bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genome-scale identification of transcription factors that mediate an inflammatory network during breast cellular transformation
Authors: Ji Zhe , He Lizhi , Rotem Asaf , Janzer Andreas , Cheng Christine S. , Regev Aviv , Struhl Kevin 
Published: May 2018

AbstractTransient activation of Src oncoprotein in non-transformed, breast epithelial cells can initiate an epigenetic switch to the stably transformed state via a positive feedback loop that involves the inflammatory transcription factors STAT3 and NF-κB. Here, we develop an experimental and computational pipeline that includes 1) a Bayesian network model (AccessTF) that accurately predicts protein-bound DNA sequence motifs based on chromatin accessibility, and 2) a scoring system (TFScore) that rank-orders transcription factors as candidates for being important for a biological process. Genetic experiments validate TFScore and suggest that more than 40 transcription factors contribute to the oncogenic state in this model. Interestingly, individual depletion of several of these factors results in similar transcriptional profiles, indicating that a complex and interconnected transcriptional network promotes a stable oncogenic state. The combined experimental and computational pipeline represents a general approach to comprehensively identify transcriptional regulators important for a biological process.
Testosterone is an endogenous regulator of BAFF and splenic B cell number
Authors: Wilhelmson Anna S. , Lantero Rodriguez Marta , Stubelius Alexandra , Fogelstrand Per , Johansson Inger , Buechler Matthew B. , Lianoglou Steve , Kapoor Varun N. , Johansson Maria E. , Fagman Johan B. , Duhlin Amanda , Tripathi Prabhanshu , Camponeschi Alessandro , Porse Bo T. , Rolink Antonius G. , Nissbrandt Hans , Turley Shannon J. , Carlsten Hans , Mårtensson Inga-Lill , Karlsson Mikael C. I. , Tivesten Åsa 
Published: May 2018

AbstractTestosterone deficiency in men is associated with increased risk for autoimmunity and increased B cell numbers through unknown mechanisms. Here we show that testosterone regulates the cytokine BAFF, an essential survival factor for B cells. Male mice lacking the androgen receptor have increased splenic B cell numbers, serum BAFF levels and splenic Baff mRNA. Testosterone deficiency by castration causes expansion of BAFF-producing fibroblastic reticular cells (FRCs) in spleen, which may be coupled to lower splenic noradrenaline levels in castrated males, as an α-adrenergic agonist decreases splenic FRC number in vitro. Antibody-mediated blockade of the BAFF receptor or treatment with the neurotoxin 6-hydroxydopamine revert the increased splenic B cell numbers induced by castration. Among healthy men, serum BAFF levels are higher in men with low testosterone. Our study uncovers a previously unrecognized regulation of BAFF by testosterone and raises important questions about BAFF in testosterone-mediated protection against autoimmunity.
Identification of a unique Ca2+-binding site in rat acid-sensing ion channel 3
Authors: Zuo Zhicheng , Smith Rachel N. , Chen Zhenglan , Agharkar Amruta S. , Snell Heather D. , Huang Renqi , Liu Jin , Gonzales Eric B. 
Published: May 2018

AbstractAcid-sensing ion channels (ASICs) evolved to sense changes in extracellular acidity with the divalent cation calcium (Ca2+) as an allosteric modulator and channel blocker. The channel-blocking activity is most apparent in ASIC3, as removing Ca2+ results in channel opening, with the site’s location remaining unresolved. Here we show that a ring of rat ASIC3 (rASIC3) glutamates (Glu435), located above the channel gate, modulates proton sensitivity and contributes to the formation of the elusive Ca2+ block site. Mutation of this residue to glycine, the equivalent residue in chicken ASIC1, diminished the rASIC3 Ca2+ block effect. Atomistic molecular dynamic simulations corroborate the involvement of this acidic residue in forming a high-affinity Ca2+ site atop the channel pore. Furthermore, the reported observations provide clarity for past controversies regarding ASIC channel gating. Our findings enhance understanding of ASIC gating mechanisms and provide structural and energetic insights into this unique calcium-binding site.
The genomic landscape of TERT promoter wildtype-IDH wildtype glioblastoma
Authors: Diplas Bill H. , He Xujun , Brosnan-Cashman Jacqueline A. , Liu Heng , Chen Lee H. , Wang Zhaohui , Moure Casey J. , Killela Patrick J. , Loriaux Daniel B. , Lipp Eric S. , Greer Paula K. , Yang Rui , Rizzo Anthony J. , Rodriguez Fausto J. , Friedman Allan H. , Friedman Henry S. , Wang Sizhen , He Yiping , McLendon Roger E. , Bigner Darell D. , Jiao Yuchen , Waitkus Matthew S. , Meeker Alan K. , Yan Hai 
Published: May 2018

