Author Correction: Optimizing the fragment complementation of APEX2 for detection of specific protein-protein interactions in live cells Sci. Rep. (IF 4.259) Pub Date : 2018-04-20 Miaomiao Xue, Junjie Hou, Linlin Wang, Dongwan Cheng, Jingze Lu, Li Zheng, Tao Xu
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.
Fluorophore labeling of a cell-penetrating peptide significantly alters the mode and degree of biomembrane interaction Sci. Rep. (IF 4.259) Pub Date : 2018-04-20 Sofie Fogh Hedegaard, Mohammed Sobhi Derbas, Tania Kjellerup Lind, Marina Robertnova Kasimova, Malene Vinther Christensen, Maria Høtoft Michaelsen, Richard A. Campbell, Lene Jorgensen, Henrik Franzyk, Marité Cárdenas, Hanne Mørck Nielsen
The demand for highly efficient macromolecular drugs, used in the treatment of many severe diseases, is continuously increasing. However, the hydrophilic character and large molecular size of these drugs significantly limit their ability to permeate across cellular membranes and thus impede the drugs in reaching their target sites in the body. Cell-penetrating peptides (CPP) have gained attention as promising drug excipients, since they can facilitate drug permeation across cell membranes constituting a major biological barrier. Fluorophores are frequently covalently conjugated to CPPs to improve detection, however, the ensuing change in physico-chemical properties of the CPPs may alter their biological properties. With complementary biophysical techniques, we show that the mode of biomembrane interaction may change considerably upon labeling of the CPP penetratin (PEN) with a fluorophore. Fluorophore-PEN conjugates display altered modes of membrane interaction with increased insertion into the core of model cell membranes thereby exerting membrane-thinning effects. This is in contrast to PEN, which localizes along the head groups of the lipid bilayer, without affecting the thickness of the lipid tails. Particularly high membrane disturbance is observed for the two most hydrophobic PEN conjugates; rhodamine B or 1-pyrene butyric acid, as compared to the four other tested fluorophore-PEN conjugates.
Popularity and Novelty Dynamics in Evolving Networks Sci. Rep. (IF 4.259) Pub Date : 2018-04-20 Khushnood Abbas, Mingsheng Shang, Alireza Abbasi, Xin Luo, Jian Jun Xu, Yu-Xia Zhang
Network science plays a big role in the representation of real-world phenomena such as user-item bipartite networks presented in e-commerce or social media platforms. It provides researchers with tools and techniques to solve complex real-world problems. Identifying and predicting future popularity and importance of items in e-commerce or social media platform is a challenging task. Some items gain popularity repeatedly over time while some become popular and novel only once. This work aims to identify the key-factors: popularity and novelty. To do so, we consider two types of novelty predictions: items appearing in the popular ranking list for the first time; and items which were not in the popular list in the past time window, but might have been popular before the recent past time window. In order to identify the popular items, a careful consideration of macro-level analysis is needed. In this work we propose a model, which exploits item level information over a span of time to rank the importance of the item. We considered ageing or decay effect along with the recent link-gain of the items. We test our proposed model on four various real-world datasets using four information retrieval based metrics.
Micro-thermocouple on nano-membrane: thermometer for nanoscale measurements Sci. Rep. (IF 4.259) Pub Date : 2018-04-20 Armandas Balčytis, Meguya Ryu, Saulius Juodkazis, Junko Morikawa
A thermocouple of Au-Ni with only 2.5-μm-wide electrodes on a 30-nm-thick Si3N4 membrane was fabricated by a simple low-resolution electron beam lithography and lift off procedure. The thermocouple is shown to be sensitive to heat generated by laser as well as an electron beam. Nano-thin membrane was used to reach a high spatial resolution of energy deposition and to realise a heat source of sub-1 μm diameter. This was achieved due to a limited generation of secondary electrons, which increase a lateral energy deposition. A low thermal capacitance of the fabricated devices is useful for the real time monitoring of small and fast temperature changes, e.g., due to convection, and can be detected through an optical and mechanical barrier of the nano-thin membrane. Temperature changes up to ~2 × 105 K/s can be measured at 10 kHz rate. A simultaneous down-sizing of both, the heat detector and heat source strongly required for creation of thermal microscopy is demonstrated. Peculiarities of Seebeck constant (thermopower) dependence on electron injection into thermocouple are discussed. Modeling of thermal flows on a nano-membrane with presence of a micro-thermocouple was carried out to compare with experimentally measured temporal response.
Exploring drying pattern of a sessile droplet of genomic DNA in the presence of hematite nanoparticles Sci. Rep. (IF 4.259) Pub Date : 2018-04-20 Rekha Bhar, Gurpreet Kaur, S. K. Mehta
For the first time, drying pattern of a sessile droplet of genomic DNA, in the presence of hematite nanoparticles was sighted by polarizing optical microscopy (POM) in this research article. POM results indicated that only at an appreciably high concentration of hematite nanoparticles dried pattern of deoxyribonucleic acid from calf thymus (CT-DNA) was altered. Iron hybridized cetylpyridinium chloride was utilized for the preparation of iron oxide nanoparticles through hydrothermal method. Fourier transforms infrared spectroscopy (FTIR) and powder x-ray diffraction (PXRD) studies confirmed the formation of highly crystalline hematite i.e. α-Fe2O3 nanoparticles. Morphology of the synthesized nanoparticle was visualized by transmission electron microscope (TEM) and field emission scanning electron microscope (FESEM), which revealed that nanoparticles were rhombohedral in shape with a size of 45 ± 10 nm. Based upon all the findings, hydrothermal growth mechanism was also proposed having bilayer protection of surfactant around the nanoparticles. UV-Vis spectroscopy and fluorescence spectroscopy were explored to study the affinity of thus prepared nanoparticles towards calf thymus deoxyribonucleic acid (CT-DNA). The low value of binding constant calculated from the spectroscopy data confirmed the weak interaction between nanoparticles and the CT-DNA.
NFκB activation in differentiating glioblastoma stem-like cells is promoted by hyaluronic acid signaling through TLR4 Sci. Rep. (IF 4.259) Pub Date : 2018-04-20 Eva Ferrandez, Olga Gutierrez, David San Segundo, Jose L. Fernandez-Luna
We have previously described that the NFκB pathway is upregulated during differentiation of glioblastoma stem-like cells (GSCs) which keeps differentiating GSCs in a proliferative astrocytic precursor state. However, extracellular signals and cellular mediators of this pathway are not clear yet. Here, we show that TLR4 is a key factor to promote NFκB activation in differentiating GSCs. TLR4 is upregulated during differentiation of GSCs and promotes transcriptional activation of NFκB as determined by luciferase-reporter assays and expression of NFκB target genes. Downregulation of TLR4 by shRNAs or blockade with anti-TLR4 specific antibodies drastically inhibited NFκB activity which promoted further differentiation and reduced proliferation of GSCs. We found that hyaluronic acid (HA), a main component of brain extracellular matrix, triggers the TLR4-NFκB pathway in differentiating GSCs. Moreover, HA is synthesized and released by GSCs undergoing differentiation and leads to transcriptional activation of NFκB, which is inhibited following downregulation of TLR4 or blockade of HA synthesis. Thus, we have demonstrated that during the process of differentiation, GSCs upregulate TLR4 and release the TLR4 ligand HA, which activates the TLR4-NFκB signaling pathway. This strategy may efficiently be used by differentiating GSCs to maintain their proliferative potential and consequently their tumorigenic capacity.
Individual and shared effects of social environment and polygenic risk scores on adolescent body mass index Sci. Rep. (IF 4.259) Pub Date : 2018-04-20 Jonathan R. I. Coleman, Eva Krapohl, Thalia C. Eley, Gerome Breen
Juvenile obesity is associated with adverse health outcomes. Understanding genetic and environmental influences on body mass index (BMI) during adolescence could inform interventions. We investigated independent and interactive effects of parenting, socioeconomic status (SES) and polygenic risk on BMI pre-adolescence, and on the rate of change in BMI across adolescence. Genome-wide genotype data, BMI and child perceptions of parental warmth and punitive discipline were available at 11 years old, and parental SES was available from birth on 3,414 unrelated participants. Linear models were used to test the effects of social environment and polygenic risk on pre-adolescent BMI. Change in BMI across adolescence was assessed in a subset (N = 1943). Sex-specific effects were assessed. Higher genetic risk was associated with increased BMI pre-adolescence and across adolescence (p < 0.00417, corrected for multiple tests). Negative parenting was not significantly associated with either phenotype, but lower SES was associated with increased BMI pre-adolescence. No interactions passed correction for multiple testing. Polygenic risk scores from adult GWAS meta-analyses are associated with BMI in juveniles, suggesting a stable genetic component. Pre-adolescent BMI was associated with social environment, but parental style has, at most, a small effect.
