bluuebunny/crossref_metadata_2025 huggingface dataset:
The use of radiocobalt as a label improves imaging of EGFR using DOTA-conjugated Affibody molecule
Authors: Garousi Javad , Andersson Ken G. , Dam Johan H. , Olsen Birgitte B. , Mitran Bogdan , Orlova Anna , Buijs Jos , Ståhl Stefan , Löfblom John , Thisgaard Helge , Tolmachev Vladimir
Published: July 2017

Several anti-cancer therapies target the epidermal growth factor receptor (EGFR). Radionuclide imaging of EGFR expression in tumours may aid in selection of optimal cancer therapy. The 111In-labelled DOTA-conjugated ZEGFR:2377 Affibody molecule was successfully used for imaging of EGFR-expressing xenografts in mice. An optimal combination of radionuclide, chelator and targeting protein may further improve the contrast of radionuclide imaging. The aim of this study was to evaluate the targeting properties of radiocobalt-labelled DOTA-ZEGFR:2377. DOTA-ZEGFR:2377 was labelled with 57Co (T1/2 = 271.8 d), 55Co (T1/2 = 17.5 h), and, for comparison, with the positron-emitting radionuclide 68Ga (T1/2 = 67.6 min) with preserved specificity of binding to EGFR-expressing A431 cells. The long-lived cobalt radioisotope 57Co was used in animal studies. Both 57Co-DOTA-ZEGFR:2377 and 68Ga-DOTA-ZEGFR:2377 demonstrated EGFR-specific accumulation in A431 xenografts and EGFR-expressing tissues in mice. Tumour-to-organ ratios for the radiocobalt-labelled DOTA-ZEGFR:2377 were significantly higher than for the gallium-labelled counterpart already at 3 h after injection. Importantly, 57Co-DOTA-ZEGFR:2377 demonstrated a tumour-to-liver ratio of 3, which is 7-fold higher than the tumour-to-liver ratio for 68Ga-DOTA-ZEGFR:2377. The results of this study suggest that the positron-emitting cobalt isotope 55Co would be an optimal label for DOTA-ZEGFR:2377 and further development should concentrate on this radionuclide as a label.
Learning a Health Knowledge Graph from Electronic Medical Records
Authors: Rotmensch Maya , Halpern Yoni , Tlimat Abdulhakim , Horng Steven , Sontag David
Published: July 2017

Demand for clinical decision support systems in medicine and self-diagnostic symptom checkers has substantially increased in recent years. Existing platforms rely on knowledge bases manually compiled through a labor-intensive process or automatically derived using simple pairwise statistics. This study explored an automated process to learn high quality knowledge bases linking diseases and symptoms directly from electronic medical records. Medical concepts were extracted from 273,174 de-identified patient records and maximum likelihood estimation of three probabilistic models was used to automatically construct knowledge graphs: logistic regression, naive Bayes classifier and a Bayesian network using noisy OR gates. A graph of disease-symptom relationships was elicited from the learned parameters and the constructed knowledge graphs were evaluated and validated, with permission, against Google’s manually-constructed knowledge graph and against expert physician opinions. Our study shows that direct and automated construction of high quality health knowledge graphs from medical records using rudimentary concept extraction is feasible. The noisy OR model produces a high quality knowledge graph reaching precision of 0.85 for a recall of 0.6 in the clinical evaluation. Noisy OR significantly outperforms all tested models across evaluation frameworks (p < 0.01).
Effects of cardiac timing and peripheral resistance on measurement of pulse wave velocity for assessment of arterial stiffness
Authors: Xiao Hanguang , Butlin Mark , Tan Isabella , Avolio Alberto
Published: July 2017

To investigate the effects of heart rate (HR), left ventricular ejection time (LVET) and wave reflection on arterial stiffness as assessed by pulse wave velocity (PWV), a pulse wave propagation simulation system (PWPSim) based on the transmission line model of the arterial tree was developed and was applied to investigate pulse wave propagation. HR, LVET, arterial elastic modulus and peripheral resistance were increased from 60 to 100 beats per minute (bpm), 0.1 to 0.45 seconds, 0.5 to 1.5 times and 0.5 to 1.5 times of the normal value, respectively. Carotid-femoral PWV (cfPWV) and brachial-ankle PWV (baPWV) were calculated by intersecting tangent method (cfPWVtan and baPWVtan), maximum slope (cfPWVmax and baPWVmax), and using the Moens-Korteweg equation ($${\bf{cfPW}}{{\bf{V}}}_{{{\bf{c}}}_{{\bf{0}}}}$$
cfPW

V

c

0

and $${\bf{baPW}}{{\bf{V}}}_{{{\bf{c}}}_{{\bf{0}}}}$$
baPW

V

c

0

). Results showed cfPWV and baPWV increased significantly with arterial elastic modulus but did not increase with HR when using a constant elastic modulus. However there were significant LVET dependencies of cfPWVtan and baPWVtan (0.17 ± 0.13 and 0.17 ± 0.08 m/s per 50 ms), and low peripheral resistance dependencies of cfPWVtan, cfPWVmax, baPWVtan and baPWVmax (0.04 ± 0.01, 0.06 ± 0.04, 0.06 ± 0.03 and 0.09 ± 0.07 m/s per 10% peripheral resistance), respectively. This study demonstrated that LVET dominates the effect on calculated PWV compared to HR and peripheral resistance when arterial elastic modulus is constant.
Remarkable hexafunctional anion receptor with operational urea-based inner cleft and thiourea-based outer cleft: Novel design with high-efficiency for sulfate binding
Authors: Emami Khansari Maryam , Mirchi Ali , Pramanik Avijit , Johnson Corey R. , Leszczynski Jerzy , Hossain Md. Alamgir
Published: July 2017

