liraglutide is an efficient anti-type 2 diabetes incretin drug, with neuroprotective effects alongside anorectic properties. Combining liraglutide with the orexigenic peptide ghrelin may potentially promote brain/cognitive function in HD. The R6/2 mouse model of HD exhibits progressive central pathology, weight loss, deranged glucose metabolism, skeletal muscle atrophy and altered body composition. In this study, we targeted energy metabolism in R6/2 mice using a co-administration of liraglutide and ghrelin. We investigated their effect on brain cortical hormone-mediated intracellular signalling pathways, metabolic and apoptotic markers, and the impact on motor function in HD. We here demonstrate that liraglutide, alone or together with ghrelin (subcutaneous daily injections of 150 µg/kg (ghrelin) and 0.2 mg/kg (liraglutide), for 2 weeks), normalized glucose homeostatic features in the R6/2 mouse, without substantially affecting body weight or body composition. Liraglutide alone decreased brain cortical active GLP-1 and IGF-1 levels in R6/2 mice, alongside higher ADP levels. Liraglutide plus ghrelin decreased brain insulin, lactate, AMP and cholesterol levels in R6/2 mice. Taken together, our findings encourage further studies targeting energy metabolism in HD.
Genome-wide association study in Japanese females identifies fifteen novel skin-related trait associations
Authors: Endo Chihiro , Johnson Todd A. , Morino Ryoko , Nakazono Kazuyuki , Kamitsuji Shigeo , Akita Masanori , Kawajiri Maiko , Yamasaki Tatsuya , Kami Azusa , Hoshi Yuria , Tada Asami , Ishikawa Kenichi , Hine Maaya , Kobayashi Miki , Kurume Nami , Tsunemi Yuichiro , Kamatani Naoyuki , Kawashima Makoto
Published: June 2018

Skin trait variation impacts quality-of-life, especially for females from the viewpoint of beauty. To investigate genetic variation related to these traits, we conducted a GWAS of various skin phenotypes in 11,311 Japanese women and identified associations for age-spots, freckles, double eyelids, straight/curly hair, eyebrow thickness, hairiness, and sweating. In silico annotation with RoadMap Epigenomics epigenetic state maps and colocalization analysis of GWAS and GTEx Project eQTL signals provided information about tissue specificity, candidate causal variants, and functional target genes. Novel signals for skin-spot traits neighboured AKAP1/MSI2 (rs17833789; P = 2.2 × 10−9), BNC2 (rs10810635; P = 2.1 × 10−22), HSPA12A (rs12259842; P = 7.1 × 10−11), PPARGC1B (rs251468; P = 1.3 × 10−21), and RAB11FIP2 (rs10444039; P = 5.6 × 10−21). HSPA12A SNPs were the only protein-coding gene eQTLs identified across skin-spot loci. Double edged eyelid analysis identified that a signal around EMX2 (rs12570134; P = 8.2 × 10−15) was also associated with expression of EMX2 and the antisense-RNA gene EMX2OS in brain putamen basal ganglia tissue. A known hair morphology signal in EDAR was associated with both eyebrow thickness (rs3827760; P = 1.7 × 10−9) and straight/curly hair (rs260643; P = 1.6 × 10−103). Excessive hairiness signals’ top SNPs were also eQTLs for TBX15 (rs984225; P = 1.6 × 10−8), BCL2 (rs7226979; P = 7.3 × 10−11), and GCC2 and LIMS1 (rs6542772; P = 2.2 × 10−9). For excessive sweating, top variants in two signals in chr2:28.82-29.05 Mb (rs56089836; P = 1.7 × 10−11) were eQTLs for either PPP1CB or PLB1, while a top chr16:48.26–48.45 Mb locus SNP was a known ABCC11 missense variant (rs6500380; P = 6.8 × 10−10). In total, we identified twelve loci containing sixteen association signals, of which fifteen were novel. These findings will help dermatologic researchers better understand the genetic underpinnings of skin-related phenotypic variation in human populations.
A platform of BRET-FRET hybrid biosensors for optogenetics, chemical screening, and in vivo imaging
Authors: Komatsu Naoki , Terai Kenta , Imanishi Ayako , Kamioka Yuji , Sumiyama Kenta , Jin Takashi , Okada Yasushi , Nagai Takeharu , Matsuda Michiyuki
Published: June 2018