Human kallikrein-related peptidase 12 stimulates endothelial cell migration by remodeling the fibronectin matrix Sci. Rep. (IF 4.259) Pub Date : 2018-04-20 T. Kryza, C. Parent, J. Pardessus, A. Petit, J. Burlaud-Gaillard, P. Reverdiau, S. Iochmann, V. Labas, Y. Courty, N. Heuzé-Vourc’h
Kallikrein-related peptidase 12 (KLK12) is a kallikrein family peptidase involved in angiogenesis – a complex biological process in which the sprouting, migration and stabilization of endothelial cells requires extracellular matrix remodeling. To characterize the molecular mechanisms associated with KLK12′s proangiogenic activity, we evaluated its ability to hydrolyze various matrix proteins. Our results show that KLK12 efficiently cleaved the human extracellular matrix proteins fibronectin and tenascin, both of which are involved in the regulation of endothelial cell adhesion and migration. For fibronectin, the major proteolytic product generated by KLK12 was a 29 kDa fragment containing the amino-terminal domain and the first five type I fibronectin-domains, which are essential for regulating fibronectin assembly. We also demonstrated that KLK12-mediated fibronectin proteolysis antagonizes fibronectin polymerization and fibronectin fibril formation by endothelial cells, leading to an increase in cell migration. Furthermore, a polyclonal antibody raised against KLK12′s proteolytic cleavage site on fibronectin prevented the KLK12-dependent inhibition of fibronectin polymerization and the KLK12-mediated pro-migratory effect on endothelial cells. Taken as a whole, our results indicate that KLK12′s proangiogenic effect is mediated through several molecular mechanisms.
Combining electrical stimulation and tissue engineering to treat large bone defects in a rat model Sci. Rep. (IF 4.259) Pub Date : 2018-04-20 Liudmila Leppik, Han Zhihua, Sahba Mobini, Vishnu Thottakkattumana Parameswaran, Maria Eischen-Loges, Andrei Slavici, Judith Helbing, Lukas Pindur, Karla M. C. Oliveira, Mit B. Bhavsar, Lukasz Hudak, Dirk Henrich, John H. Barker
Bone Tissue engineering (BTE) has recently been introduced as an alternative to conventional treatments for large non-healing bone defects. BTE approaches mimic autologous bone grafts, by combining cells, scaffold, and growth factors, and have the added benefit of being able to manipulate these constituents to optimize healing. Electrical stimulation (ES) has long been used to successfully treat non-healing fractures and has recently been shown to stimulate bone cells to migrate, proliferate, align, differentiate, and adhere to bio compatible scaffolds, all cell behaviors that could improve BTE treatment outcomes. With the above in mind we performed in vitro experiments and demonstrated that exposing Mesenchymal Stem Cells (MSC) + scaffold to ES for 3 weeks resulted in significant increases in osteogenic differentiation. Then in in vivo experiments, for the first time, we demonstrated that exposing BTE treated rat femur large defects to ES for 8 weeks, caused improved healing, as indicated by increased bone formation, strength, vessel density, and osteogenic gene expression. Our results demonstrate that ES significantly increases osteogenic differentiation in vitro and that this effect is translated into improved healing in vivo. These findings support the use of ES to help BTE treatments achieve their full therapeutic potential.
Author Correction: Introduced ascidians harbor highly diverse and host-specific symbiotic microbial assemblages Sci. Rep. (IF 4.259) Pub Date : 2018-04-20 James S. Evans, Patrick M. Erwin, Noa Shenkar, Susanna López-Legentil
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.
Systematic evaluation of RNA quality, microarray data reliability and pathway analysis in fresh, fresh frozen and formalin-fixed paraffin-embedded tissue samples Sci. Rep. (IF 4.259) Pub Date : 2018-04-20 Isabella Wimmer, Anna R. Tröscher, Florian Brunner, Stephen J. Rubino, Christian G. Bien, Howard L. Weiner, Hans Lassmann, Jan Bauer
Formalin-fixed paraffin-embedded (FFPE) tissues are valuable resources commonly used in pathology. However, formalin fixation modifies nucleic acids challenging the isolation of high-quality RNA for genetic profiling. Here, we assessed feasibility and reliability of microarray studies analysing transcriptome data from fresh, fresh-frozen (FF) and FFPE tissues. We show that reproducible microarray data can be generated from only 2 ng FFPE-derived RNA. For RNA quality assessment, fragment size distribution (DV200) and qPCR proved most suitable. During RNA isolation, extending tissue lysis time to 10 hours reduced high-molecular-weight species, while additional incubation at 70 °C markedly increased RNA yields. Since FF- and FFPE-derived microarrays constitute different data entities, we used indirect measures to investigate gene signal variation and relative gene expression. Whole-genome analyses revealed high concordance rates, while reviewing on single-genes basis showed higher data variation in FFPE than FF arrays. Using an experimental model, gene set enrichment analysis (GSEA) of FFPE-derived microarrays and fresh tissue-derived RNA-Seq datasets yielded similarly affected pathways confirming the applicability of FFPE tissue in global gene expression analysis. Our study provides a workflow comprising RNA isolation, quality assessment and microarray profiling using minimal RNA input, thus enabling hypothesis-generating pathway analyses from limited amounts of precious, pathologically significant FFPE tissues.
MISP regulates the IQGAP1/Cdc42 complex to collectively orchestrate spindle orientation and mitotic progression Sci. Rep. (IF 4.259) Pub Date : 2018-04-20 Barbara Vodicska, Berati Cerikan, Elmar Schiebel, Ingrid Hoffmann
Precise mitotic spindle orientation is essential for both cell fate and tissue organization while defects in this process are associated with tumorigenesis and other diseases. In most animal cell types, the dynein motor complex is anchored at the cell cortex and exerts pulling forces on astral microtubules to position the spindle. The actin-binding protein MISP controls spindle orientation and mitotic progression in human cells. However, the exact underlying mechanism remains to be elucidated. Here we report that MISP interacts with the multidomain scaffolding protein IQGAP1. We further show that MISP binds to the active form of Cdc42 through IQGAP1. Depletion of MISP promotes increased accumulation of IQGAP1 at the cell cortex and a decrease in its Cdc42-binding capacity leading to reduced active Cdc42 levels. Interestingly, overexpression of IQGAP1 can rescue mitotic defects caused by MISP downregulation including spindle misorientation, loss of astral microtubules and prolonged mitosis and also restores active Cdc42 levels. Importantly, we find that IQGAP1 acts downsteam of MISP in regulating astral microtubule dynamics and the localization of the dynactin subunit p150glued that is crucial for proper spindle positioning. We propose that MISP regulates IQGAP1 and Cdc42 to ensure proper mitotic progression and correct spindle orientation.
The Role of Macrophage Migration Inhibitory Factor in the Function of Intestinal Barrier Sci. Rep. (IF 4.259) Pub Date : 2018-04-20 Milica Vujicic, Tamara Saksida, Sanja Despotovic, Svetlana Sokovic Bajic, Ivana Lalić, Ivan Koprivica, Dragica Gajic, Natasa Golic, Maja Tolinacki, Ivana Stojanovic
Macrophage migration inhibitory factor (MIF) is a multifunctional protein that is involved in the development of gut-related inflammation. To investigate the role of MIF in the function of the intestinal barrier, we have explored intestinal permeability and gut-associated immune response in MIF-deficient (MIF-KO) mice. The absence of MIF provoked impairment of tight and adherens epithelial junctions in the colon through the disturbance of E-cadherin, zonula occludens-1, occludin and claudin-2 expression, which lead to the increase of intestinal barrier permeability. In these circumstances the diversity and content of gut microbiota in MIF-KO mice was considerably different compared to wild type mice. This change in microbiota was accompanied by an increased intestinal IgA concentration and a higher production of pro-inflammatory cytokines TNF and IFN-γ in mesenteric lymph nodes of MIF-KO mice. The forced changes of microbiota executed by antibiotics prevented the “leakage” of the barrier in MIF-KO mice, probably through up-regulation of occludin expression and normalization of cellular pore diameters. In addition, cytokine secretion was normalized after the treatment with antibiotics. These results suggest that MIF participates in the maintenance of physiological microbiota diversity and immunosurveillance, which in turn enables the proper intestinal barrier function.
aPKCζ-dependent Repression of Yap is Necessary for Functional Restoration of Irradiated Salivary Glands with IGF-1 Sci. Rep. (IF 4.259) Pub Date : 2018-04-20 Alejandro M. Chibly, Wen Yu Wong, Maricela Pier, Hongqiang Cheng, Yongxin Mu, Ju Chen, Sourav Ghosh, Kirsten H. Limesand
Xerostomia and salivary hypofunction often result as a consequence of radiation therapy for head and neck cancers, which are diagnosed in roughly 60,000 individuals every year in the U.S. Due to the lack of effective treatments for radiation-induced salivary hypofunction, stem cell-based therapies have been suggested to regenerate the irradiated salivary glands. Pharmacologically, restoration of salivary gland function has been accomplished in mice by administering IGF-1 shortly after radiation treatment, but it is not known if salivary stem and progenitor cells play a role. We show that radiation inactivates aPKCζ and promotes nuclear redistribution of Yap in a population of label-retaining cells in the acinar compartment of the parotid gland (PG)– which comprises a heterogeneous pool of salivary progenitors. Administration of IGF-1 post-radiation maintains activation of aPKCζ and partially rescues Yap’s cellular localization in label retaining cells, while restoring salivary function. Finally, IGF-1 fails to restore saliva production in mice lacking aPKCζ, demonstrating the importance of the kinase as a potential therapeutic target.
Towards annotating the plant epigenome: the Arabidopsis thaliana small RNA locus map Sci. Rep. (IF 4.259) Pub Date : 2018-04-20 Thomas J. Hardcastle, Sebastian Y. Müller, David C. Baulcombe
Based on 98 public and internal small RNA high throughput sequencing libraries, we mapped small RNAs to the genome of the model organism Arabidopsis thaliana and defined loci based on their expression using an empirical Bayesian approach. The resulting loci were subsequently classified based on their genetic and epigenetic context as well as their expression properties. We present the results of this classification, which broadly conforms to previously reported divisions between transcriptional and post-transcriptional gene silencing small RNAs, and to PolIV and PolV dependencies. However, we are able to demonstrate the existence of further subdivisions in the small RNA population of functional significance. Moreover, we present a framework for similar analyses of small RNA populations in all species.