The recognition of anions by designed receptors has attracted much attention in recent days. In particular, the selective binding of sulfate with artificial receptors is important because of its relevance to many biological and environmental applications. However, the development of organized molecular receptors with high-efficiency for sulfate binding still remains a significant challenge. We report a novel para-phenylene-bridged hexafunctional tripodal receptor that contains a urea-based inner cleft and a thiourea-based outer cleft, providing perfect sites for step-wise binding of two anions within a single cavity. The new receptor was synthesized in a three-step process, and was investigated for its anion binding properties by 1H NMR titrations, 2D NOESY experiments and computational studies. As indicated by solution binding studies, the receptor selectively binds sulfate over other oxoanions, forming a 1:2 stoichiometric complex that is stabilized via strong H-bonding interactions. High-level DFT calculations reveal that the receptor, owing to the enhanced H-bonding ability of thiourea groups, initially encapsulates one sulfate in its thiourea-based outer cleft, followed by a second encapsulation in its urea-based inner cleft. Such a functionalized receptor with the unique combination of urea-based cleft and thiourea-based cleft in a single receptor has not been reported previously.
Deletion of the celA gene in Aspergillus nidulans triggers overexpression of secondary metabolite biosynthetic genes
Authors: Guerriero Gea , Silvestrini Lucia , Legay Sylvain , Maixner Frank , Sulyok Michael , Hausman Jean-Francois , Strauss Joseph
Published: July 2017

Although much progress has been made in the study of cell wall biosynthetic genes in the model filamentous fungus Aspergillus nidulans, there are still targets awaiting characterization. An example is the gene celA (ANIA_08444) encoding a putative mixed linkage glucan synthase. To characterize the role of celA, we deleted it in A. nidulans, analyzed the phenotype of the mycelium and performed RNA-Seq. The strain shows a very strong phenotype, namely “balloons” along the hyphae and aberrant conidiophores, as well as an altered susceptibility to cell wall drugs. These data suggest a potential role of the gene in cell wall-related processes. The Gene Ontology term Enrichment analysis shows increased expression of secondary metabolite biosynthetic genes (sterigmatocystin in particular) in the deleted strain. Our results show that the deletion of celA triggers a strong phenotype reminiscent of cell wall-related aberrations and the upregulation of some secondary metabolite gene clusters in A. nidulans.
Sphingomimetic multiple sclerosis drug FTY720 activates vesicular synaptobrevin and augments neuroendocrine secretion
Authors: Darios Frederic D. , Jorgacevski Jernej , Flašker Ajda , Zorec Robert , García-Martinez Virginia , Villanueva José , Gutiérrez Luis M. , Leese Charlotte , Bal Manjot , Nosyreva Elena , Kavalali Ege T. , Davletov Bazbek
Published: July 2017

Neurotransmission and secretion of hormones involve a sequence of protein/lipid interactions with lipid turnover impacting on vesicle trafficking and ultimately fusion of secretory vesicles with the plasma membrane. We previously demonstrated that sphingosine, a sphingolipid metabolite, promotes formation of the SNARE complex required for membrane fusion and also increases the rate of exocytosis in isolated nerve terminals, neuromuscular junctions, neuroendocrine cells and in hippocampal neurons. Recently a fungi-derived sphingosine homologue, FTY720, has been approved for treatment of multiple sclerosis. In its non-phosphorylated form FTY720 accumulates in the central nervous system, reaching high levels which could affect neuronal function. Considering close structural similarity of sphingosine and FTY720 we investigated whether FTY720 has an effect on regulated exocytosis. Our data demonstrate that FTY720 can activate vesicular synaptobrevin for SNARE complex formation and enhance exocytosis in neuroendocrine cells and neurons.
A new approach for ratiometric in vivo calcium imaging of microglia
Authors: Brawek Bianca , Liang Yajie , Savitska Daria , Li Kaizhen , Fomin-Thunemann Natalie , Kovalchuk Yury , Zirdum Elizabeta , Jakobsson Johan , Garaschuk Olga
Published: July 2017

Microglia, resident immune cells of the brain, react to the presence of pathogens/danger signals with a large repertoire of functional responses including morphological changes, proliferation, chemotaxis, production/release of cytokines, and phagocytosis. In vitro studies suggest that many of these effector functions are Ca2+-dependent, but our knowledge about in vivo Ca2+ signalling in microglia is rudimentary. This is mostly due to technical reasons, as microglia largely resisted all attempts of in vivo labelling with Ca2+ indicators. Here, we introduce a novel approach, utilizing a microglia-specific microRNA-9-regulated viral vector, enabling the expression of a genetically-encoded ratiometric Ca2+ sensor Twitch-2B in microglia. The Twitch-2B-assisted in vivo imaging enables recording of spontaneous and evoked microglial Ca2+ signals and allows for the first time to monitor the steady state intracellular Ca2+ levels in microglia. Intact in vivo microglia show very homogenous and low steady state intracellular Ca2+ levels. However, the levels increase significantly after acute slice preparation and cell culturing along with an increase in the expression of activation markers CD68 and IL-1β. These data identify the steady state intracellular Ca2+ level as a versatile microglial activation marker, which is highly sensitive to the cell’s environment.
An ecological and digital epidemiology analysis on the role of human behavior on the 2014 Chikungunya outbreak in Martinique
Authors: Roche Benjamin , Gaillard Béatrice , Léger Lucas , Pélagie-Moutenda Renélise , Sochacki Thomas , Cazelles Bernard , Ledrans Martine , Blateau Alain , Fontenille Didier , Etienne Manuel , Simard Frédéric , Salathé Marcel , Yébakima André
Published: July 2017

