bluuebunny/crossref_metadata_2025_split huggingface dataset:
Topologically associating domains are ancient features that coincide with Metazoan clusters of extreme noncoding conservation
Authors: Harmston Nathan , Ing-Simmons Elizabeth , Tan Ge , Perry Malcolm , Merkenschlager Matthias , Lenhard Boris 
Published: August 2017

AbstractDevelopmental genes in metazoan genomes are surrounded by dense clusters of conserved noncoding elements (CNEs). CNEs exhibit unexplained extreme levels of sequence conservation, with many acting as developmental long-range enhancers. Clusters of CNEs define the span of regulatory inputs for many important developmental regulators and have been described previously as genomic regulatory blocks (GRBs). Their function and distribution around important regulatory genes raises the question of how they relate to 3D conformation of these loci. Here, we show that clusters of CNEs strongly coincide with topological organisation, predicting the boundaries of hundreds of topologically associating domains (TADs) in human and Drosophila. The set of TADs that are associated with high levels of noncoding conservation exhibit distinct properties compared to TADs devoid of extreme noncoding conservation. The close correspondence between extreme noncoding conservation and TADs suggests that these TADs are ancient, revealing a regulatory architecture conserved over hundreds of millions of years.
A potent series targeting the malarial cGMP-dependent protein kinase clears infection and blocks transmission
Authors: Baker David A. , Stewart Lindsay B. , Large Jonathan M. , Bowyer Paul W. , Ansell Keith H. , Jiménez-Díaz María B. , El Bakkouri Majida , Birchall Kristian , Dechering Koen J. , Bouloc Nathalie S. , Coombs Peter J. , Whalley David , Harding Denise J. , Smiljanic-Hurley Ela , Wheldon Mary C. , Walker Eloise M. , Dessens Johannes T. , Lafuente María José , Sanz Laura M. , Gamo Francisco-Javier , Ferrer Santiago B. , Hui Raymond , Bousema Teun , Angulo-Barturén Iñigo , Merritt Andy T. , Croft Simon L. , Gutteridge Winston E. , Kettleborough Catherine A. , Osborne Simon A. 
Published: August 2017

AbstractTo combat drug resistance, new chemical entities are urgently required for use in next generation anti-malarial combinations. We report here the results of a medicinal chemistry programme focused on an imidazopyridine series targeting the Plasmodium falciparum cyclic GMP-dependent protein kinase (PfPKG). The most potent compound (ML10) has an IC50 of 160 pM in a PfPKG kinase assay and inhibits P. falciparum blood stage proliferation in vitro with an EC50 of 2.1 nM. Oral dosing renders blood stage parasitaemia undetectable in vivo using a P. falciparum SCID mouse model. The series targets both merozoite egress and erythrocyte invasion, but crucially, also blocks transmission of mature P. falciparum gametocytes to Anopheles stephensi mosquitoes. A co-crystal structure of PvPKG bound to ML10, reveals intimate molecular contacts that explain the high levels of potency and selectivity we have measured. The properties of this series warrant consideration for further development to produce an antimalarial drug.
Signalling strength determines proapoptotic functions of STING
Authors: Gulen Muhammet F. , Koch Ute , Haag Simone M. , Schuler Fabian , Apetoh Lionel , Villunger Andreas , Radtke Freddy , Ablasser Andrea 
Published: August 2017

AbstractMammalian cells use cytosolic nucleic acid receptors to detect pathogens and other stress signals. In innate immune cells the presence of cytosolic DNA is sensed by the cGAS–STING signalling pathway, which initiates a gene expression programme linked to cellular activation and cytokine production. Whether the outcome of the STING response varies between distinct cell types remains largely unknown. Here we show that T cells exhibit an intensified STING response, which leads to the expression of a distinct set of genes and results in the induction of apoptosis. Of note, this proapoptotic STING response is still functional in cancerous T cells and delivery of small molecule STING agonists prevents in vivo growth of T-cell-derived tumours independent of its adjuvant activity. Our results demonstrate how the magnitude of STING signalling can shape distinct effector responses, which may permit for cell type-adjusted behaviours towards endogenous or exogenous insults.
Observing the oxidation of platinum
Authors: van Spronsen Matthijs A. , Frenken Joost W. M. , Groot Irene M. N. 
Published: August 2017