Computational Protein Design with Deep Learning Neural Networks Sci. Rep. (IF 4.259) Pub Date : 2018-04-20 Jingxue Wang, Huali Cao, John Z. H. Zhang, Yifei Qi
Computational protein design has a wide variety of applications. Despite its remarkable success, designing a protein for a given structure and function is still a challenging task. On the other hand, the number of solved protein structures is rapidly increasing while the number of unique protein folds has reached a steady number, suggesting more structural information is being accumulated on each fold. Deep learning neural network is a powerful method to learn such big data set and has shown superior performance in many machine learning fields. In this study, we applied the deep learning neural network approach to computational protein design for predicting the probability of 20 natural amino acids on each residue in a protein. A large set of protein structures was collected and a multi-layer neural network was constructed. A number of structural properties were extracted as input features and the best network achieved an accuracy of 38.3%. Using the network output as residue type restraints improves the average sequence identity in designing three natural proteins using Rosetta. Moreover, the predictions from our network show ~3% higher sequence identity than a previous method. Results from this study may benefit further development of computational protein design methods.
Pregnancy-associated diamine oxidase originates from extravillous trophoblasts and is decreased in early-onset preeclampsia Sci. Rep. (IF 4.259) Pub Date : 2018-04-20 Philipp Velicky, Karin Windsperger, Karin Petroczi, Sophie Pils, Birgit Reiter, Tamara Weiss, Sigrid Vondra, Robin Ristl, Sabine Dekan, Christian Fiala, David E. Cantonwine, Thomas F. McElrath, Bernd Jilma, Martin Knöfler, Thomas Boehm, Jürgen Pollheimer
Human extravillous trophoblast (EVT) invasion of the pregnant uterus constitutes a pivotal event for the establishment of the maternal-fetal interface. Compromised EVT function manifesting in inadequate arterial remodeling is associated with the severe pregnancy disorder early-onset preeclampsia (eoPE). Recent studies suggest that EVTs invade the entire uterine vasculature including arteries, veins and lymphatics in the first trimester of pregnancy. We therefore hypothesized that EVT-derived factors accumulate in the circulation of pregnant women early in gestation and may serve to predict eoPE. In contrast to published literature, we demonstrate that placenta-associated diamine oxidase (DAO) is not expressed by maternal decidual cells but solely by EVTs, especially when in close proximity to decidual vessels. Cultures of primary EVTs express and secret large amounts of bioactive DAO. ELISA measurements indicate a pregnancy-specific rise in maternal DAO plasma levels around gestational week (GW) 7 coinciding with vascular invasion of EVTs. Strikingly, DAO levels from eoPE cases were significantly lower (40%) compared to controls in the first trimester of pregnancy but revealed no difference at mid gestation. Furthermore, DAO-containing pregnancy plasma rapidly inactivates pathophysiologically relevant histamine levels. This study represents the first proof of concept suggesting EVT-specific signatures as diagnostic targets for the prediction of eoPE.
Author Correction: Circulating Haptoglobin and Metabolic Syndrome in Renal Transplant Recipients Sci. Rep. (IF 4.259) Pub Date : 2018-04-20 Isidor Minović, Michele F. Eisenga, Ineke J. Riphagen, Else Berg, Jenny Kootstra-Ros, Anne-Roos S. Frenay, Harry Goor, Gerald Rimbach, Tuba Esatbeyoglu, Andy P. Levy, Carlo A. J. M. Gaillard, Johanna M. Geleijnse, Manfred L. Eggersdorfer, Gerjan J. Navis, Ido P. Kema, Stephan J. L. Bakker
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.
Enteric Nervous System Regulation of Intestinal Stem Cell Differentiation and Epithelial Monolayer Function Sci. Rep. (IF 4.259) Pub Date : 2018-04-20 Marissa Puzan, Sanjin Hosic, Caroline Ghio, Abigail Koppes
The Enteric Nervous System (ENS) is a complex network of neurons and glia, which regulates sensorimotor function throughout the gastroinestinal tract (GI). Here we investigated the role of the ENS and intestinal myofibroblasts in the maintenance of a primary intestinal epithelial barrier through regulation of monolayer permeability, cytokine production, and differentiation of intestinal stem cells. Utilizing a novel, in vitro, transwell-based coculture system, murine small intestinal stem cells were isolated and cultured with ENS neurons and glia or subepithelial myofibroblasts. Results show that the ENS contributes to regulation of intestinal stem cell fate, promoting differentiation into chemosensory enteroendocrine cells, with 0.9% of cells expressing chromogranin A when cultured with ENS versus 0.6% in cocultures with myofibroblasts and 0.3% in epithelial cultures alone. Additionally, enteric neurons and myofibroblasts differentially release cytokines Macrophage Inflammatory Protein 2 (MIP-2), Transforming Growth Factor beta 1 (TGF-β1), and Interleukin 10 (IL-10) when cultured with intestinal epithelial cells, with a 1.5 fold increase of IL-10 and a 3 fold increase in MIP-2 in ENS cocultures compared to coculture with myofibroblasts. These results indicate the importance of enteric populations in the regulation of intestinal barrier function.
Changes in gene expression in chronic allergy mouse model exposed to natural environmental PM2.5-rich ambient air pollution Sci. Rep. (IF 4.259) Pub Date : 2018-04-20 Yuhui Ouyang, Zhaojun Xu, Erzhong Fan, Ying Li, Kunio Miyake, Xianyan Xu, Luo Zhang
Particulate matter (PM) air pollution has been associated with an increase in the incidence of chronic allergic diseases; however, the mechanisms underlying the effect of exposure to natural ambient air pollution in chronic allergic diseases have not been fully elucidated. In the present study, we aimed to investigate the cellular responses induced by exposure to natural ambient air pollution, employing a mouse model of chronic allergy. The results indicated that exposure to ambient air pollution significantly increased the number of eosinophils in the nasal mucosa. The modulation of gene expression profile identified a set of regulated genes, and the Triggering Receptor Expressed on Myeloid cells1(TREM1) signaling canonical pathway was increased after exposure to ambient air pollution. In vitro, PM2.5 increased Nucleotide-binding oligomerization domain-containing protein 1 (Nod1) and nuclear factor (NF)-κB signaling pathway activation in A549 and HEK293 cell cultures. These results suggest a novel mechanism by which, PM2.5 in ambient air pollution may stimulate the innate immune system through the PM2.5-Nod1-NF-κB axis in chronic allergic disease.
Differential contribution of cis and trans gene transcription regulatory mechanisms in amygdala and prefrontal cortex and modulation by social stress Sci. Rep. (IF 4.259) Pub Date : 2018-04-20 Eli Reuveni, Dmitry Getselter, Oded Oron, Evan Elliott
While both individual transcription factors and cis-acting sites have been studied in relation to psychiatric disorders, there is little knowledge of the relative contribution of trans-acting and cis-acting factors to gene transcription in the brain. Using an RNA-seq approach in mice bred from two evolutionary-distinct mice strains, we determined the contribution of cis and trans factors to gene expression in the prefrontal cortex and amygdala, two regions of the brain relevant to the stress response, and the contribution of cis and trans factors in the prefrontal cortex after Chronic Social Defeat (CSD) in mice. More genes were regulated by cis-regulatory factors in both brain regions, underlying the importance of cis-acting gene regulation in the brain. However, there was an increase in genes regulated by trans-regulatory mechanisms in the amygdala, compared to the prefrontal cortex. These genes were involved in synaptic functions, and were enriched for binding sites for transcription factors, including Egr1. CSD induced an increase in genes regulated by trans-regulatory mechanisms in the prefrontal cortex, and induced a pattern similar to the unstressed amygdala. Overall, we show brain site-specific patterns in cis and trans regulatory mechanisms, and show that these patterns can be modified by a psychological trigger.
Comparison of an unsupervised machine learning algorithm and surgeon diagnosis in the clinical differentiation of metopic craniosynostosis and benign metopic ridge Sci. Rep. (IF 4.259) Pub Date : 2018-04-20 Min-Jeong Cho, Rami R. Hallac, Maleeh Effendi, James R. Seaward, Alex A. Kane
Metopic suture closure can manifest as a benign metopic ridge (BMR), a variant of normal, to “true” metopic craniosynostosis (MCS), which is associated with severe trigonocephaly. Currently, there is no gold standard for how much associated orbitofrontal dysmorphology should trigger surgical intervention. In our study, we used three-dimensional (3D) curvature analysis to separate the phenotypes along the spectrum, and to compare surgeons’ thresholds for operation. Three-dimensional curvature analyses on 43 subject patients revealed that the mean curvature of mid-forehead vertical ridge was higher for patients who underwent operation than those who did not undergo operation by 1.3 m−1 (p < 0.0001). In addition, these patients had more retruded supraorbital areas by −16.1 m−1 (p < 0.0001). K-means clustering classified patients into two different severity groups, and with the exception of 2 patients, the algorithm’s classification of deformity completely agreed with the surgeons’ decisions to offer either conservative or operative therapy (i.e. 96% agreement). The described methods are effective in classifying severity of deformity and in our experience closely approximate surgeon therapeutic decision making. These methods offer the possibility to consistently determine when surgical intervention may be beneficial and to avoid unnecessary surgeries on children with benign metopic ridge and associated minimal orbitofrontal deformity.
