bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractAttempts 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

AbstractVisual 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

AbstractOxidized 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

AbstractFinding 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

AbstractSynthetic 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.
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

AbstractMonitoring 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

AbstractMicrosporidia 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.
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

AbstractMonoacylglycerol 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

AbstractWe 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

AbstractNCAM1 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

AbstractStochastic 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

AbstractSpontaneous 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

AbstractThe 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

AbstractNeuronal 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

AbstractSkin 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.