AbstractThe majority of glioblastomas can be classified into molecular subgroups based on mutations in the TERT promoter (TERTp) and isocitrate dehydrogenase 1 or 2 (IDH). These molecular subgroups utilize distinct genetic mechanisms of telomere maintenance, either TERTp mutation leading to telomerase activation or ATRX-mutation leading to an alternative lengthening of telomeres phenotype (ALT). However, about 20% of glioblastomas lack alterations in TERTp and IDH. These tumors, designated TERTpWT-IDHWT glioblastomas, do not have well-established genetic biomarkers or defined mechanisms of telomere maintenance. Here we report the genetic landscape of TERTpWT-IDHWT glioblastoma and identify SMARCAL1 inactivating mutations as a novel genetic mechanism of ALT. Furthermore, we identify a novel mechanism of telomerase activation in glioblastomas that occurs via chromosomal rearrangements upstream of TERT. Collectively, our findings define novel molecular subgroups of glioblastoma, including a telomerase-positive subgroup driven by TERT-structural rearrangements (IDHWT-TERTSV), and an ALT-positive subgroup (IDHWT-ALT) with mutations in ATRX or SMARCAL1.
Molecular basis of dimer formation during the biosynthesis of benzofluorene-containing atypical angucyclines
Authors: Huang Chunshuai , Yang Chunfang , Zhang Wenjun , Zhang Liping , De Bidhan Chandra , Zhu Yiguang , Jiang Xiaodong , Fang Chunyan , Zhang Qingbo , Yuan Cheng-Shan , Liu Hung-wen , Zhang Changsheng 
Published: May 2018

AbstractLomaiviticin A and difluostatin A are benzofluorene-containing aromatic polyketides in the atypical angucycline family. Although these dimeric compounds are potent antitumor agents, how nature constructs their complex structures remains poorly understood. Herein, we report the discovery of a number of fluostatin type dimeric aromatic polyketides with varied C−C and C−N coupling patterns. We also demonstrate that these dimers are not true secondary metabolites, but are instead derived from non-enzymatic deacylation of biosynthetic acyl fluostatins. The non-enzymatic deacylation proceeds via a transient quinone methide like intermediate which facilitates the subsequent C–C/C−N coupled dimerization. Characterization of this unusual property of acyl fluostatins explains how dimerization takes place, and suggests a strategy for the assembly of C–C and C–N coupled aromatic polyketide dimers. Additionally, a deacylase FlsH was identified which may help to prevent accumulation of toxic quinone methides by catalyzing hydrolysis of the acyl group.
Zinc ion flux during mammalian sperm capacitation
Authors: Kerns Karl , Zigo Michal , Drobnis Erma Z. , Sutovsky Miriam , Sutovsky Peter 
Published: May 2018

AbstractSperm capacitation, the ultimate maturation event preparing mammalian spermatozoa for fertilization, was first described in 1951, yet its regulatory mechanisms remain poorly understood. The capacitation process encompasses an influx of bicarbonate and calcium ions, removal of decapacitating factors, changes of pH and sperm proteasomal activities, and the increased protein tyrosine phosphorylation. Here, we document a novel biological phenomenon of a unique zinc (Zn2+) ion redistribution associated with mammalian sperm in vitro capacitation (IVC). Using image-based flow cytometry (IBFC), we identified four distinct types of sperm zinc ion distribution patterns (further zinc signature) and their changes during IVC. The zinc signature was altered after sperm capacitation, reduced by proteasomal inhibitors, removed by zinc chelators, and maintained with addition of external ZnCl2. These findings represent a fundamental shift in the understanding of mammalian fertilization, paving the way for improved semen analysis, in vitro fertilization (IVF), and artificial insemination (AI).
Coil-globule transitions drive discontinuous volume conserving deformation in locally restrained gels
Authors: Yamamoto Tetsuya , Masubuchi Yuichi , Doi Masao 
Published: May 2018

AbstractThe equilibrium volume of a thermoresponsive polymer gel changes dramatically across a temperature due to the coil–globule transitions of the polymers. When cofacially oriented nanosheets are embedded in such a gel, the composite gel deforms at the temperature, without changing the volume, and the response time is considerably shorter. We here theoretically predict that the deformation of the composite gel results from the fact that the nanosheets restrain the deformation of some polymers, while other polymers deform relatively freely. The unrestrained polymers collapse due to the coil–globule transitions and this generates the solvent flows to the restrained regions. The response time of this process is rather fast because solvent molecules travel only by the distance of the size of a nanosheet, instead of permeating out to the external solution. This concept may provide insight in the physics of composite gels and the design of thermoresponsive gels of fast response.
ON-OFF receptive fields in auditory cortex diverge during development and contribute to directional sweep selectivity
Authors: Sollini Joseph , Chapuis Gaëlle A. , Clopath Claudia , Chadderton Paul 
Published: May 2018