Understanding the spatio-temporal dynamics of endemic infections is of critical importance for a deeper understanding of pathogen transmission, and for the design of more efficient public health strategies. However, very few studies in this domain have focused on emerging infections, generating a gap of knowledge that hampers epidemiological response planning. Here, we analyze the case of a Chikungunya outbreak that occurred in Martinique in 2014. Using time series estimates from a network of sentinel practitioners covering the entire island, we first analyze the spatio-temporal dynamics and show that the largest city has served as the epicenter of this epidemic. We further show that the epidemic spread from there through two different propagation waves moving northwards and southwards, probably by individuals moving along the road network. We then develop a mathematical model to explore the drivers of the temporal dynamics of this mosquito-borne virus. Finally, we show that human behavior, inferred by a textual analysis of messages published on the social network Twitter, is required to explain the epidemiological dynamics over time. Overall, our results suggest that human behavior has been a key component of the outbreak propagation, and we argue that such results can lead to more efficient public health strategies specifically targeting the propagation process.
Multiomics analysis of the giant triton snail salivary gland, a crown-of-thorns starfish predator
Authors: Bose U. , Wang T. , Zhao M. , Motti C. A. , Hall M. R. , Cummins S. F.
Published: July 2017

The giant triton snail (Charonia tritonis) is one of the few natural predators of the adult Crown-of-Thorns starfish (COTS), a corallivore that has been damaging to many reefs in the Indo-Pacific. Charonia species have large salivary glands (SGs) that are suspected to produce either a venom and/or sulphuric acid which can immobilize their prey and neutralize the intrinsic toxic properties of COTS. To date, there is little information on the types of toxins produced by tritons. In this paper, the predatory behaviour of the C. tritonis is described. Then, the C. tritonis SG, which itself is made up of an anterior lobe (AL) and posterior lobe (PL), was analyzed using an integrated transcriptomics and proteomics approach, to identify putative toxin- and feeding-related proteins. A de novo transcriptome database and in silico protein analysis predicts that ~3800 proteins have features consistent with being secreted. A gland-specific proteomics analysis confirmed the presence of numerous SG-AL and SG-PL proteins, including those with similarity to cysteine-rich venom proteins. Sulfuric acid biosynthesis enzymes were identified, specific to the SG-PL. Our analysis of the C. tritonis SG (AL and PL) has provided a deeper insight into the biomolecular toolkit used for predation and feeding by C. tritonis.
Extensive astrocyte synchronization advances neuronal coupling in slow wave activity in vivo
Authors: Szabó Zsolt , Héja László , Szalay Gergely , Kékesi Orsolya , Füredi András , Szebényi Kornélia , Dobolyi Árpád , Orbán Tamás I. , Kolacsek Orsolya , Tompa Tamás , Miskolczy Zsombor , Biczók László , Rózsa Balázs , Sarkadi Balázs , Kardos Julianna
Published: July 2017

Slow wave activity (SWA) is a characteristic brain oscillation in sleep and quiet wakefulness. Although the cell types contributing to SWA genesis are not yet identified, the principal role of neurons in the emergence of this essential cognitive mechanism has not been questioned. To address the possibility of astrocytic involvement in SWA, we used a transgenic rat line expressing a calcium sensitive fluorescent protein in both astrocytes and interneurons and simultaneously imaged astrocytic and neuronal activityin vivo. Here we demonstrate, for the first time, that the astrocyte network display synchronized recurrent activityin vivocoupled to UP states measured by field recording and neuronal calcium imaging. Furthermore, we present evidence that extensive synchronization of the astrocytic network precedes the spatial build-up of neuronal synchronization. The earlier extensive recruitment of astrocytes in the synchronized activity is reinforced by the observation that neurons surrounded by active astrocytes are more likely to join SWA, suggesting causality. Further supporting this notion, we demonstrate that blockade of astrocytic gap junctional communication or inhibition of astrocytic Ca2+transients reduces the ratio of both astrocytes and neurons involved in SWA. Thesein vivofindings conclusively suggest a causal role of the astrocytic syncytium in SWA generation.
A genomic glance through the fog of plasticity and diversification in Pocillopora
Authors: Johnston Erika C. , Forsman Zac H. , Flot Jean-François , Schmidt-Roach Sebastian , Pinzón Jorge H. , Knapp Ingrid S. S. , Toonen Robert J.
Published: July 2017

Scleractinian corals of the genus Pocillopora (Lamarck, 1816) are notoriously difficult to identify morphologically with considerable debate on the degree to which phenotypic plasticity, introgressive hybridization and incomplete lineage sorting obscure well-defined taxonomic lineages. Here, we used RAD-seq to resolve the phylogenetic relationships among seven species of Pocillopora represented by 15 coral holobiont metagenomic libraries. We found strong concordance between the coral holobiont datasets, reads that mapped to the Pocillopora damicornis (Linnaeus, 1758) transcriptome, nearly complete mitochondrial genomes, 430 unlinked high-quality SNPs shared across all Pocillopora taxa, and a conspecificity matrix of the holobiont dataset. These datasets also show strong concordance with previously published clustering of the mitochondrial clades based on the mtDNA open reading frame (ORF). We resolve seven clear monophyletic groups, with no evidence for introgressive hybridization among any but the most recently derived sister species. In contrast, ribosomal and histone datasets, which are most commonly used in coral phylogenies to date, were less informative and contradictory to these other datasets. These data indicate that extant Pocillopora species diversified from a common ancestral lineage within the last ~3 million years. Key to this evolutionary success story may be the high phenotypic plasticity exhibited by Pocillopora species.
The rhizosphere microbiome of burned holm-oak: potential role of the genus Arthrobacter in the recovery of burned soils
Authors: Fernández-González Antonio J. , Martínez-Hidalgo Pilar , Cobo-Díaz José F. , Villadas Pablo J. , Martínez-Molina Eustoquio , Toro Nicolás , Tringe Susannah G. , Fernández-López Manuel
Published: July 2017