Genetically encoded biosensors based on the principle of Förster resonance energy transfer comprise two major classes: biosensors based on fluorescence resonance energy transfer (FRET) and those based on bioluminescence energy transfer (BRET). The FRET biosensors visualize signaling-molecule activity in cells or tissues with high resolution. Meanwhile, due to the low background signal, the BRET biosensors are primarily used in drug screening. Here, we report a protocol to transform intramolecular FRET biosensors to BRET-FRET hybrid biosensors called hyBRET biosensors. The hyBRET biosensors retain all properties of the prototype FRET biosensors and also work as BRET biosensors with dynamic ranges comparable to the prototype FRET biosensors. The hyBRET biosensors are compatible with optogenetics, luminescence microplate reader assays, and non-invasive whole-body imaging of xenograft and transgenic mice. This simple protocol will expand the use of FRET biosensors and enable visualization of the multiscale dynamics of cell signaling in live animals.
Metabolic Patterning on a Chip: Towards in vitro Liver Zonation of Primary Rat and Human Hepatocytes
Authors: Kang Young Bok , Eo Jinsu , Mert Safak , Yarmush Martin L. , Usta O. Berk
Published: June 2018

An important number of healthy and diseased tissues shows spatial variations in their metabolic capacities across the tissue. The liver is a prime example of such heterogeneity where the gradual changes in various metabolic activities across the liver sinusoid is termed as “zonation” of the liver. Here, we introduce the Metabolic Patterning on a Chip (MPOC) platform capable of dynamically creating metabolic patterns across the length of a microchamber of liver tissue via actively enforced gradients of various metabolic modulators such as hormones and inducers. Using this platform, we were able to create continuous liver tissues of both rat and human origin with gradually changing metabolic activities. The gradients we have created in nitrogen, carbohydrate and xenobiotic metabolisms recapitulated an in vivo like zonation and zonal toxic response. Beyond its application in recapitulation of liver zonation in vitro as we demonstrate here, the MPOC platform can be used and expanded for a variety of purposes including better understanding of heterogeneity in many different tissues during developmental and adult stages.
A System of Cytokines Encapsulated in ExtraCellular Vesicles
Authors: Fitzgerald Wendy , Freeman Michael L. , Lederman Michael M. , Vasilieva Elena , Romero Roberto , Margolis Leonid
Published: June 2018

Cytokines are soluble factors that mediate cell–cell communications in multicellular organisms. Recently, another system of cell–cell communication was discovered, which is mediated by extracellular vesicles (EVs). Here, we demonstrate that these two systems are not strictly separated, as many cytokines in vitro, ex vivo, and in vivo are released in EV-encapsulated forms and are capable of eliciting biological effects upon contact with sensitive cells. Association with EVs is not necessarily a property of a particular cytokine but rather of a biological system and can be changed upon system activation. EV-encapsulated cytokines were not detected by standard cytokine assays. Deciphering the regulatory mechanisms of EV-encapsulation will lead to a better understanding of cell–cell communications in health and disease.
Printed 5-V organic operational amplifiers for various signal processing
Authors: Matsui Hiroyuki , Hayasaka Kazuma , Takeda Yasunori , Shiwaku Rei , Kwon Jimin , Tokito Shizuo
Published: June 2018