AbstractDespite its importance in oxidation catalysis, the active phase of Pt remains uncertain, even for the Pt(111) single-crystal surface. Here, using a ReactorSTM, the catalytically relevant structures are identified as two surface oxides, different from bulk α-PtO2, previously observed. They are constructed from expanded oxide rows with a lattice constant close to that of α-PtO2, either assembling into spoked wheels, 1–5 bar O2, or closely packed in parallel lines, above 2.2 bar. Both are only ordered at elevated temperatures (400–500 K). The triangular oxide can also form on the square lattice of Pt(100). Under NO and CO oxidation conditions, similar features are observed. Furthermore, both oxides are unstable outside the O2 atmosphere, indicating the presence of active O atoms, crucial for oxidation catalysts.
Abnormalities of signal transduction networks in chronic schizophrenia
Authors: McGuire Jennifer L. , Depasquale Erica A. , Funk Adam J. , O’Donnovan Sinead M. , Hasselfeld Kathryn , Marwaha Shruti , Hammond John H. , Hartounian Vahram , Meador-Woodruff James H. , Meller Jarek , McCullumsmith Robert E. 
Published: August 2017

AbstractSchizophrenia is a serious neuropsychiatric disorder characterized by disruptions of brain cell metabolism, microstructure, and neurotransmission. All of these processes require coordination of multiple kinase-mediated signaling events. We hypothesize that imbalances in kinase activity propagate through an interconnected network of intracellular signaling with potential to simultaneously contribute to many or all of the observed deficits in schizophrenia. We established a workflow distinguishing schizophrenia-altered kinases in anterior cingulate cortex using a previously published kinome array data set. We compared schizophrenia-altered kinases to haloperidol-altered kinases, and identified systems, functions, and regulators predicted using pathway analyses. We used kinase inhibitors with the kinome array to test hypotheses about imbalance in signaling and conducted preliminary studies of kinase proteins, phosphoproteins, and activity for kinases of interest. We investigated schizophrenia-associated single nucleotide polymorphisms in one of these kinases, AKT, for genotype-dependent changes in AKT protein or activity. Kinome analyses identified new kinases as well as some previously implicated in schizophrenia. These results were not explained by chronic antipsychotic treatment. Kinases identified in our analyses aligned with cytoskeletal arrangement and molecular trafficking. Of the kinases we investigated further, AKT and (unexpectedly) JNK, showed the most dysregulation in the anterior cingulate cortex of schizophrenia subjects. Changes in kinase activity did not correspond to protein or phosphoprotein levels. We also show that AKT single nucleotide polymorphism rs1130214, previously associated with schizophrenia, influenced enzyme activity but not protein or phosphoprotein levels. Our data indicate subtle changes in kinase activity and regulation across an interlinked kinase network, suggesting signaling imbalances underlie the core symptoms of schizophrenia.
CRISPR-Cas9 mediated one-step disabling of pancreatogenesis in pigs
Authors: Wu Jun , Vilarino Marcela , Suzuki Keiichiro , Okamura Daiji , Bogliotti Yanina Soledad , Park Insung , Rowe Joan , McNabb Bret , Ross Pablo Juan , Belmonte Juan Carlos Izpisua 
Published: August 2017

AbstractGenome editing using programmable nucleases has revolutionized biomedical research. CRISPR-Cas9 mediated zygote genome editing enables high efficient production of knockout animals suitable for studying development and relevant human diseases. Here we report efficient disabling pancreatogenesis in pig embryos via zygotic co-delivery of Cas9 mRNA and dual sgRNAs targeting the PDX1 gene, which when combined with chimeric-competent human pluriopotent stem cells may serve as a suitable platform for the xeno-generation of human tissues and organs in pigs.
Automated analysis of liver fat, muscle and adipose tissue distribution from CT suitable for large-scale studies
Authors: Kullberg Joel , Hedström Anders , Brandberg John , Strand Robin , Johansson Lars , Bergström Göran , Ahlström Håkan 
Published: August 2017