After a forest wildfire, the microbial communities have a transient alteration in their composition. The role of the soil microbial community in the recovery of an ecosystem following such an event remains poorly understood. Thus, it is necessary to understand the plant-microbe interactions that occur in burned soils. By high-throughput sequencing, we identified the main bacterial taxa of burnt holm-oak rhizosphere, then we obtained an isolate collection of the most abundant genus and its growth promoting activities were characterised. 16S rRNA amplicon sequencing showed that the genus Arthrobacter comprised more than 21% of the total community. 55 Arthrobacter strains were isolated and characterized using RAPDs and sequencing of the almost complete 16S rRNA gene. Our results indicate that isolated Arthrobacter strains present a very high genetic diversity, and they could play an important ecological role in interaction with the host plant by enhancing aerial growth. Most of the selected strains exhibited a great ability to degrade organic polymers in vitro as well as possibly presenting a direct mechanism for plant growth promotion. All the above data suggests that Arthrobacter can be considered as an excellent PGP rhizobacterium that may play an important role in the recovery of burned holm-oak forests.
Identification and structural characterization of LytU, a unique peptidoglycan endopeptidase from the lysostaphin family
Authors: Raulinaitis Vytas , Tossavainen Helena , Aitio Olli , Juuti Jarmo T. , Hiramatsu Keiichi , Kontinen Vesa , Permi Perttu
Published: July 2017

We introduce LytU, a short member of the lysostaphin family of zinc-dependent pentaglycine endopeptidases. It is a potential antimicrobial agent for S. aureus infections and its gene transcription is highly upregulated upon antibiotic treatments along with other genes involved in cell wall synthesis. We found this enzyme to be responsible for the opening of the cell wall peptidoglycan layer during cell divisions in S. aureus. LytU is anchored in the plasma membrane with the active part residing in the periplasmic space. It has a unique Ile/Lys insertion at position 151 that resides in the catalytic site-neighbouring loop and is vital for the enzymatic activity but not affecting the overall structure common to the lysostaphin family. Purified LytU lyses S. aureus cells and cleaves pentaglycine, a reaction conveniently monitored by NMR spectroscopy. Substituting the cofactor zinc ion with a copper or cobalt ion remarkably increases the rate of pentaglycine cleavage. NMR and isothermal titration calorimetry further reveal that, uniquely for its family, LytU is able to bind a second zinc ion which is coordinated by catalytic histidines and is therefore inhibitory. The pH-dependence and high affinity of binding carry further physiological implications.
Maize (Zea mays L.) genome size indicated by 180-bp knob abundance is associated with flowering time
Authors: Jian Yinqiao , Xu Cheng , Guo Zifeng , Wang Shanhong , Xu Yunbi , Zou Cheng
Published: July 2017

Flowering time is considered one of the most important agronomic traits in maize (Zea mays L.), and previous studies have indicated that this trait is correlated with genome size. We observed a significant difference in genome size between tropical and temperate inbred lines and a moderate positive correlation between genome size and 180-bp knob abundance determined by high-throughput sequencing in maize inbred lines in this study. We assembled the reads that were mapped to 180-bp knob sequences and found that the top ten abundant 180-bp knob sequences are highly variable. Moreover, our results indicate that genome size is associated with the flowering time of both male and female flowers, in both tropical and temperate inbred lines and under both tropical and temperate environments. To identify loci associated with genome size, we performed a genome-wide association study. The analysis identified three genomic regions associated with genome size, of which two were novel while the third one is located close to the known knobs K8L1 and K8L2. Overall, our results indicate that selection for breeding materials with earlier flowering times can be assisted by choosing germplasms with smaller genome sizes and that genome size can be determined based on the abundance of 180-bp knobs.
Genetic variants including markers from the exome chip and metabolite traits of type 2 diabetes
Authors: Jäger Susanne , Wahl Simone , Kröger Janine , Sharma Sapna , Hoffmann Per , Floegel Anna , Pischon Tobias , Prehn Cornelia , Adamski Jerzy , Müller-Nurasyid Martina , Waldenberger Melanie , Strauch Konstantin , Peters Annette , Gieger Christian , Suhre Karsten , Grallert Harald , Boeing Heiner , Schulze Matthias B. , Meidtner Karina
Published: July 2017