AbstractNeurons in the auditory cortex exhibit distinct frequency tuning to the onset and offset of sounds, but the cause and significance of ON and OFF receptive field (RF) organisation are not understood. Here we demonstrate that distinct ON and OFF frequency tuning is largely absent in immature mouse auditory cortex and is thus a consequence of cortical development. Simulations using a novel implementation of a standard Hebbian plasticity model show that the natural alternation of sound onset and offset is sufficient for the formation of non-overlapping adjacent ON and OFF RFs in cortical neurons. Our model predicts that ON/OFF RF arrangement contributes towards direction selectivity to frequency-modulated tone sweeps, which we confirm by neuronal recordings. These data reveal that a simple and universally accepted learning rule can explain the organisation of ON and OFF RFs and direction selectivity in the developing auditory cortex.
CD11c+ M1-like macrophages (MΦs) but not CD206+ M2-like MΦ are involved in folliculogenesis in mice ovary
Authors: Ono Yosuke , Nagai Miwako , Yoshino Osamu , Koga Kaori , Nawaz Allah , Hatta Hideki , Nishizono Hirofumi , Izumi Gentaro , Nakashima Akitoshi , Imura Johji , Tobe Kazuyuki , Fujii Tomoyuki , Osuga Yutaka , Saito Shigeru 
Published: May 2018

AbstractMacrophages (MΦs) are involved in folliculogenesis and ovulation. However, it is unknown which type of MΦ, M1 or M2, plays a more essential role in the ovary. CD206 or CD11c diphtheria toxin receptor transgenic (DTR) mice, which enable depletion of CD206+ M2 MΦs and CD11c+ MΦ or CD11c+ Dendritic cells (DCs), respectively, were used. Oocytes were used for in vitro fertilization and embryo transfer. In vitro fertilized embryos derived from M2 MΦ depleted oocytes were transferred to pseudo pregnant wild type mice. CD11c DTR mice were also used to investigate the role of CD11c cells, M1 MΦ and DCs in folliculogenesis. In WT mice, the proportion of CD206+ M2-like MΦs was not increased in follicular induction, while that of CD11c+ M1-like MΦs was increased. In CD206 DTR mice, folliculogenesis was normal and the ovulation number, fertilization rate, and implantation rate were similar to those in WT mice. In CD11c DTR mice, folliculogenesis was impaired with ovarian hemorrhage and the staining of platelet derived growth factor-receptor β (PDGF-Rβ), a marker of pericytes, and CD34, a marker of endothelial cells, was reduced. CD11c+ cells, M1 MΦs or DCs, may be involved in folliculogenesis, while M2 MΦs are not involved in folliculogenesis.
Developmental temperature has persistent, sexually dimorphic effects on zebrafish cardiac anatomy
Authors: Dimitriadi Anastasia , Beis Dimitris , Arvanitidis Christos , Adriaens Dominique , Koumoundouros George 
Published: May 2018

AbstractOver the next century, climate change of anthropogenic origin is a major threat to global biodiversity. We show here that developmental temperature can have significant effects on zebrafish cardiac anatomy and swimming performance. Zebrafish embryos were subjected to three developmental temperature treatments (TD = 24, 28 or 32 °C) up to metamorphosis and then all maintained under common conditions (28 °C) to adulthood. We found that developmental temperature affected cardiac anatomy of juveniles and adults even eight months after the different thermal treatments had been applied. The elevation of TD induced a significant increase of the ventricle roundness in juvenile (10% increase) and male (22% increase), but not in female zebrafish. The aerobic exercise performance of adult zebrafish was significantly decreased as TD elevated from 24 to 32 °C. Gene expression analysis that was performed at the end of the temperature treatments revealed significant up-regulation of nppa, myh7 and mybpc3 genes at the colder temperature. Our work provides the first evidence for a direct link between developmental temperature and cardiac form at later life-stages. Our results also add to the emerging rationale for understanding the potential effects of global warming on how fish will perform in their natural environment.
Enabling STD-NMR fragment screening using stabilized native GPCR: A case study of adenosine receptor
Authors: Igonet Sébastien , Raingeval Claire , Cecon Erika , Pučić-Baković Maja , Lauc Gordan , Cala Olivier , Baranowski Maciej , Perez Javier , Jockers Ralf , Krimm Isabelle , Jawhari Anass 
Published: May 2018