AbstractComputed Tomography (CT) allows detailed studies of body composition and its association with metabolic and cardiovascular disease. The purpose of this work was to develop and validate automated and manual image processing techniques for detailed and efficient analysis of body composition from CT data. The study comprised 107 subjects examined in the Swedish CArdioPulmonary BioImage Study (SCAPIS) using a 3-slice CT protocol covering liver, abdomen, and thighs. Algorithms were developed for automated assessment of liver attenuation, visceral (VAT) and subcutaneous (SAT) abdominal adipose tissue, thigh muscles, subcutaneous, subfascial (SFAT) and intermuscular adipose tissue. These were validated using manual reference measurements. SFAT was studied in selected subjects were the fascia lata could be visually identified (approx. 5%). In addition, precision of manual measurements of intra- (IPAT) and retroperitoneal adipose tissue (RPAT) and deep- and superficial SAT was evaluated using repeated measurements. Automated measurements correlated strongly to manual reference measurements. The SFAT depot showed the weakest correlation (r = 0.744). Automated VAT and SAT measurements were slightly, but significantly overestimated (≤4.6%, p ≤ 0.001). Manual segmentation of abdominal sub-depots showed high repeatability (CV ≤ 8.1%, r ≥ 0.930). We conclude that the low dose CT-scanning and automated analysis makes the setup suitable for large-scale studies.
Controlled self-organization of polymer nanopatterns over large areas
Authors: Eryilmaz Ilknur Hatice , Mohanraj John , Dal Zilio Simone , Fraleoni-Morgera Alessandro 
Published: August 2017

AbstractSelf-assembly methods allow to obtain ordered patterns on surfaces with exquisite precision, but often lack in effectiveness over large areas. Here we report on the realization of hierarchically ordered polymethylmethacrylate (PMMA) nanofibres and nanodots over large areas from solution via a fast, easy and low-cost method named ASB-SANS, based on a ternary solution that is cast on the substrate. Simple changes to the ternary solution composition allow to control the transition from nanofibres to nanodots, via a wide range of intermediate topologies. The ternary solution includes the material to be patterned, a liquid solvent and a solid substance able to sublimate. The analysis of the fibres/dots width and inter-pattern distance variations with respect to the ratio between the solution components suggests that the macromolecular chains mobility in the solidified sublimating substance follows Zimm-like models (mobility of macromolecules in diluted liquid solutions). A qualitative explanation of the self-assembly phenomena originating the observed nanopatterns is given. Finally, ASB-SANS-generated PMMA nanodots arrays have been used as lithographic masks for a silicon substrate and submitted to Inductively Coupled Plasma-Reactive Ion Etching (ICP-RIE). As a result, nanopillars with remarkably high aspect ratios have been achieved over areas as large as several millimeters square, highlighting an interesting potential of ASB-SANS in practical applications like photon trapping in photovoltaic cells, surface-enhanced sensors, plasmonics.
ROS-induced Oxidative Injury involved in Pathogenesis of Fungal Keratitis via p38 MAPK Activation
Authors: Hua Xia , Chi Wei , Su Long , Li Jin , Zhang Zongduan , Yuan Xiaoyong 
Published: August 2017

AbstractThis study was to explore the mechanism by which reactive oxygen species (ROS)-induced oxidative stress involved in the pathogenesis of fungal keratitis using an in vivo experimental keratitis mouse model and an in vitro culture model of human corneal epithelial cells (HCECs). Compared to normal control mice and HCECs, ROS production was markedly increased in fungal corneas and HCECs exposed to Candida albicans, accompanied by p38 mitogen-activated protein kinases (MAPK) activation. Increased products of oxidative markers, malondialdehyde (MDA), 4–hydroxynonenal (HNE), mitochondria DNA 8-OHdG and aconitase-2 were observed in fungal infected corneas and HCECs. Fungal infection also increased the mRNA expression and protein production of heme oxygenase-1 (HMOX1) and cyclooxygenase-2 (COX2), with suppressed levels of antioxidant enzymes, superoxide dismutase-1 (SOD1), glutathione peroxidase-1 (GPx1) and peroxiredoxin-4 (PRDX4). Interestingly, the levels of ROS, oxidative markers and oxygenases were significantly reduced by co-cultured p38 inhibitor SB203580. Furthermore, SB203580 restored the levels of antioxidant enzymes suppressed by fungus. Our findings demonstrated for the first time that ROS-induced oxidative injury is involved in pathogenesis of fungal keratitis via p38 MAPK pathway, suggesting the novel therapeutic targets for the potential treatment of fungal keratitis.
Modeling protein quaternary structure of homo- and hetero-oligomers beyond binary interactions by homology
Authors: Bertoni Martino , Kiefer Florian , Biasini Marco , Bordoli Lorenza , Schwede Torsten 
Published: August 2017