Diabetes-associated metabolites may aid the identification of new risk variants for type 2 diabetes. Using targeted metabolomics within a subsample of the German EPIC-Potsdam study (n = 2500), we tested previously published SNPs for their association with diabetes-associated metabolites and conducted an additional exploratory analysis using data from the exome chip including replication within 2,692 individuals from the German KORA F4 study. We identified a total of 16 loci associated with diabetes-related metabolite traits, including one novel association between rs499974 (MOGAT2) and a diacyl-phosphatidylcholine ratio (PC aa C40:5/PC aa C38:5). Gene-based tests on all exome chip variants revealed associations betweenGFRALand PC aa C42:1/PC aa C42:0,BIN1and SM (OH) C22:2/SM C18:0 andTFRCand SM (OH) C22:2/SM C16:1). Selecting variants for gene-based tests based on functional annotation identified one additional association betweenOR51Q1and hexoses. Among single genetic variants consistently associated with diabetes-related metabolites, two (rs174550 (FADS1), rs3204953 (REV3L)) were significantly associated with type 2 diabetes in large-scale meta-analysis for type 2 diabetes. In conclusion, we identified a novel metabolite locus in single variant analyses and four genes within gene-based tests and confirmed two previously known mGWAS loci which might be relevant for the risk of type 2 diabetes.
Proteomic profiling of the weed feverfew, a neglected pollen allergen source
Authors: Pablos Isabel , Eichhorn Stephanie , Briza Peter , Asam Claudia , Gartner Ulrike , Wolf Martin , Ebner Christof , Bohle Barbara , Arora Naveen , Vieths Stefan , Ferreira Fatima , Gadermaier Gabriele
Published: July 2017

Feverfew (Parthenium hysterophorus), an invasive weed from the Asteraceae family, has been reported as allergen source. Despite its relevance, knowledge of allergens is restricted to a partial sequence of a hydroxyproline-rich glycoprotein. We aimed to obtain the entire sequence for recombinant production and characterize feverfew pollen using proteomics and immunological assays. Par h 1, a defensin-proline fusion allergen was obtained by cDNA cloning and recombinantly produced in E. coli. Using two complementary proteomic strategies, a total of 258 proteins were identified in feverfew pollen among those 47 proteins belonging to allergenic families. Feverfew sensitized patients’ sera from India revealed IgE reactivity with a pectate lyase, PR-1 protein and thioredoxin in immonoblot. In ELISA, recombinant Par h 1 was recognized by 60 and 40% of Austrian and Indian sera, respectively. Inhibition assays demonstrated the presence of IgE cross-reactive Par h 1, pectate lyase, lipid-transfer protein, profilin and polcalcin in feverfew pollen. This study reveals significant data on the allergenic composition of feverfew pollen and makes recombinant Par h 1 available for cross-reactivity studies. Feverfew might become a global player in weed pollen allergy and inclusion of standardized extracts in routine allergy diagnosis is suggested in exposed populations.
Inflammatory monocytes regulate Th1 oriented immunity to CpG adjuvanted protein vaccines through production of IL-12
Authors: De Koker S. , Van Hoecke L. , De Beuckelaer A. , Roose K. , Deswarte K. , Willart M. A. , Bogaert P. , Naessens T. , De Geest B. G. , Saelens X. , Lambrecht B. N. , Grooten J.
Published: July 2017

Due to their capacity to skew T cell responses towards Th1 oriented immunity, oligonucleotides containing unmethylated CpG motifs (CpG) have emerged as interesting adjuvants for vaccination. Whereas the signalling pathways in response to CpG mediated TLR9 activation have been extensively documented at the level of the individual cell, little is however known on the precise identity of the innate immune cells that govern T cell priming and polarisation to CpG adjuvanted protein antigens in vivo. In this study, we demonstrate that optimal induction of Th1 oriented immunity to CpG adjuvanted protein vaccines requires the coordinated actions of conventional DCs and of monocytes. Whilst conventional DCs were required for antigen presentation and initial T cell priming, monocytes constitute the main source of the Th1 polarising cytokine IL-12.
Lowered fasting chenodeoxycholic acid correlated with the decrease of fibroblast growth factor 19 in Chinese subjects with impaired fasting glucose
Authors: Zhang Jing , Li Huating , Zhou Hu , Fang Li , Xu Jingjing , Yan Han , Chen Shuqin , Song Qianqian , Zhang Yinan , Xu Aimin , Fang Qichen , Ye Yang , Jia Weiping
Published: July 2017

The gut-derived hormone Fibroblast growth factor 19 (FGF19) could regulate glucose metabolism and is induced by bile acids (BAs) through activating Farnesoid X Receptor (FXR). FGF19 was found to decrease in subjects with isolated-impaired fasting glucose (I-IFG) and type 2 diabetes mellitus (T2DM). However, the reason for the change of FGF19 in subjects with different glucometabolic status remained unclear. Here we measured six BAs including chenodeoxycholic acid (CDCA), cholic acid, deoxycholic acid, their glycine conjugates and FGF19 levels during oral glucose tolerance test (OGTT) in normal glucose tolerance (NGT), isolated-impaired glucose tolerance, I-IFG, combined glucose intolerance (CGI) and T2DM subjects. After OGTT, serum FGF19 peaked at 120 min in all subjects. Glycine conjugated BAs peaked at 30 min, while free BAs did not elevated significantly. Consistent with the decrease trend in FGF19 levels, fasting serum CDCA levels in subjects with I-IFG, CGI and T2DM were significantly lower than NGT subjects (P < 0.05). Fasting serum CDCA was independently associated with FGF19. CDCA strongly upregulated FGF19 mRNA levels in LS174T cells in a dose- and time-dependent manner. These results suggest that the decrease of FGF19 in subjects with I-IFG was at least partially due to their decrease of CDCA acting via FXR.
Paracrine cyclooxygenase-2 activity by macrophages drives colorectal adenoma progression in the Apc

Min/+ mouse model of intestinal tumorigenesis
Authors: Hull Mark A. , Cuthbert Richard J. , Ko C. W. Stanley , Scott Daniel J. , Cartwright Elizabeth J. , Hawcroft Gillian , Perry Sarah L. , Ingram Nicola , Carr Ian M. , Markham Alexander F. , Bonifer Constanze , Coletta P. Louise
Published: July 2017