The important concept of printable functional materials is about to cause a paradigm shift that we will be able to fabricate electronic devices by printing methods in air at room temperature. One of the promising applications of the printed electronics is a disposable electronic patch sensing system which can monitor the health conditions without any restraint. Operational amplifiers (OPAs) are an essential component for such sensing system, since an OPA enables a wide variety of signal processing. Here we demonstrate printed OPAs based on complementary organic semiconductor technology. They can be operated with a standard safe power source of 5 V with a minimal power consumption of 150 nW, and used as amplifiers, a variety of mathematical operators, signal converters, and oscillators. The printed micropower organic OPAs with the low voltage operation and the high versatility will open up the disposable electronic patch sensing system in near future.
Suppression of mitochondrial oxygen metabolism mediated by the transcription factor HIF-1 alleviates propofol-induced cell toxicity
Authors: Sumi Chisato , Okamoto Akihisa , Tanaka Hiromasa , Kusunoki Munenori , Shoji Tomohiro , Uba Takeo , Adachi Takehiko , Iwai Teppei , Nishi Kenichiro , Harada Hiroshi , Bono Hidemasa , Matsuo Yoshiyuki , Hirota Kiichi
Published: June 2018

A line of studies strongly suggest that the intravenous anesthetic, propofol, suppresses mitochondrial oxygen metabolism. It is also indicated that propofol induces the cell death in a reactive oxygen species (ROS)-dependent manner. Because hypoxia-inducible factor 1 (HIF-1) is a transcription factor which is involved in cellular metabolic reprogramming by modulating gene expressions of enzymes including glycolysis pathway and oxygen utilization of mitochondria, we examined the functional role of HIF-1 activity in propofol-induced cell death. The role of HIF-1 activity on oxygen and energy metabolisms and propofol-induced cell death and caspase activity was examined in renal cell-derived RCC4 cells: RCC4-EV cells which lack von Hippel-Lindau protein (VHL) protein expression and RCC4-VHL cells, which express exogenous VHL, and in neuronal SH-SY5Y cells. It was demonstrated that HIF-1 is involved in suppressing oxygen consumption and facilitating glycolysis in cells and that the resistance to propofol-induced cell death was established in a HIF-1 activation-dependent manner. It was also demonstrated that HIF-1 activation by treatment with HIFα-hydroxylase inhibitors such as n-propyl gallate and dimethyloxaloylglycine, alleviated the toxic effects of propofol. Thus, the resistance to propofol toxicity was conferred by HIF-1 activation by not only genetic deletion of VHL but also exposure to HIFα-hydroxylase inhibitors.
The Antiviral Drug Arbidol Inhibits Zika Virus
Authors: Fink Susan L. , Vojtech Lucia , Wagoner Jessica , Slivinski Natalie S. J. , Jackson Konner J. , Wang Ruofan , Khadka Sudip , Luthra Priya , Basler Christopher F. , Polyak Stephen J.
Published: June 2018

There are many emerging and re-emerging globally prevalent viruses for which there are no licensed vaccines or antiviral medicines. Arbidol (ARB, umifenovir), used clinically for decades in several countries as an anti-influenza virus drug, inhibits many other viruses. In the current study, we show that ARB inhibits six different isolates of Zika virus (ZIKV), including African and Asian lineage viruses in multiple cell lines and primary human vaginal and cervical epithelial cells. ARB protects against ZIKV-induced cytopathic effects. Time of addition studies indicate that ARB is most effective at suppressing ZIKV when added to cells prior to infection. Moreover, ARB inhibits pseudoviruses expressing the ZIKV Envelope glycoprotein. Thus, ARB, a broadly acting anti-viral agent with a well-established safety profile, inhibits ZIKV, likely by blocking viral entry.
Toward a translational molecular ratchet: face-selective translation coincident with deuteration in a pseudo-rotaxane
Authors: Hashidzume Akihito , Kuse Akihiro , Oshikiri Tomoya , Adachi Seiji , Okumura Mitsutaka , Yamaguchi Hiroyasu , Harada Akira
Published: June 2018

In the molecular world, molecular ratchets can realize the unidirectional movement in molecular machines. However, construction of artificial molecular ratchets has been still a great challenge. In this study, we investigate the formation of pseudo-rotaxane of a newly designed two-station axis molecule with α-cyclodextrin (α-CD) and the deuteration of acidic protons in the axis in D2O by 1H NMR at varying temperatures. Using the NMR data, we roughly estimate apparent rate constants for association, dissociation, and translation of α-CD during the pseudo-rotaxane formation based on a simplified kinetic model. These rate constants are indicative of face-selective and ratchet-like translation of α-CD on the axis because of the 2-methylpyridinium residues in the axis. We also evaluate apparent first-order rate constants for the deuteration. Comparison of these rate constants indicates that the face-selective translation of α-CD somehow couples with the deuteration. On the basis of this study, it is concluded that a translational molecular ratchet can be constructed using a large energy gradient with appropriate energy barriers and an enthalpically-driven coupled reaction.
Prion-like Domains in Eukaryotic Viruses
Authors: Tetz George , Tetz Victor
Published: June 2018