A molecular dynamics simulation study decodes the Zika virus NS5 methyltransferase bound to SAH and RNA analogue Sci. Rep. (IF 4.259) Pub Date : 2018-04-20 Chih-Hung Chuang, Shean-jaw Chiou, Tian-Lu Cheng, Yeng-Tseng Wang
Since 2015, widespread Zika virus outbreaks in Central and South America have caused increases in microcephaly cases, and this acute problem requires urgent attention. We employed molecular dynamics and Gaussian accelerated molecular dynamics techniques to investigate the structure of Zika NS5 protein with S-adenosyl-L-homocysteine (SAH) and an RNA analogue, namely 7-methylguanosine 5′-triphosphate (m7GTP). For the binding motif of Zika virus NS5 protein and SAH, we suggest that the four Zika NS5 substructures (residue orders: 101–112, 54–86, 127–136 and 146–161) and the residues (Ser56, Gly81, Arg84, Trp87, Thr104, Gly106, Gly107, His110, Asp146, Ile147, and Gly148) might be responsible for the selectivity of the new Zika virus drugs. For the binding motif of Zika NS5 protein and m7GTP, we suggest that the three Zika NS5 substructures (residue orders: 11–31, 146–161 and 207–218) and the residues (Asn17, Phe24, Lys28, Lys29, Ser150, Arg213, and Ser215) might be responsible for the selectivity of the new Zika virus drugs.
Springtime photoinhibition constrains regeneration of forest floor seedlings of Abies sachalinensis after a removal of canopy trees during winter Sci. Rep. (IF 4.259) Pub Date : 2018-04-20 Mitsutoshi Kitao, Hisanori Harayama, Qingmin Han, Evgenios Agathokleous, Akira Uemura, Naoyuki Furuya, Satoshi Ishibashi
A clear-cutting of canopy trees during winter often causes severe foliar damage during the following spring in forest floor seedlings of Abies sachalinensis, a typical shade-tolerant evergreen coniferous species. The maximum photochemical efficiency of photosystem II after an overnight dark adaptation showed a temporary decrease immediately before budbreak in 1-year-old shoots of A. sachalinensis seedlings grown under full sunlight in a nursery, suggesting “springtime photoinhibition” related to the phenology of evergreen coniferous species. In the field, a greater rate of canopy tree cutting during winter was associated with more severe photoinhibition in the following spring, immediately before budbreak, which subsequently resulted in a reduction in carbon gain in 1-year-old shoots, and consequently suppressed the growth of current-year shoots. Although photoinhibition under low temperature is a well-known factor to determine the survival rate of tree seedlings during winter in cool regions, the present study additionally proposes that the temporary increase in the susceptibility to photoinhibition in springtime i.e. “springtime photoinhibition” would be a constraint for the regeneration of coniferous seedlings especially when the canopy trees are removed during winter.
Gas permeation through rubbery polymer nano-corrugated membranes Sci. Rep. (IF 4.259) Pub Date : 2018-04-20 Giuseppe Firpo, Elena Angeli, Patrizia Guida, Roberto Lo Savio, Luca Repetto, Ugo Valbusa
The purpose of this investigation is to fabricate PDMS membranes with reliable surface roughness in order to reduce the surface resistances and to study its impact on the permeation rate. The permeance of CO2 through PDMS membranes with rough surfaces at nanoscale is studied and compared with the one of membranes with flat surfaces. At very low thickness, rough membranes have a permeance greater than that of membranes with flat surfaces. The enhancement occurs in a regime where the gas transport is sorption desorption surface rate limited, and cannot be explained by the increase in surface area due to the corrugation. The analysis, introducing a phenomenological model in analogy with electrical flow, indicates that nano-corrugation reduces the surface resistance. To test the model, the permeance of N2 is also measured in the same experimental conditions and the influence of surface roughness on permeation rate of CO2, He, CH4 and N2 is studied. The comparison among the gases suggests that the Henry’s coefficient depends on the surface roughness and allows discussing the role of roughness on membrane selectivity.
Clinical Assistant Diagnosis for Electronic Medical Record Based on Convolutional Neural Network Sci. Rep. (IF 4.259) Pub Date : 2018-04-20 Zhongliang Yang, Yongfeng Huang, Yiran Jiang, Yuxi Sun, Yu-Jin Zhang, Pengcheng Luo
Automatically extracting useful information from electronic medical records along with conducting disease diagnoses is a promising task for both clinical decision support(CDS) and neural language processing(NLP). Most of the existing systems are based on artificially constructed knowledge bases, and then auxiliary diagnosis is done by rule matching. In this study, we present a clinical intelligent decision approach based on Convolutional Neural Networks(CNN), which can automatically extract high-level semantic information of electronic medical records and then perform automatic diagnosis without artificial construction of rules or knowledge bases. We use collected 18,590 copies of the real-world clinical electronic medical records to train and test the proposed model. Experimental results show that the proposed model can achieve 98.67% accuracy and 96.02% recall, which strongly supports that using convolutional neural network to automatically learn high-level semantic features of electronic medical records and then conduct assist diagnosis is feasible and effective.
Disruption of Hox9,10,11 function results in cellular level lineage infidelity in the kidney Sci. Rep. (IF 4.259) Pub Date : 2018-04-20 Keri A. Drake, Mike Adam, Robert Mahoney, S. Steven Potter
Hox genes are important regulators of development. The 39 mammalian Hox genes have considerable functional overlap, greatly confounding their study. In this report, we generated mice with multiple combinations of paralogous and flanking Abd-B Hox gene mutations to investigate functional redundancies in kidney development. The resulting mice developed a number of kidney abnormalities, including hypoplasia, agenesis, and severe cysts, with distinct Hox functions observed in early metanephric kidney formation and nephron progenitor maintenance. Most surprising, however, was that extensive removal of Hox shared function in these kidneys resulted in cellular level lineage infidelity. Strikingly, mutant nephron tubules consisted of intermixed cells with proximal tubule, loop of Henle, and collecting duct identities, with some single cells expressing markers associated with more than one nephron segment. These results indicate that Hox genes are required for proper lineage selection/maintenance and full repression of genes involved in cell fate restriction in the developing kidney.
Author Correction: Enhanced Skin Permeation of Anti-wrinkle Peptides via Molecular Modification Sci. Rep. (IF 4.259) Pub Date : 2018-04-20 Seng Han Lim, Yuanyuan Sun, Thulasi Thiruvallur Madanagopal, Vinicius Rosa, Lifeng Kang
The association between skin auto-fluorescence of palmoplantar sites and microvascular complications in Asian patients with type 2 diabetes mellitus Sci. Rep. (IF 4.259) Pub Date : 2018-04-20 Jong Jin Kim, Bosu Jeong, Yongin Cho, Mi-hyang Kwon, Yong-ho Lee, Uk Kang, Eun Seok Kang
Skin auto-fluorescence (SAF) has generated broad interest about the prospects for non-invasive advanced glycation end product assessment and its direct interplay with the development of microvascular complications, but clinical application of the existing SAF measuring of non-palmoplantar sites in non-Caucasian subjects with dark skin type is still controversial. Here, we tested the diabetic complication screening performance of a novel SAF measuring system in Asian type 2 diabetes mellitus (T2DM) subjects. A total of 166 Korean patients with T2DM were enrolled in this study and palmoplantar SAF was measured by a newly developed transmission-geometry noninvasive optical system. We found that transmitted SAF values of palmoplantar sites, 1st dorsal interossei muscles of the hand, in a complication group were significantly higher than in a non-complication group while no differences were observed between the two groups in reflected SAF of non-palmoplantar sites. The transmitted SAF values of palmoplantar sites were dramatically increased in subjects with multiple complications and were tightly correlated with the duration of microvascular complications. In conclusion, the SAF measurement in the palmoplantar sites with a non-invasive transmission-geometry optical system provided better microvascular complication screening performance compared to the SAF measurement of non-palmoplantar sites specifically in Asian T2DM subjects.
Generalized conditions of spherical carbonate concretion formation around decaying organic matter in early diagenesis Sci. Rep. (IF 4.259) Pub Date : 2018-04-20 Hidekazu Yoshida, Koshi Yamamoto, Masayo Minami, Nagayoshi Katsuta, Sirono Sin-ichi, Richard Metcalfe
Isolated spherical carbonate concretions observed in marine sediments are fascinating natural objet trouve because of their rounded shapes and distinct sharp boundaries. They occur in varied matrices and often contain well preserved fossils. The formation process of such concretions has been explained by diffusion and rapid syn-depositional reactions with organic solutes and other pore water constituents. However, the rates, conditions and formation process of syngenetic spherical concretions are still not fully clear. Based on the examination of different kinds of spherical concretions from several locations in Japan, a diffusion based growth diagram was applied to define the generalized growth conditions of spherical concretions formed around decaying organic matter. All analytical data imply that the spherical concretions formed very rapidly, at least three to four orders of magnitude faster than previously estimated timescales. The values indicate that spherical concretions are preferentially grown within clay- to silt-grade marine sediments deposited in relatively deep (a few tens of metres) environments dominated by diffusive solute transport, very early in diagenesis.