Genetic deletion or pharmacological inhibition of cyclooxygenase (COX)-2 abrogates intestinal adenoma development at early stages of colorectal carcinogenesis. COX-2 is localised to stromal cells (predominantly macrophages) in human and mouse intestinal adenomas. Therefore, we tested the hypothesis that paracrine Cox-2-mediated signalling from macrophages drives adenoma growth and progression in vivo in the Apc
Min/+ mouse model of intestinal tumorigenesis. Using a transgenic C57Bl/6 mouse model of Cox-2 over-expression driven by the chicken lysozyme locus (cLys-Cox-2), which directs integration site-independent, copy number-dependent transgene expression restricted to macrophages, we demonstrated that stromal macrophage Cox-2 in colorectal (but not small intestinal) adenomas from cLys-Cox-2 x Apc
Min/+ mice was associated with significantly increased tumour size (P = 0.025) and multiplicity (P = 0.025), compared with control Apc
Min/+ mice. Transgenic macrophage Cox-2 expression was associated with increased dysplasia, epithelial cell Cox-2 expression and submucosal tumour invasion, as well as increased nuclear β-catenin translocation in dysplastic epithelial cells. In vitro studies confirmed that paracrine macrophage Cox-2 signalling drives catenin-related transcription in intestinal epithelial cells. Paracrine macrophage Cox-2 activity drives growth and progression of Apc
Min/+ mouse colonic adenomas, linked to increased epithelial cell β-catenin dysregulation. Stromal cell (macrophage) gene regulation and signalling represent valid targets for chemoprevention of colorectal cancer.
Spatial and temporal changes of parasitic chytrids of cyanobacteria
Authors: Gerphagnon Mélanie , Colombet Jonathan , Latour Delphine , Sime-Ngando Télesphore
Published: July 2017

Parasitism is certainly one of the most important driving biotic factors of cyanobacterial blooms which remains largely understudied. Among these parasites, fungi from the phylum Chytridiomycota (i.e. chytrids) are the only eukaryotic microorganisms infecting cyanobacteria. Here, we address spatiotemporal dynamics of the cyanobacterial hostDolichospermum macrosporum(syn. Anabaena macrospora) and its associated chytrid parasites,Rhizosiphonspp., in an eutrophic lake by studying spatial (vertical, horizontal) and temporal (annual and inter-annual) variations. Our results show homogenous chytrid infection patterns along the water column and across sampling stations. However, the prevalence of infection presented drastic changes with time, at both intra- and inter-annual scales. In 2007, a maximum of 98% of vegetative cells were infected byR. crassumwhereas this fungal species was not reported seven years later. In opposite,R. akinetum, a chytrid infecting only akinetes, increased its prevalence by 42% during the same period. High chytrid infection rate on the akinetes might have sizeable consequences on host recruitment (and proliferation) success from year to year, as supported by the recorded inter-annual host dynamics (affecting also the success of other chytrid parasites). The spatial homogenous chytrid infection on this cyanobacterium, coupled to both seasonal and inter-annual changes indicates that time, rather than space, controls such highly dynamic host-parasite relationships.
Surface Modification of Anisotropic Dielectric Elastomer Actuators with Uni- and Bi-axially Wrinkled Carbon Electrodes for Wettability Control
Authors: Jun Kiwoo , Kim Donggyu , Ryu Seunghwa , Oh Il-Kwon
Published: July 2017

Interest in soft actuators for next-generation electronic devices, such as wearable electronics, haptic feedback systems, rollable flexible displays, and soft robotics, is rapidly growing. However, for more practical applications in diverse electronic devices, soft actuators require multiple functionalities including anisotropic actuation in three-dimensional space, active tactile feedback, and controllable wettability. Herein, we report anisotropic dielectric elastomer actuators with uni- and bi-axially wrinkled carbon black electrodes that are formed through pre-streching and relaxation processes. The wrinkled dielectric elastomer actuator (WDEA) that shows directional actuation under electric fields is used to control the anisotropic wettability. The morphology changes of the electrode surfaces under various electric stimuli are investigated by measuring the contact angles of water droplets, and the results show that the controllable wettability has a broad range from 141° to 161° along the wrinkle direction. The present study successfully demonstrates that the WDEA under electrically controlled inputs can be used to modulate the uni- or bi-axially wrinkled electrode surfaces with continous roughness levels. The controllable wrinkled structures can play an important role in creating adaptable water repellency and tunable anisotropic wettability.
Neural determinants of human goal-directed vs. habitual action control and their relation to trait motivation
Authors: Eryilmaz Hamdi , Rodriguez-Thompson Anais , Tanner Alexandra S. , Giegold Madeline , Huntington Franklin C. , Roffman Joshua L.
Published: July 2017

Instrumental learning is mediated by goal-directed and habit systems in the brain. While rodent studies implicate distinct prefrontal/striatal regions in goal-directed and habit learning, neural systems underpinning these two processes in humans remain poorly understood. Here, using a validated discrimination learning task that distinguishes goal-directed learning from habit learning in 72 subjects in fMRI, we investigated the corticostriatal correlates of goal-directed learning and tested whether brain activation during learning is associated with trait motivation and behavioral performance in the post-learning test phase. Participants showed enhanced activation in medial prefrontal and posterior cingulate cortices during goal-directed action selection in the training phase, whereas habitual action selection activated bilateral insula, bilateral dorsal caudate and left precentral gyrus. In addition, early phase of learning was associated with increased activation in the frontoparietal control network and dorsal striatum, whereas default mode regions depicted increased activation in the late phase. Finally, avoidance motivation scores measured by Behavioral Inhibition/Activation System (BIS/BAS) correlated with accuracy during goal-directed learning and showed a nominally significant correlation with activation in dorsomedial prefrontal cortex during goal-directed acquisition of stimuli. These findings reveal the temporal dynamics of instrumental behavior and suggest that avoidance motivation predicts performance and brain activity during goal-directed learning.
Ab initio calculation of energy levels for phosphorus donors in silicon
Authors: Smith J. S. , Budi A. , Per M. C. , Vogt N. , Drumm D. W. , Hollenberg L. C. L. , Cole J. H. , Russo S. P.
Published: July 2017