Prions are proteins that can self-propagate, leading to the misfolding of proteins. In addition to the previously demonstrated pathogenic roles of prions during the development of different mammalian diseases, including neurodegenerative diseases, they have recently been shown to represent an important functional component in many prokaryotic and eukaryotic organisms and bacteriophages, confirming the previously unexplored important regulatory and functional roles. However, an in-depth analysis of these domains in eukaryotic viruses has not been performed. Here, we examined the presence of prion-like proteins in eukaryotic viruses that play a primary role in different ecosystems and that are associated with emerging diseases in humans. We identified relevant functional associations in different viral processes and regularities in their presence at different taxonomic levels. Using the prion-like amino-acid composition computational algorithm, we detected 2679 unique putative prion-like domains within 2,742,160 publicly available viral protein sequences. Our findings indicate that viral prion-like proteins can be found in different viruses of insects, plants, mammals, and humans. The analysis performed here demonstrated common patterns in the distribution of prion-like domains across viral orders and families, and revealed probable functional associations with different steps of viral replication and interaction with host cells. These data allow the identification of the viral prion-like proteins as potential novel regulators of viral infections.
A Versatile Safeguard for Chimeric Antigen Receptor T-Cell Immunotherapies
Authors: Valton Julien , Guyot Valerie , Boldajipour Bijan , Sommer Cesar , Pertel Thomas , Juillerat Alexandre , Duclert Aymeric , Sasu Barbra Johnson , Duchateau Philippe , Poirot Laurent
Published: June 2018

CAR T-cell therapies hold great promise for treating a range of malignancies but are however challenged by the complexity of their production and by the adverse events related to their activity. Here we report the development of the CubiCAR, a tri-functional CAR architecture that enables CAR T-cell detection, purification and on-demand depletion by the FDA-approved antibody Rituximab. This novel architecture has the potential to streamline the manufacturing of CAR T-cells, allow their tracking and improve their overall safety.
Universal response in the RKO colon cancer cell line to distinct antimitotic therapies
Authors: Lorz Alexander , Botesteanu Dana-Adriana , Levy Doron
Published: June 2018

Both classic and newer antimitotics commonly induce a prolonged mitotic arrest in cell culture. During arrest, cells predominantly undergo one of two fates: cell death by apoptosis, or mitotic slippage and survival. To refine this binary description, a quantitative understanding of these cell responses is needed. Herein, we propose a quantitative description of the kinetics of colon carcinoma RKO cell fates in response to different antimitotics, using data from the single cell experiments of Gascoigne and Taylor (2008). The mathematical model is calibrated using the in vitro experiments of Gascoigne and Taylor (2008). We show that the time-dependent probability of cell death or slippage is universally identical for monastrol, nocodazole and two different doses of AZ138, but significantly different for taxol. Death and slippage responses across drugs can be characterized by Gamma distributions. We demonstrate numerically that these rates increase with prolonged mitotic arrest. Our model demonstrates that RKO cells exhibit a triphasic response - first, remain in mitosis, then undergo fast and slow transition, respectively- dependent on the length of mitotic arrest and irrespective of cell fate, drug type or dose.
Opioid receptor signaling, analgesic and side effects induced by a computationally designed pH-dependent agonist
Authors: Spahn Viola , Del Vecchio Giovanna , Rodriguez-Gaztelumendi Antonio , Temp Julia , Labuz Dominika , Kloner Michael , Reidelbach Marco , Machelska Halina , Weber Marcus , Stein Christoph
Published: June 2018