Genetically engineered two-warhead evasins provide a method to achieve precision targeting of disease-relevant chemokine subsets Sci. Rep. (IF 4.259) Pub Date : 2018-04-20 Yara Alenazi, Kamayani Singh, Graham Davies, James R. O. Eaton, Philip Elders, Akane Kawamura, Shoumo Bhattacharya
Both CC and CXC-class chemokines drive inflammatory disease. Tick salivary chemokine-binding proteins (CKBPs), or evasins, specifically bind subsets of CC- or CXC-chemokines, and could precisely target disease-relevant chemokines. Here we have used yeast surface display to identify two tick evasins: a CC-CKBP, P1243 from Amblyomma americanum and a CXC-CKBP, P1156 from Ixodes ricinus. P1243 binds 11 CC-chemokines with Kd < 10 nM, and 10 CC-chemokines with Kd between 10 and 100 nM. P1156 binds two ELR + CXC-chemokines with Kd < 10 nM, and four ELR + CXC-chemokines with Kd between 10 and 100 nM. Both CKBPs neutralize chemokine activity with IC50 < 10 nM in cell migration assays. As both CC- and CXC-CKBP activities are desirable in a single agent, we have engineered “two-warhead” CKBPs to create single agents that bind and neutralize subsets of CC and CXC chemokines. These results show that tick evasins can be linked to create non-natural proteins that target subsets of CC and CXC chemokines. We suggest that “two-warhead” evasins, designed by matching the activities of parental evasins to CC and CXC chemokines expressed in disease, would achieve precision targeting of inflammatory disease-relevant chemokines by a single agent.
Comparative genomics provides insights into the lifestyle and reveals functional heterogeneity of dark septate endophytic fungi Sci. Rep. (IF 4.259) Pub Date : 2018-04-20 Dániel G. Knapp, Julianna B. Németh, Kerrie Barry, Matthieu Hainaut, Bernard Henrissat, Jenifer Johnson, Alan Kuo, Joanne Hui Ping Lim, Anna Lipzen, Matt Nolan, Robin A. Ohm, László Tamás, Igor V. Grigoriev, Joseph W. Spatafora, László G. Nagy, Gábor M. Kovács
Dark septate endophytes (DSE) are a form-group of root endophytic fungi with elusive functions. Here, the genomes of two common DSE of semiarid areas, Cadophora sp. and Periconia macrospinosa were sequenced and analyzed with another 32 ascomycetes of different lifestyles. Cadophora sp. (Helotiales) and P. macrospinosa (Pleosporales) have genomes of 70.46 Mb and 54.99 Mb with 22,766 and 18,750 gene models, respectively. The majority of DSE-specific protein clusters lack functional annotation with no similarity to characterized proteins, implying that they have evolved unique genetic innovations. Both DSE possess an expanded number of carbohydrate active enzymes (CAZymes), including plant cell wall degrading enzymes (PCWDEs). Those were similar in three other DSE, and contributed a signal for the separation of root endophytes in principal component analyses of CAZymes, indicating shared genomic traits of DSE fungi. Number of secreted proteases and lipases, aquaporins, and genes linked to melanin synthesis were also relatively high in our fungi. In spite of certain similarities between our two DSE, we observed low levels of convergence in their gene family evolution. This suggests that, despite originating from the same habitat, these two fungi evolved along different evolutionary trajectories and display considerable functional differences within the endophytic lifestyle.
Author Correction: Gray and white matter integrity influence TMS signal propagation: a multimodal evaluation in cocaine-dependent individuals Sci. Rep. (IF 4.259) Pub Date : 2018-04-20 Tonisha E. Kearney-Ramos, Daniel H. Lench, Michaela Hoffman, Brittany Correia, Logan T. Dowdle, Colleen A. Hanlon
A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
Tunable Transmission and Deterministic Interface states in Double-zero-index Acoustic Metamaterials Sci. Rep. (IF 4.259) Pub Date : 2018-04-20 Wei Zhao, Yuting Yang, Zhi Tao, Zhi Hong Hang
Following the seminal work by Dubois et al. (Nat. Commun. 8, 14871 (2017)), we study a double-zero-index acoustic metamaterial with triangular lattice. By varying the height and diameter of air scatterers inside a parallel-plate acoustic waveguide, acoustic dispersion of the first-order waveguide mode can be manipulated and various interesting properties are explored. With accidental degeneracy of monopolar and dipolar modes, we numerically prove the double-zero-index properties of this novel acoustic metamaterial. Acoustic waveguides with tunable and asymmetric transmission are realized with this double-zero-index acoustic metamaterial embedded. Band inversion occurs if the bulk acoustic band diagram of this acoustic metamaterial is tuned. Deterministic interface states are found to exist on the interface between two acoustic metamaterials with inverted band diagrams.
The Therapeutic Potential and Molecular Mechanism of Isoflavone Extract against Psoriasis Sci. Rep. (IF 4.259) Pub Date : 2018-04-20 Hsin-Ju Li, Nan-Lin Wu, Gon-Ann Lee, Chi-Feng Hung
Psoriasis is a common inflammatory disease. It affects 1–3% of the population worldwide and is associated with increasing medical costs every year. Typical psoriatic skin lesions are reddish, thick, scaly plaques that can occur on multiple skin sites all over the body. Topical application of imiquimod (IMQ), a toll-like receptor (TLR)7 agonist and potent immune system activator, can induce and exacerbate psoriasis. Previous studies have demonstrated that isoflavone extract has an antioxidant effect which may help decrease inflammation and inflammatory pain. Through in vivo studies in mice, we found that the topical application to the shaved back and right ear of mice of isoflavone extract prior to IMQ treatment significantly decreased trans-epidermal water loss (TEWL), erythema, blood flow speed, and ear thickness, while it increased surface skin hydration, and attenuated epidermal hyperplasia and inflammatory cell infiltration. Through in vitro experiments, we found that isoflavone extract can reduce IL-22, IL-17A, and TNF-α-induced MAPK, NF-κB, and JAK-STAT activation in normal human epidermal keratinocytes. At the mRNA level, we determined that isoflavone extract attenuated the increased response of the TNF-α-, IL-17A-, and IL-22- related pathways. These results indicate that isoflavone extract has great potential as an anti-psoriatic agent and in the treatment of other inflammatory skin diseases.
Theory of current-driven skyrmions in disordered magnets Sci. Rep. (IF 4.259) Pub Date : 2018-04-20 Wataru Koshibae, Naoto Nagaosa
An emergent topological particle in magnets, skyrmion, has several unique features distinct from the other magnetic textures such as domain wall, helical structure, and vortex. It is characterized by a topological integer called skyrmion number N sk , which counts how many times the directions of the magnetic moments wrap the unit sphere. This N sk gives the chiral nature of the skyrmion dynamics, and leads to the extremely small critical current density j c for the current-driven motion in terms of spin transfer torque effect. The finite j c indicates the pinning effect due to the disorder such as impurities and defects, and the behaviors of skyrmions under disorder have not been explored well theoretically although it is always relevant in real systems. Here we reveal by a numerical simulation of Landau-Lifshitz-Gilbert equation that there are four different skyrmion phases with the strong disorder, i.e., (A) pinned state, (B) depinned state, (C) skyrmion multiplication/annihilation, and (D) segregation of skyrmions, as the current density increases, while only two phases (A) and (B) appear in the weak disorder case. The microscopic mechanisms of the new phases (C) and (D) are analyzed theoretically. These results offer a coherent understanding of the skyrmion dynamics under current with disorder.
Radiosensitization by Marine Sponge Agelas sp. Extracts in Hepatocellular Carcinoma Cells with Autophagy Induction Sci. Rep. (IF 4.259) Pub Date : 2018-04-20 Changhoon Choi, Arang Son, Hyi-Seung Lee, Yeon-Ju Lee, Hee Chul Park
Although radiation therapy is an effective treatment modality in many cancers, there is an urgent need to develop therapeutic drugs capable of overcoming radioresistance or minimizing normal tissue toxicity. A wide variety of marine-derived bioactive compounds have been screened for anti-cancer drug discovery, but little is known regarding radiation therapy applications. In this study, six different extracts of marine sponges collected from the Micronesian sea were screened for anti-cancer and radiosensitizing activity. Two extracts derived from Agelas sponges collected off the coast of Kosrae and Chuuk, the Federated States of Micronesia significantly decreased clonogenic survival of hepatocellular carcinoma (HCC) cells after exposure to ionizing radiation (IR). The Agelas extracts augmented IR-induced apoptosis and accumulation of reactive oxygen species (ROS). Endoplasmic reticulum (ER) stress was increased via unfolded protein response stimulation, which induced autophagy. N-acetylcysteine, a ROS scavenger, diminished ER stress and autophagy induction effects. This result indicated that Agelas extracts may sensitize HCC cells to IR via ROS overproduction in vitro. Our findings suggest that the Agelas sp. may have potential utility in radiosensitizer development.
Profiling of 179 miRNA Expression in Blood Plasma of Lung Cancer Patients and Cancer-Free Individuals Sci. Rep. (IF 4.259) Pub Date : 2018-04-20 Ivan A. Zaporozhchenko, Evgeny S. Morozkin, Anastasia A. Ponomaryova, Elena Y. Rykova, Nadezhda V. Cherdyntseva, Aleksandr A. Zheravin, Oksana A. Pashkovskaya, Evgeny A. Pokushalov, Valentin V. Vlassov, Pavel P. Laktionov
Lung cancer is one of major cancers, and survival of lung cancer patients is dictated by the timely detection and diagnosis. Cell-free circulating miRNAs were proposed as candidate biomarkers for lung cancer. These RNAs are frequently deregulated in lung cancer and can persist in bodily fluids for extended periods of time, shielded from degradation by membrane vesicles and biopolymer complexes. To date, several groups reported the presence of lung tumour-specific subsets of miRNAs in blood. Here we describe the profiling of blood plasma miRNAs in lung cancer patients, healthy individuals and endobronchitis patients using miRCURY LNA miRNA qPCR Serum/Plasma Panel (Exiqon). From 241 ratios differently expressed between cancer patients and healthy individuals 19 miRNAs were selected for verification using the same platform. LASSO-penalized logistic regression model, including 10 miRNA ratios comprised of 14 individual miRNAs discriminated lung cancer patients from both control groups with AUC of 0.979.