The s manifold energy levels for phosphorus donors in silicon are important input parameters for the design and modeling of electronic devices on the nanoscale. In this paper we calculate these energy levels from first principles using density functional theory. The wavefunction of the donor electron’s ground state is found to have a form that is similar to an atomic s orbital, with an effective Bohr radius of 1.8 nm. The corresponding binding energy of this state is found to be 41 meV, which is in good agreement with the currently accepted value of 45.59 meV. We also calculate the energies of the excited 1s(T2) and 1s(E) states, finding them to be 32 and 31 meV respectively.
Direct binding to GABARAP family members is essential for HIV-1 Nef plasma membrane localization
Authors: Boeske Alexandra , Schwarten Melanie , Ma Peixiang , Tusche Markus , Mötter Jessica , Möller Christina , Neudecker Philipp , Hoffmann Silke , Willbold Dieter
Published: July 2017

HIV-1 Nef is an important pathogenic factor for HIV/AIDS pathogenesis. Studies have shown that the association of Nef with the inner leaflet of the plasma membrane and with endocytic and perinuclear vesicles is essential for most activities of Nef. Using purified recombinant proteins in pull-down assays and by co-immunoprecipitation assays we demonstrate that Nef binds directly and specifically to all GABARAP family members, but not to LC3 family members. Based on nuclear magnetic resonance (NMR) experiments we showed that Nef binds to GABARAP via two surface exposed hydrophobic pockets. S53 and F62 of GABARAP were identified as key residues for the interaction with Nef. During live-cell fluorescence microscopy an accumulation of Nef and all GABARAP family members in vesicular structures throughout the cytoplasm and at the plasma membrane was observed. This plasma membrane accumulation was significantly reduced after knocking down GABARAP, GABARAPL1 and GABARAPL2 with respective siRNAs. We identified GABARAPs as the first known direct interaction partners of Nef that are essential for its plasma membrane localization.
Dietary constraints can preclude the expression of an honest chemical sexual signal
Authors: García-Roa Roberto , Sáiz Jorge , Gómara Belén , López Pilar , Martín José
Published: July 2017

Identifying the factors that underlie signal divergences remains challenging in studies of animal communication. Regarding the chemical signalling, different compounds can be found in some species but be absent in others. We hypothesized that if the costs that are associated with the expression of some compounds are too high, their presence in the signal may be restricted. However, these compounds may be expressed and be functional when those costs are relaxed. Vitamin E (α-tocopherol), a dietary compound with metabolic relevancy, acts as an honest chemical sexual signal in many lizards but no in others such as the Carpetan Rock lizard (Iberolacerta cyreni). We investigated whether dietary supplementation favours the expression of this vitamin in scents of I. cyreni. We show that dietary constraints can preclude the expression of vitamin E in chemical secretions of wild males because was expressed when it was experimentally provided in the diet. Vitamin E supplementation also heightened the immune response of males and increased the interest of their scent for females, highlighting the vitamin E as a chemical sexual signal in this species. We suggest that diet could decisively act as a driver of intra- and interspecific divergences in the chemical signalling of lizards.
Landscape of somatic mutations in different subtypes of advanced breast cancer with circulating tumor DNA analysis
Authors: Yi Zongbi , Ma Fei , Li Chunxiao , Chen Rongrong , Yuan Lifang , Sun Xiaoying , Guan Xiuwen , Li Lixi , Liu Binliang , Guan Yanfang , Qian Haili , Xu Binghe
Published: July 2017

It is particularly important to provide precise therapies and understand tumor heterogeneity based on the molecular typing of mutational landscape. However, the landscape of somatic mutations in different subtypes of advanced breast cancer (ABC) is largely unknown. We applied target-region capture deep sequencing to determine the frequency and spectrum of common cancer-related gene mutations in circulating tumor DNA (ctDNA) among different ABC subtypes and analyze their association with clinical features. In this retrospective study of 100 female advanced breast cancer patients, 96 (96.0%) had somatic genomic alterations in ctDNA, including copy number variants and point mutations. The results revealed that different subtypes of ABC have distinct features in terms of genetic alterations. Multivariate regression analyses revealed that the number of somatic mutations increased with the line of endocrine therapy and the fractions of trunk mutations was positive associated with the line of target therapy.
Effects of Sintering Temperature on Crystallization and Fabrication of Porous Bioactive Glass Scaffolds for Bone Regeneration
Authors: Erasmus E. P. , Johnson O. T. , Sigalas I. , Massera J.
Published: July 2017