AbstractCellular processes often depend on interactions between proteins and the formation of macromolecular complexes. The impairment of such interactions can lead to deregulation of pathways resulting in disease states, and it is hence crucial to gain insights into the nature of macromolecular assemblies. Detailed structural knowledge about complexes and protein-protein interactions is growing, but experimentally determined three-dimensional multimeric assemblies are outnumbered by complexes supported by non-structural experimental evidence. Here, we aim to fill this gap by modeling multimeric structures by homology, only using amino acid sequences to infer the stoichiometry and the overall structure of the assembly. We ask which properties of proteins within a family can assist in the prediction of correct quaternary structure. Specifically, we introduce a description of protein-protein interface conservation as a function of evolutionary distance to reduce the noise in deep multiple sequence alignments. We also define a distance measure to structurally compare homologous multimeric protein complexes. This allows us to hierarchically cluster protein structures and quantify the diversity of alternative biological assemblies known today. We find that a combination of conservation scores, structural clustering, and classical interface descriptors, can improve the selection of homologous protein templates leading to reliable models of protein complexes.
Zinc depletion promotes apoptosis-like death in drug-sensitive and antimony-resistance Leishmania donovani
Authors: Saini Shalini , Bharati Kavita , Shaha Chandrima , Mukhopadhyay Chinmay K. 
Published: August 2017

AbstractMicronutrients are essential for survival and growth for all the organisms including pathogens. In this manuscript, we report that zinc (Zn) chelator N,N,N’,N’-tetrakis(2-pyridinylmethyl)-1,2-ethylenediamine (TPEN) affects growth and viability of intracellular pathogen Leishmania donovani (LD) by a concentration and time dependent manner. Simultaneous addition of zinc salt reverses the effect of TPEN. Further experiments provide evidence of apoptosis-like death of the parasite due to Zn-depletion. TPEN treatment enhances caspase-like activity suggesting increase in apoptosis-like events in LD. Specific inhibitors of cathepsin B and Endoclease G block TPEN-induced leishmanial death. Evidences show involvement of reactive oxygen species (ROS) potentially of extra-mitochondrial origin in TPEN-induced LD death. Pentavalent antimonials remained the prime source of treatment against leishmaniasis for several decades; however, antimony-resistant Leishmania is now common source of the disease. We also reveal that Zn-depletion can promote apoptosis-like death in antimony-resistant parasites. In summary, we present a new finding about the role of zinc in the survival of drug sensitive and antimony-resistant LD.
Differences between the most used equations in BAT-human studies to estimate parameters of skin temperature in young lean men
Authors: Martinez-Tellez Borja , Sanchez-Delgado Guillermo , Acosta Francisco M. , Alcantara Juan M. A. , Boon Mariëtte R. , Rensen Patrick C. N. , Ruiz Jonatan R. 
Published: August 2017

AbstractCold exposure is necessary to activate human brown adipose tissue (BAT), resulting in heat production. Skin temperature is an indirect measure to monitor the body’s reaction to cold. The aim of this research was to study whether the most used equations to estimate parameters of skin temperature in BAT-human studies measure the same values of temperature in young lean men (n = 11: 23.4 ± 0.5 years, fat mass: 19.9 ± 1.2%). Skin temperature was measured with 26 ibuttons at 1-minute intervals in warm and cold room conditions. We used 12 equations to estimate parameters of mean, proximal, and distal skin temperature as well as skin temperature gradients. Data were analysed with Temperatus software. Significant differences were found across equations to measure the same parameters of skin temperature in warm and cold room conditions, hampering comparison across studies. Based on these findings, we suggest to use a set of 14 ibuttons at anatomical positions reported by ISO STANDARD 9886:2004 plus five ibuttons placed on the right supraclavicular fossa, right middle clavicular bone, right middle upper forearm, right top of forefinger, and right upper chest.
Natural (∆9-THC) and synthetic (JWH-018) cannabinoids induce seizures by acting through the cannabinoid CB1 receptor
Authors: Malyshevskaya Olga , Aritake Kosuke , Kaushik Mahesh K. , Uchiyama Nahoko , Cherasse Yoan , Kikura-Hanajiri Ruri , Urade Yoshihiro 
Published: August 2017