Complete agreement of the post-spinel transition with the 660-km seismic discontinuity Sci. Rep. (IF 4.259) Pub Date : 2018-04-20 Takayuki Ishii, Rong Huang, Hongzhan Fei, Iuliia Koemets, Zhaodong Liu, Fumiya Maeda, Liang Yuan, Lin Wang, Dmitry Druzhbin, Takafumi Yamamoto, Shrikant Bhat, Robert Farla, Takaaki Kawazoe, Noriyoshi Tsujino, Eleonora Kulik, Yuji Higo, Yoshinori Tange, Tomoo Katsura
The 660-km seismic discontinuity, which is a significant structure in the Earth’s mantle, is generally interpreted as the post-spinel transition, as indicated by the decomposition of ringwoodite to bridgmanite + ferropericlase. All precise high-pressure and high-temperature experiments nevertheless report 0.5–2 GPa lower transition pressures than those expected at the discontinuity depth (i.e. 23.4 GPa). These results are inconsistent with the post-spinel transition hypothesis and, therefore, do not support widely accepted models of mantle composition such as the pyrolite and CI chondrite models. Here, we present new experimental data showing post-spinel transition pressures in complete agreement with the 660-km discontinuity depth obtained by high-resolution in situ X-ray diffraction in a large-volume high-pressure apparatus with a tightly controlled sample pressure. These data affirm the applicability of the prevailing mantle models. We infer that the apparently lower pressures reported by previous studies are experimental artefacts due to the pressure drop upon heating. The present results indicate the necessity of reinvestigating the position of mantle mineral phase boundaries previously obtained by in situ X-ray diffraction in high-pressure–temperature apparatuses.
Author Correction: Machine learning for the meta-analyses of microbial pathogens’ volatile signatures Sci. Rep. (IF 4.259) Pub Date : 2018-04-20 Susana I. C. J. Palma, Ana P. Traguedo, Ana R. Porteira, Maria J. Frias, Hugo Gamboa, Ana C. A. Roque
A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
A Legionella pneumophila amylase is essential for intracellular replication in human macrophages and amoebae Sci. Rep. (IF 4.259) Pub Date : 2018-04-20 Ashley Best, Christopher Price, Mateja Ozanic, Marina Santic, Snake Jones, Yousef Abu Kwaik
Legionella pneumophila invades protozoa with an “accidental” ability to cause pneumonia upon transmission to humans. To support its nutrition during intracellular residence, L. pneumophila relies on host amino acids as the main source of carbon and energy to feed the TCA cycle. Despite the apparent lack of a requirement for glucose for L. pneumophila growth in vitro and intracellularly, the organism contains multiple amylases, which hydrolyze polysaccharides into glucose monomers. Here we describe one predicted putative amylase, LamB, which is uniquely present only in L. pneumophila and L. steigerwaltii among the ~60 species of Legionella. Our data show that LamB has a strong amylase activity, which is abolished upon substitutions of amino acids that are conserved in the catalytic pocket of amylases. Loss of LamB or expression of catalytically-inactive variants of LamB results in a severe growth defect of L. pneumophila in Acanthamoeba polyphaga and human monocytes-derived macrophages. Importantly, the lamB null mutant is severely attenuated in intra-pulmonary proliferation in the mouse model and is defective in dissemination to the liver and spleen. Our data show an essential role for LamB in intracellular replication of L. pneumophila in amoeba and human macrophages and in virulence in vivo.
Postprandial glycemic control during gestational diabetes pregnancy predicts the risk of recurrence Sci. Rep. (IF 4.259) Pub Date : 2018-04-20 Naama Schwartz, Manfred S. Green, Enav Yefet, Zohar Nachum
In this study we aimed to explore the significance of glycemic control during gestational diabetes mellitus (GDM) pregnancy in predicting recurrence as this is unknown. A retrospective population-based cohort study of women with first diagnosed GDM pregnancy was conducted. A total of 426 women with 4,226 glucose charts were obtained. Daily glucose values were collected from the glucose charts. Non-parametric (LOWESS) regression was used to present the glucose measurements along the gestational weeks. The analyses revealed that the 2-hour postprandial levels among women with GDM recurrence were substantially higher throughout gestation (PR = 1.89 [95% CI: 1.33, 2.73] for every 20 mg/dl increase). In a multivariable log-binomial regression, the mean postprandial glucose was significantly associated with GDM recurrence (p = 0.017) after adjusting for maternal age, family history of diabetes, insulin use, and inter-pregnancy interval (PR = 1.04 [95% CI: 1.01, 1.07]). The study conclusion is that tighter postprandial glycemic control should be considered. Future studies should explore tighter cutoffs of the 2-hour postprandial glucose.
Innovatively Therapeutic Strategy on Lung Cancer by Daily Drinking Antioxidative Plasmon-Induced Activated Water Sci. Rep. (IF 4.259) Pub Date : 2018-04-20 Chien-Kai Wang, Hsiao-Chien Chen, Sheng-Uei Fang, Chia-Wen Ho, Cheng-Jeng Tai, Chih-Ping Yang, Yu-Chuan Liu
Many human diseases are inflammation-related, such as cancer and those associated with aging. Previous studies demonstrated that plasmon-induced activated (PIA) water with electron-doping character, created from hot electron transfer via decay of excited Au nanoparticles (NPs) under resonant illumination, owns reduced hydrogen-bonded networks and physchemically antioxidative properties. In this study, it is demonstrated PIA water dramatically induced a major antioxidative Nrf2 gene in human gingival fibroblasts which further confirms its cellular antioxidative and anti-inflammatory properties. Furthermore, mice implanted with mouse Lewis lung carcinoma (LLC-1) cells drinking PIA water alone or together with cisplatin treatment showed improved survival time compared to mice which consumed only deionized (DI) water. With the combination of PIA water and cisplatin administration, the survival time of LLC-1-implanted mice markedly increased to 8.01 ± 0.77 days compared to 6.38 ± 0.61 days of mice given cisplatin and normal drinking DI water. This survival time of 8.01 ± 0.77 days compared to 4.62 ± 0.71 days of mice just given normal drinking water is statistically significant (p = 0.009). Also, the gross observations and eosin staining results suggested that LLC-1-implanted mice drinking PIA water tended to exhibit less metastasis than mice given only DI water.
Psychological Stress Deteriorates Skin Barrier Function by Activating 11β-Hydroxysteroid Dehydrogenase 1 and the HPA Axis Sci. Rep. (IF 4.259) Pub Date : 2018-04-20 Sung Jay Choe, Donghye Kim, Eun Jung Kim, Joung-Sook Ahn, Eun-Jeong Choi, Eui Dong Son, Tae Ryong Lee, Eung Ho Choi
Psychological stress (PS) increases endogenous glucocorticoids (GC) by activating the hypothalamic-pituitary-adrenal axis. The negative effects of GC on skin barrier function under PS have been well-established. However, endogenous GC can also be active when cortisone (inactive form) is converted to cortisol (active form) by 11β-hydroxysteroid dehydrogenase type I (11ß-HSD1) in the peripheral tissue. Here, we evaluated the changes in 11ß-HSD1 and barrier function under PS. Elevated 11ß-HSD1 in oral mucosa correlated with increased cortisol in the stratum corneum and deteriorated barrier function. Expression of 11ß-HSD1 in the oral mucosa correlated with that in the epidermal keratinocytes. We further investigated whether barrier function improved when PS was relieved using a selective serotonin reuptake inhibitor (SSRI) in patients with anxiety. Decreased 11ß-HSD1 and improved barrier function were observed after SSRI treatment. The collective findings suggest that elevated 11ß-HSD1 under PS increases the level of cutaneous GC and eventually impairs barrier function. PS-alleviating drugs, such as SSRI, may help to treat PS-aggravated skin diseases.
Grain and starch granule morphology in superior and inferior kernels of maize in response to nitrogen Sci. Rep. (IF 4.259) Pub Date : 2018-04-20 Fucheng Zhao, Liquan Jing, Decheng Wang, Fei Bao, Weiping Lu, Guiyue Wang
Maize (Zea mays L.) contributes approximately 55% of China’s grain production. The effects of nitrogen (N) on maize grain morphology and starch granules remain elusive. In this study, a field experiment in clay loam soil was conducted using three maize hybrids (Suyu 30, Suyu 20, and Suyu 29) and four N levels (0, 360, 450, and 540 kg ha−1) in 2010 and 2012. The results indicated that increased grain length and width, starch granule number, surface area, and volume, was associated with the application of 450 kg ha−1 of N. Differences between superior (ear base) and inferior (apical) grains decreased under highest yield treatments. The effects of N levels on inferior grains was more than that on superior grains. The starch granules of superior grains showed more polygonal, and bigger shape than inferior grains. The results revealed that N levels affected size and morphology of starch granules and grains. The application of 450 kg N ha−1 resulted in larger-sized starch granules and less difference between superior and inferior grains.