In this work the sintering ability of borosilicate (S53B50), borophosphate (P40B10) and phosphate (Sr) bioactive glasses was investigated. The glass powders were crushed and sintered in air at a heating rate of 10 °C/min for 2 hours at sintering temperatures between 480 °C–600 °C. The aim was to define the optimum sintering temperature prior to glass crystallization. The density of the samples was found to decrease when the temperature was increased up to 580 °C; probably due to the inhibition of the viscous flow of the particles during sintering thereby reducing the densification of the material. Such low porosity is not suitable in tissue engineering. To process highly porous scaffolds with porosity required for scaffold applicable to tissue engineering, the powders were further mixed with 60 vol.% and 70 vol.% of NH4(HCO3) foaming agent. Meanwhile, the density of the samples sintered with NH4(HCO3) was found to decrease with an increase in NH4(HCO3) content. This indicates an increase in porosity of the samples. The glass compositions reached an open porosity of more than 60% at the addition of 70 vol.% NH4(HCO3). In addition, SEM micrograph revealed large pores with good interconnection between the pores.
New Mycobacterium tuberculosis Beijing clonal complexes in China revealed by phylogenetic and Bayesian population structure analyses of 24-loci MIRU-VNTRs
Authors: Zheng Chao , Reynaud Yann , Zhao Changsong , Zozio Thierry , Li Song , Luo Dongxia , Sun Qun , Rastogi Nalin
Published: July 2017

Beijing lineage of Mycobacterium tuberculosis constitutes the most predominant lineage in East Asia. Beijing epidemiology, evolutionary history, genetics are studied in details for years revealing probable origin from China followed by worldwide expansion, partially linked to higher mutation rate, hypervirulence, drug-resistance, and association with cases of mixed infections. Considering huge amount of data available for 24-loci Mycobacterial Interspersed Repetitive Units-Variable Number of Tandem Repeats, we performed detailed phylogenetic and Bayesian population structure analyses of Beijing lineage strains in mainland China and Taiwan using available 24-loci MIRU-VNTR data extracted from publications or the SITVIT2 database (n = 1490). Results on genetic structuration were compared to previously published data. A total of three new Beijing clonal complexes tentatively named BSP1, BPS2 and BSP3 were revealed with surprising phylogeographical specificities to previously unstudied regions in Sichuan, Chongqing and Taiwan, proving the need for continued investigations with extended datasets. Such geographical restriction could correspond to local adaptation of these “ecological specialist” Beijing isolates to local human host populations in contrast with “generalist pathogens” able to adapt to several human populations and to spread worldwide.
Inhibition of phosphodiesterase-5 suppresses calcineurin/NFAT- mediated TRPC6 expression in pulmonary artery smooth muscle cells
Authors: Li Shaojun , Pan Yilin , Ke Rui , Xie Xinming , Zhai Cui , Shi Wenhua , Wang Jian , Yan Xin , Chai Limin , Wang Qingting , Zhang Qianqian , Su Xiaofan , Yang Lan , Gao Li , Li Manxiang
Published: July 2017

The up-regulation of transient receptor potential channel 6 (TRPC6) has been found to contribute to the proliferation of pulmonary artery smooth muscle cells (PASMCs), and inhibition of phosphodiesterase-5 (PDE5) has been shown to suppress TRPC6 expression in PASMCs. However, the molecular mechanisms underlying the up-regulation of TRPC6 expression and PDE5 modulation of TRPC6 expression in PASMCs remain largely unclear. The aim of this study is to address these issues. Endothelin-1 (ET-1) dose and time-dependently up-regulated TRPC6 expression in primary cultured rat PASMCs, and this was accompanied with the activation of calcineurin and subsequent translocation of NFATc4 to the nucleus. Further study indicated that inhibition of calcineurin by cyclosporine A or knockdown of NFATc4 using small interfering RNA suppressed ET-1-induced TRPC6 up-regulation. In addition, luciferase reporter assay showed that NFATc4 directly regulated the expression of TRPC6 in PASMCs. Inhibition of PDE5 by sildenafil suppressed ET-1-induced activation of calcineurin/NFATc4 signaling pathway and consequent TRPC6 up-regulation in PASMCs, while these inhibitory effects of sildenafil were abolished by PKG inhibitor Rp-8Br-cGMPs. Taken together, our study indicates that ET-1 stimulates TRPC6 expression by activation of calcineurin/NFATc4 signaling pathway, and inhibition of PDE5 suppresses calcineurin/NFATc4- mediated TRPC6 expression in PASMCs in a cGMP-PKG-dependent manner.
Evaluation of ATM heterozygous mutations underlying individual differences in radiosensitivity using genome editing in human cultured cells
Authors: Royba Ekaterina , Miyamoto Tatsuo , Natsuko Akutsu Silvia , Hosoba Kosuke , Tauchi Hiroshi , Kudo Yoshiki , Tashiro Satoshi , Yamamoto Takashi , Matsuura Shinya
Published: July 2017

Ionizing radiation (IR) induces DNA double-strand breaks (DSBs), which are an initial step towards chromosomal aberrations and cell death. It has been suggested that there are individual differences in radiosensitivity within human populations, and that the variations in DNA repair genes might determine this heterogeneity. However, it is difficult to quantify the effect of genetic variants on the individual differences in radiosensitivity, since confounding factors such as smoking and the diverse genetic backgrounds within human populations affect radiosensitivity. To precisely quantify the effect of a genetic variation on radiosensitivity, we here used the CRISPR-ObLiGaRe (Obligate Ligation-Gated Recombination) method combined with the CRISPR/Cas9 system and a nonhomologous end joining (NHEJ)-mediated knock-in technique in human cultured cells with a uniform genetic background. We generated ATM heterozygous knock-out (ATM+/−) cell clones as a carrier model of a radiation-hypersensitive autosomal-recessive disorder, ataxia-telangiectasia (A-T). Cytokinesis-blocked micronucleus assay and chromosome aberration assay showed that the radiosensitivity of ATM+/− cell clones was significantly higher than that of ATM+/+ cells, suggesting that ATM gene variants are indeed involved in determining individual radiosensitivity. Importantly, the differences in radiosensitivity among the same genotype clones were small, unlike the individual differences in fibroblasts derived from A-T-affected family members.