AbstractNatural cannabinoids and their synthetic substitutes are the most widely used recreational drugs. Numerous clinical cases describe acute toxic symptoms and neurological consequences following inhalation of the mixture of synthetic cannabinoids known as “Spice.” Here we report that an intraperitoneal administration of the natural cannabinoid Δ9-tetrahydrocannabinol (10 mg/kg), one of the main constituent of marijuana, or the synthetic cannabinoid JWH-018 (2.5 mg/kg) triggered electrographic seizures in mice, recorded by electroencephalography and videography. Administration of JWH-018 (1.5, 2.5 and 5 mg/kg) increased seizure spikes dose-dependently. Pretreatment of mice with AM-251 (5 mg/kg), a cannabinoid receptor 1-selective antagonist, completely prevented cannabinoid-induced seizures. These data imply that abuse of cannabinoids can be dangerous and represents an emerging public health threat. Additionally, our data strongly suggest that AM-251 could be used as a crucial prophylactic therapy for cannabinoid-induced seizures or similar life-threatening conditions.
Metamaterial Perfect Absorber Analyzed by a Meta-cavity Model Consisting of Multilayer Metasurfaces
Authors: Bhattarai Khagendra , Silva Sinhara , Song Kun , Urbas Augustine , Lee Sang Jun , Ku Zahyun , Zhou Jiangfeng 
Published: August 2017

AbstractWe demonstrate that the metamaterial perfect absorber behaves as a meta-cavity bounded between a resonant metasurface and a metallic thin-film reflector. The perfect absorption is achieved by the Fabry-Perot cavity resonance via multiple reflections between the “quasi-open” boundary of resonator and the “close” boundary of reflector. The characteristic features including angle independence, ultra-thin thickness and strong field localization can be well explained by this meta-cavity model. With this model, metamaterial perfect absorber can be redefined as a meta-cavity exhibiting high Q-factor, strong field enhancement and extremely high photonic density of states, thereby promising novel applications for high performance sensor, infrared photodetector and cavity quantum electrodynamics devices.
NF-κB inhibitors, unique γ-pyranol-γ-lactams with sulfide and sulfoxide moieties from Hawaiian plant Lycopodiella cernua derived fungus Paraphaeosphaeria neglecta FT462
Authors: Li Chun-Shun , Sarotti Ariel M. , Huang Peng , Dang Uyen T. , Hurdle Julian G. , Kondratyuk Tamara P. , Pezzuto John M. , Turkson James , Cao Shugeng 
Published: August 2017

AbstractLC-UV/MS-based metabolomic analysis of the Hawaiian endophytic fungus Paraphaeosphaeria neglecta FT462 led to the identification of four unique mercaptolactated γ-pyranol–γ-lactams, paraphaeosphaerides E–H (1–4) together with one γ-lactone (5) and the methyl ester of compound 2 (11). The structures of the new compounds (1–5 and 11) were elucidated through the analysis of HRMS and NMR spectroscopic data. The absolute configuration was determined by chemical reactions with sodium borohydride, hydrogen peroxide, α-methoxy-α-(trifluoromethyl)phenylacetyl chlorides (Mosher reagents), and DP4 + NMR calculations. All the compounds were tested against STAT3, A2780 and A2780cisR cancer cell lines, E. coli JW2496, and NF-κB. Compounds 1 and 3 strongly inhibited NF-κB with IC50 values of 7.1 and 1.5 μM, respectively.
Focusing analytes from 50 μL into 500 pL: On-chip focusing from large sample volumes using isotachophoresis
Authors: van Kooten Xander F. , Truman-Rosentsvit Marianna , Kaigala Govind V. , Bercovici Moran 
Published: August 2017

AbstractThe use of on-chip isotachophoresis assays for diagnostic applications is often limited by the small volumes of standard microfluidic channels. Overcoming this limitation is particularly important for detection of ‘discrete’ biological targets (such as bacteria) at low concentrations, where the volume of processed liquid in a standard microchannel might not contain any targets. We present a novel microfluidic chip that enables ITP focusing of target analytes from initial sample volumes of 50 μL into a concentrated zone with a volume of 500 pL, corresponding to a 100,000-fold increase in mean concentration, and a 300,000-fold increase in peak concentration. We present design considerations for limiting sample dispersion in such large-volume focusing (LVF) chips and discuss the trade-off between assay time and Joule heating, which ultimately governs the scalability of LVF designs. Finally, we demonstrate a 100-fold improvement of ITP focusing performance in the LVF chip as compared to conventional microchannels, and apply this enhancement to achieve highly sensitive detection of both molecular targets (DNA, down to 10 fM) and whole bacteria (down to 100 cfu/mL).