Flux-tunable heat sink for quantum electric circuits Sci. Rep. (IF 4.259) Pub Date : 2018-04-20 M. Partanen, K. Y. Tan, S. Masuda, J. Govenius, R. E. Lake, M. Jenei, L. Grönberg, J. Hassel, S. Simbierowicz, V. Vesterinen, J. Tuorila, T. Ala-Nissila, M. Möttönen
Superconducting microwave circuits show great potential for practical quantum technological applications such as quantum information processing. However, fast and on-demand initialization of the quantum degrees of freedom in these devices remains a challenge. Here, we experimentally implement a tunable heat sink that is potentially suitable for the initialization of superconducting qubits. Our device consists of two coupled resonators. The first resonator has a high quality factor and a fixed frequency whereas the second resonator is designed to have a low quality factor and a tunable resonance frequency. We engineer the low quality factor using an on-chip resistor and the frequency tunability using a superconducting quantum interference device. When the two resonators are in resonance, the photons in the high-quality resonator can be efficiently dissipated. We show that the corresponding loaded quality factor can be tuned from above 105 down to a few thousand at 10 GHz in good quantitative agreement with our theoretical model.
Physiological function of phospholipase D2 in anti-tumor immunity: regulation of CD8+ T lymphocyte proliferation Sci. Rep. (IF 4.259) Pub Date : 2018-04-19 Van Ngo Thai Bich, Tsunaki Hongu, Yuki Miura, Naohiro Katagiri, Norihiko Ohbayashi, Yumi Yamashita-Kanemaru, Akira Shibuya, Yuji Funakoshi, Yasunori Kanaho
Two major phospholipase D (PLD) isozymes in mammals, PLD1 and PLD2, hydrolyze the membrane phospholipid phosphatidylcholine to choline and the lipid messenger phosphatidic acid. Although their roles in cancer cells have been well studied, their functions in tumor microenvironment have not yet been clarified. Here, we demonstrate that PLD2 in cytotoxic CD8+ T cells plays a crucial role in anti-tumor immunity by regulating their cell proliferation. We found that growth of tumors formed by subcutaneously transplanted cancer cells is enhanced in Pld2-knockout mice. Interestingly, this phenotype was found to be at least in part attributable to the ablation of Pld2 from bone marrow cells. The number of CD8+ T cells, which induce cancer cell death, significantly decreased in the tumor produced in Pld2-knockout mice. In addition, CD3/CD28-stimulated proliferation of primary cultured splenic CD8+ T cells is markedly suppressed by Pld2 ablation. Finally, CD3/CD28-dependent activation of Erk1/2 and Ras is inhibited in Pld2-deleted CD8+ T cells. Collectively, these results indicate that PLD2 in CD8+ T cells plays a key role in their proliferation through activation of the Ras/Erk signaling pathway, thereby regulating anti-tumor immunity.
iTRAQ-based quantitative proteomic analysis of embryonic developmental stages in Amur sturgeon, Acipenser schrenckii Sci. Rep. (IF 4.259) Pub Date : 2018-04-19 Shubo Jin, Dajiang Sun, Dan Song, Nianmin Wang, Hongtuo Fu, Feng Ji, Ying Zhang
The Amur sturgeon, Acipenser schrenckii, is an important aquaculture species in China with annual production of about 150 thousand tons in 2015. In this study, we investigated the regulatory proteins and pathways affecting embryonic development of Amur sturgeon, by analyzing of the differential proteomes among four embryonic developmental stages using isobaric tags for relative and absolute quantitation (iTRAQ), combined with the analysis of effects of microelements and antioxidants on embryonic development. Seventy-four, 77, and 76 proteins were differentially expressed according to iTRAQ analysis between the fertilized egg and blastula, blastula and neurula, and neurula and heart-beat stages, respectively. GO and KEGG enrichment analyses indicated that Gluconeogenesis, Ribosome and Proteasome were the most enriched pathways, which may promote energy formation, immune system protection and protein synthesis process in A. schrenckii. The measurement of microelements indicated that Mn, Cu and Fe were obtained from their parents or water environment in A. schrenckii, while Zn plays vital roles throughout embryonic development. The dramatically high level of malondialdehyde (MDA) across the embryonic development may be the main reason leading to a low hatching rate in A. schrenckii. This study provides the basis for further proteome analysis of embryonic development in A. schrenckii.
Light-induced propulsion of a giant liposome driven by peptide nanofibre growth Sci. Rep. (IF 4.259) Pub Date : 2018-04-19 Hiroshi Inaba, Akihito Uemura, Kazushi Morishita, Taiki Kohiki, Akira Shigenaga, Akira Otaka, Kazunori Matsuura
Light-driven nano/micromotors are attracting much attention, not only as molecular devices but also as components of bioinspired robots. In nature, several pathogens such as Listeria use actin polymerisation machinery for their propulsion. Despite the development of various motors, it remains challenging to mimic natural systems to create artificial motors propelled by fibre formation. Herein, we report the propulsion of giant liposomes driven by light-induced peptide nanofibre growth on their surface. Peptide-DNA conjugates connected by a photocleavage unit were asymmetrically introduced onto phase-separated giant liposomes. Ultraviolet (UV) light irradiation cleaved the conjugates and released peptide units, which self-assembled into nanofibres, driving the translational movement of the liposomes. The velocity of the liposomes reflected the rates of the photocleavage reaction and subsequent fibre formation of the peptide-DNA conjugates. These results showed that chemical design of the light-induced peptide nanofibre formation is a useful approach to fabricating bioinspired motors with controllable motility.
Oriented Polyaniline Nanowire Arrays Grown on Dendrimer (PAMAM) Functionalized Multiwalled Carbon Nanotubes as Supercapacitor Electrode Materials Sci. Rep. (IF 4.259) Pub Date : 2018-04-19 Lin Jin, Yu Jiang, Mengjie Zhang, Honglong Li, Linghan Xiao, Ming Li, Yuhui Ao
At present, PANI/MWNT composites have been paid more attention as promising electrode materials in supercapacitors. Yet some shortcomings still limit the widely application of PANI/MWNT electrolytes. In this work, in order to improve capacitance ability and long-term stability of electrode, a multi-amino dendrimer (PAMAM) had been covalently linked onto multi-walled carbon nanotubes (MWNT) as a bridge to facilitating covalent graft of polyaniline (PANI), affording P-MWNT/PANI electrode composites for supercapacitor. Surprisingly, ordered arrays of PANI nanowires on MWNT (setaria-like morphology) had been observed by scanning electron microscopy (SEM). Electrochemical properties of P-MWNT/PANI electrode had been characterized by cyclic voltammetry (CV) and galvanostatic charge-discharge technique. The specific capacitance and long cycle life of P-MWNT-PANI electrode material were both much higher than MWNT/PANI. These interesting results indicate that multi-amino dendrimer, PAMAM, covalently linked on MWNT provides more reaction sites for in-situ polymerization of ordered PANI, which could efficiently shorten the ion diffusion length in electrolytes and lead to making fully use of conducting materials.
Comparative transcriptome analysis to investigate the potential role of miRNAs in milk protein/fat quality Sci. Rep. (IF 4.259) Pub Date : 2018-04-19 Xuehui Wang, Li Zhang, Jing Jin, Anting Xia, Chunmei Wang, Yingjun Cui, Bo Qu, Qingzhang Li, Chunyan Sheng
miRNAs play an important role in the processes of cell differentiation, biological development, and physiology. Here we investigated the molecular mechanisms regulating milk secretion and quality in dairy cows via transcriptome analyses of mammary gland tissues from dairy cows during the high-protein/high-fat, low-protein/low-fat or dry periods. To characterize the important roles of miRNAs and mRNAs in milk quality and to elucidate their regulatory networks in relation to milk secretion and quality, an integrated analysis was performed. A total of 25 core miRNAs were found to be differentially expressed (DE) during lactation compared to non-lactation, and these miRNAs were involved in epithelial cell terminal differentiation and mammary gland development. In addition, comprehensive analysis of mRNA and miRNA expression between high-protein/high-fat group and low-protein/low-fat groups indicated that, 38 miRNAs and 944 mRNAs were differentially expressed between them. Furthermore, 38 DE miRNAs putatively negatively regulated 253 DE mRNAs. The putative genes (253 DE mRNAs) were enriched in lipid biosynthetic process and amino acid transmembrane transporter activity. Moreover, putative DE genes were significantly enriched in fatty acid (FA) metabolism, biosynthesis of amino acids, synthesis and degradation of ketone bodies and biosynthesis of unsaturated FAs. Our results suggest that DE miRNAs might play roles as regulators of milk quality and milk secretion during mammary gland differentiation.
Short-term visual deprivation boosts the flexibility of body representation Sci. Rep. (IF 4.259) Pub Date : 2018-04-19 Dominika Radziun, H. Henrik Ehrsson
Short-term visual deprivation by blindfolding influences tactile acuity and orientation in space and, on a neural level, leads to enhanced excitability of visual and motor cortices. However, to the best of our knowledge, the possible effects of short-term visual deprivation on body representation have not been examined. In the present study, we tested two groups of 30 healthy participants with the somatic rubber hand illusion, a well-established paradigm to probe the dynamic plasticity of body representation. Before the start of the procedure, the experimental group was blindfolded for 120 minutes, while the control group wore transparent goggles for the same amount of time. We found that although there was no difference in the subjective feeling of ownership of the rubber hand during the illusion, the blindfolded group showed a significantly larger recalibration of hand position sense towards the location of the rubber hand than the control group. This finding suggests that short-term visual deprivation boosts plasticity of body representation in terms of multisensory spatial recalibration of hand position sense.