Novel pain killers without adverse effects are urgently needed. Opioids induce central and intestinal side effects such as respiratory depression, sedation, addiction, and constipation. We have recently shown that a newly designed agonist with a reduced acid dissociation constant (pKa) abolished pain by selectively activating peripheral μ-opioid receptors (MOR) in inflamed (acidic) tissues without eliciting side effects. Here, we extended this concept in that pKa reduction to 7.22 was achieved by placing a fluorine atom at the ethylidene bridge in the parental molecule fentanyl. The new compound (FF3) showed pH-sensitive MOR affinity, [35S]-GTPγS binding, and G protein dissociation by fluorescence resonance energy transfer. It produced injury-restricted analgesia in rat models of inflammatory, postoperative, abdominal, and neuropathic pain. At high dosages, FF3 induced sedation, motor disturbance, reward, constipation, and respiratory depression. These results support our hypothesis that a ligand’s pKa should be close to the pH of injured tissue to obtain analgesia without side effects.
Associations of social and economic and pregnancy exposures with blood pressure in UK White British and Pakistani children age 4/5
Authors: West Jane , Lawlor Debbie A. , Santorelli Gillian , Collings Paul , Whincup Peter H. , Sattar Naveed A. , Farrar Diane , Wright John
Published: June 2018

South Asians have higher rates of coronary heart disease (CHD) than White European individuals. Blood pressure (BP) is one of the most important risk factors for CHD and ethnic differences in BP have been identified in childhood. Early life exposures could explain some of these differences. We examined associations of family social and economic and maternal pregnancy exposures and BP at age 4/5 in 1644 White British and 1824 Pakistani mother-offspring pairs from the Born in Bradford study. We found that systolic BP was similar but diastolic BP was higher, in Pakistani compared to White British children (adjusted mean differences were −0.170 mmHg 95% CI −0.884, 0.543 for systolic BP; 1.328 mmHg 95% CI 0.592, 2.064 for diastolic BP). Social and economic exposures were not associated with BP in either ethnic group. Maternal BMI was positively associated with BP in both groups but this association was mediated by child BMI. Only gestational hypertension was associated with child systolic and diastolic BP and this was only identified in Pakistani mother-offspring pairs. These findings suggest that Pakistani populations may have a different BP trajectory compared to White British groups and that this is already evident at age 4/5 years.
Ischemia-reperfusion injury and the risk of hepatocellular carcinoma recurrence after deceased donor liver transplantation
Authors: Grąt Michał , Krawczyk Marek , Wronka Karolina M. , Stypułkowski Jan , Lewandowski Zbigniew , Wasilewicz Michał , Krawczyk Piotr , Grąt Karolina , Patkowski Waldemar , Zieniewicz Krzysztof
Published: June 2018

This study aimed to evaluate the effects of ischemia-reperfusion injury (IRI) on the risk of hepatocellular carcinoma (HCC) recurrence after liver transplantation. Data of 195 patients were retrospectively analysed. Post-reperfusion aspartate (AST), alanine transaminase, and lactate dehydrogenase (LDH) levels were the primary measures of IRI. Tumour recurrence was the primary endpoint. Post-reperfusion AST was a continuous risk factor for tumour recurrence in patients within Milan criteria (p = 0.035), with an optimal cut-off of 1896 U/L. Recurrence-free survival of patients within Milan criteria and post-reperfusion AST of <1896 and ≥1896 U/L was 96.6% and 71.9% at 5 and 3.7 years, respectively (p = 0.006). Additionally, post-reperfusion AST and LDH exceeding the upper quartile significantly increased the risk of HCC recurrence in patients within Milan criteria (p = 0.039, hazard ratio [HR] = 5.99 and p = 0.040, HR = 6.08, respectively) and to a lesser extent, in patients within Up-to-7 criteria (p = 0.028, HR = 3.58 and p = 0.039, HR = 3.33, respectively). No other significant IRI effects were found in patients beyond the Up-to-7 criteria and in analyses stratified for independent risk factors for recurrence: tumour number and differentiation, alpha-fetoprotein, and microvascular invasion. Thus, IRI exerts major negative effects on the risk of HCC recurrence after liver transplantation in patients within standard and extended criteria.