Celecoxib exerts protective effects in the vascular endothelium via COX-2-independent activation of AMPK-CREB-Nrf2 signalling Sci. Rep. (IF 4.259) Pub Date : 2018-04-19 Fahad Al-Rashed, Damien Calay, Marie Lang, Clare C. Thornton, Andrea Bauer, Allan Kiprianos, Dorian O. Haskard, Anusha Seneviratne, Joseph J. Boyle, Alex H. Schönthal, Caroline P. Wheeler-Jones, Justin C. Mason
Although concern remains about the athero-thrombotic risk posed by cyclo-oxygenase (COX)-2-selective inhibitors, recent data implicates rofecoxib, while celecoxib appears equivalent to NSAIDs naproxen and ibuprofen. We investigated the hypothesis that celecoxib activates AMP kinase (AMPK) signalling to enhance vascular endothelial protection. In human arterial and venous endothelial cells (EC), and in contrast to ibuprofen and naproxen, celecoxib induced the protective protein heme oxygenase-1 (HO-1). Celecoxib derivative 2,5-dimethyl-celecoxib (DMC) which lacks COX-2 inhibition also upregulated HO-1, implicating a COX-2-independent mechanism. Celecoxib activated AMPKα(Thr172) and CREB-1(Ser133) phosphorylation leading to Nrf2 nuclear translocation. Importantly, these responses were not reproduced by ibuprofen or naproxen, while AMPKα silencing abrogated celecoxib-mediated CREB and Nrf2 activation. Moreover, celecoxib induced H-ferritin via the same pathway, and increased HO-1 and H-ferritin in the aortic endothelium of mice fed celecoxib (1000 ppm) or control chow. Functionally, celecoxib inhibited TNF-α-induced NF-κB p65(Ser536) phosphorylation by activating AMPK. This attenuated VCAM-1 upregulation via induction of HO-1, a response reproduced by DMC but not ibuprofen or naproxen. Similarly, celecoxib prevented IL-1β-mediated induction of IL-6. Celecoxib enhances vascular protection via AMPK-CREB-Nrf2 signalling, a mechanism which may mitigate cardiovascular risk in patients prescribed celecoxib. Understanding NSAID heterogeneity and COX-2-independent signalling will ultimately lead to safer anti-inflammatory drugs.
Author Correction: Effect of compressibility and non-uniformity in flow on the scattering pattern of acoustic cloak Sci. Rep. (IF 4.259) Pub Date : 2018-04-19 Hyeonbin Ryoo, Wonju Jeon
A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
Difference in virulence and composition of a cariogenic biofilm according to substratum direction Sci. Rep. (IF 4.259) Pub Date : 2018-04-19 Minh-Huy Dang, Ji-Eun Jung, Hyeon-Mi Choi, Jae-Gyu Jeon
The aim of this study was to investigate the difference in composition and virulence of Streptococcus mutans biofilms according to substratum direction. S. mutans biofilms (46-h-old) were formed on three different saliva-coated hydroxyapatite (sHA) disc direction groups: downward (discs placed in the direction of gravity), vertical (discs placed parallel to gravity direction), and upward (discs placed opposite to gravity). The 46-h-old biofilms on sHA discs in the upward direction showed the highest biofilm accumulation, colony forming unit (CFU) count, and extracellular polysaccharide (EPS) amount, followed by those in the vertical and downward directions. In the confocal laser scanning microscopy (CLSM) study, the biofilms in the upward direction also showed the highest bacterial count (live or dead cells) and EPS biovolume. Scanning electron microscopy (SEM) analysis confirmed the microbiological and biochemical results. In addition, biofilm density and acid production were higher in the upward direction than those in the other directions. Our findings suggest that substratum direction, which might be related to gravity, strongly influences the formation and virulence of cariogenic biofilms and subsequent initiation of dental caries. Collectively, the differences in the formation and virulence of cariogenic biofilms are related to the direction of tooth surface (occlusal surfaces of mandibular teeth > proximal surfaces > occlusal surfaces of maxillary teeth).
Ultrasound-Activated Piezoelectric Nanoparticles Inhibit Proliferation of Breast Cancer Cells Sci. Rep. (IF 4.259) Pub Date : 2018-04-19 Attilio Marino, Matteo Battaglini, Daniele De Pasquale, Andrea Degl’Innocenti, Gianni Ciofani
A nanotechnology-based approach for the inhibition of breast cancer cell proliferation is proposed. The innovative solution consists in a platform based on biocompatible piezoelectric nanoparticles able to target and remotely stimulate HER2-positive breast cancer cells. The anti-proliferative effects of the ultrasound-driven piezoelectric nanoparticle-assisted stimulation significantly reduced the proliferation by inducing the cell cycle arrest. Similarly to a low-intensity alternating electric field, chronic piezoelectric stimulation resulted able to inhibit cancer cell proliferation by upregulating the expression of the gene encoding Kir3.2 inward rectifier potassium channels, by interfering on Ca2+ homeostasis, and by affecting the organization of mitotic spindles during mitosis. The proposed platform, even if specific for HER2-positive cells, shows huge potential and versatility for the treatment of different type of cancers.
Emergence of Vancomycin-Resistant Enterococcus faecium at an Australian Hospital: A Whole Genome Sequencing Analysis Sci. Rep. (IF 4.259) Pub Date : 2018-04-19 Kelvin W. C. Leong, Louise A. Cooley, Tara L. Anderson, Sanjay S. Gautam, Belinda McEwan, Anne Wells, Fiona Wilson, Lucy Hughson, Ronan F. O’Toole
In 2015, a marked increase in vancomycin-resistant Enterococcus faecium (VREfm) isolation was detected at the Royal Hobart Hospital, Australia. The primary objective of this work was to examine the dynamics of VREfm transmission using whole genome data mapped to public health surveillance information. Screening and clinical isolates of VREfm from patients were typed for the specific vancomycin-resistance locus present. Of total isolates collected from 2014–2016 (n = 222), 15.3% and 84.7% harboured either the vanA or the vanB vancomycin-resistance locus, respectively. Whole-genome sequencing of 80 isolates was performed in conjunction with single-nucleotide polymorphic (SNP) analysis and in silico multi-locus sequence typing (MLST). Among the isolates sequenced, 5 phylogenetic clades were identified. The largest vanB clade belonged to MLST sequence type ST796 and contained clinical isolates from VREfm infections that clustered closely with isolates from colonised patients. Correlation of VREfm genotypes with spatio-temporal patient movements detected potential points of transmission within the hospital. ST80 emerged as the major vanA sequence type for which the most likely index case of a patient cluster was ascertained from SNP analyses. This work has identified the dominant clones associated with increased VREfm prevalence in a healthcare setting, and their likely direction of transmission.
Author Correction: Exercise – induced changes in cerebrospinal fluid miRNAs in Gulf War Illness, Chronic Fatigue Syndrome and sedentary control subjects Sci. Rep. (IF 4.259) Pub Date : 2018-04-19 James N. Baraniuk, Narayan Shivapurkar
Population Structure Promotes the Evolution of Intuitive Cooperation and Inhibits Deliberation Sci. Rep. (IF 4.259) Pub Date : 2018-04-19 Mohsen Mosleh, David G. Rand
Spatial structure is one of the most studied mechanisms in evolutionary game theory. Here, we explore the consequences of spatial structure for a question which has received considerable empirical and theoretical attention in recent years, but has not yet been studied from a network perspective: whether cooperation relies on intuitive predispositions or deliberative self-control. We examine this question using a model which integrates the “dual-process” framework from cognitive science with evolutionary game theory, and considers the evolution of agents who are embedded within a social network and only interact with their neighbors. In line with past work in well-mixed populations, we find that selection favors either the intuitive defector strategy which never deliberates, or the dual-process cooperator strategy which intuitively cooperates but uses deliberation to switch to defection when doing so is payoff-maximizing. We find that sparser networks (i.e., smaller average degree) facilitate the success of dual-process cooperators over intuitive defectors, while also reducing the level of deliberation that dual-process cooperators engage in; and that these results generalize across different kinds of networks. These observations demonstrate the important role that spatial structure can have not just on the evolution of cooperation, but on the co-evolution of cooperation and cognition.
Amino Acid Signature in Human Melanoma Cell Lines from Different Disease Stages Sci. Rep. (IF 4.259) Pub Date : 2018-04-19 Christine Wasinger, Alexandra Hofer, Oliver Spadiut, Martin Hohenegger
Cancer cells rewire metabolism to sustain high proliferation rates. Beside glycolysis and glutaminolysis, amino acids substitute as energy source, feed fatty acid biosynthesis and represent part of the secretome of transformed cells, including melanoma. We have therefore investigated acetate, pyruvate and the amino acid composition of the secretome of human melanoma cells representing the early slow (WM35, WM278, WM793b and VM21) and metastatic fast (A375, 518a2, 6F and WM8) growth phase in order to identify possible signalling components within these profiles. Proliferation assays and a principle component analysis revealed a stringent difference between the fast and slow growing melanoma cells. Moreover, upon inhibition of the mevalonate pathway, glutamic acid and alanine were identified as the central difference in the conditional media. A supplementation of the media with glutamic acid and the combination with alanine significantly accelerated the proliferation, migration and invasion of early stage melanoma cells, but not metastatic cells. Finally, the inhibition of the mevalonate pathway abolished the growth advantage of the melanoma cells in a time dependent manner. Taken together, these data corroborate a stage specific response in growth and aggressiveness to extracellular glutamic acid and alanine, indicative for microenvironmental signalling of individual amino acids.
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