AbstractStructural studies of integral membrane proteins have been limited by the intrinsic conformational flexibility and the need to stabilize the proteins in solution. Stabilization by mutagenesis was very successful for structural biology of G protein-coupled receptors (GPCRs). However, it requires heavy protein engineering and may introduce structural deviations. Here we describe the use of specific calixarenes-based detergents for native GPCR stabilization. Wild type, full length human adenosine A2A receptor was used to exemplify the approach. We could stabilize native, glycosylated, non-aggregated and homogenous A2AR that maintained its ligand binding capacity. The benefit of the preparation for fragment screening, using the Saturation-Transfer Difference nuclear magnetic resonance (STD-NMR) experiment is reported. The binding of the agonist adenosine and the antagonist caffeine were observed and competition experiments with CGS-21680 and ZM241385 were performed, demonstrating the feasibility of the STD-based fragment screening on the native A2A receptor. Interestingly, adenosine was shown to bind a second binding site in the presence of the agonist CGS-21680 which corroborates published results obtained with molecular dynamics simulation. Fragment-like compounds identified using STD-NMR showed antagonistic effects on A2AR in the cAMP cellular assay. Taken together, our study shows that stabilization of native GPCRs represents an attractive approach for STD-based fragment screening and drug design.
Hot-Hole Cooling Controls the Initial Ultrafast Relaxation in Methylammonium Lead Iodide Perovskite
Authors: Hedley Gordon J. , Quarti Claudio , Harwell Jonathon , Prezhdo Oleg V. , Beljonne David , Samuel Ifor D. W. 
Published: May 2018

AbstractUnderstanding the initial ultrafast excited state dynamics of methylammonium lead iodide (MAPI) perovskite is of vital importance to enable its fullest utilisation in optoelectronic devices and the design of improved materials. Here we have combined advanced measurements of the ultrafast photoluminescence from MAPI films up to 0.6 eV above the relaxed excited state with cutting-edge advanced non-adiabatic quantum dynamics simulations, to provide a powerful unique insight into the earliest time behaviour in MAPI. Our joint experimental-theoretical approach highlights that the cooling of holes from deep in the valence band to the valence band edge is fast, occurring on a 100–500 fs timescale. Cooling of electrons from high in the conduction band to the conduction band edge, however, is much slower, on the order of 1–10 ps. Density of states calculations indicate that excited states with holes deep in the valence band are greatly favoured upon photoexcitation, and this matches well with the fast (100–500 fs) formation time for the relaxed excited state observed in our ultrafast PL measurements. Consequently we are able to provide a complete observation of the initial excited state evolution in this important prototypical material.
Sorting Five Human Tumor Types Reveals Specific Biomarkers and Background Classification Genes
Authors: Roche Kimberly E. , Weinstein Marvin , Dunwoodie Leland J. , Poehlman William L. , Feltus Frank A. 
Published: May 2018

AbstractWe applied two state-of-the-art, knowledge independent data-mining methods – Dynamic Quantum Clustering (DQC) and t-Distributed Stochastic Neighbor Embedding (t-SNE) – to data from The Cancer Genome Atlas (TCGA). We showed that the RNA expression patterns for a mixture of 2,016 samples from five tumor types can sort the tumors into groups enriched for relevant annotations including tumor type, gender, tumor stage, and ethnicity. DQC feature selection analysis discovered 48 core biomarker transcripts that clustered tumors by tumor type. When these transcripts were removed, the geometry of tumor relationships changed, but it was still possible to classify the tumors using the RNA expression profiles of the remaining transcripts. We continued to remove the top biomarkers for several iterations and performed cluster analysis. Even though the most informative transcripts were removed from the cluster analysis, the sorting ability of remaining transcripts remained strong after each iteration. Further, in some iterations we detected a repeating pattern of biological function that wasn’t detectable with the core biomarker transcripts present. This suggests the existence of a “background classification” potential in which the pattern of gene expression after continued removal of “biomarker” transcripts could still classify tumors in agreement with the tumor type.
Rapid in situ assessment of Cu-ion mediated effects and antibacterial efficacy of copper surfaces
Authors: Rosenberg Merilin , Vija Heiki , Kahru Anne , Keevil C. William , Ivask Angela 
Published: May 2018

AbstractRelease of metal ions from metal-based surfaces has been considered one of the main drivers of their antimicrobial activity. Here we describe a method that enables parallel assessment of metal ion release from solid metallic surfaces and antimicrobial efficacy of these surfaces in a short time period. The protocol involves placement of a small volume of bioluminescent bacteria onto the tested surface and direct measurement of bioluminescence at various time points. In this study, two recombinant Escherichia coli strains, one expressing bioluminescence constitutively and applicable for general antimicrobial testing, and the other induced by Cu ions, were selected. Decrease in bioluminescence of constitutive E. coli on the surfaces showed a good correlation with the decrease in bacterial viability. Response of Cu-inducible E. coli showed a correlation with Cu content in the tested surfaces but not with Cu dissolution suggesting the role of direct bacteria-surface contact in Cu ion-driven antibacterial effects. In summary, the presented protocol enables the analysis of microbial toxicity and bioavailability of surface-released metal ions directly on solid surfaces within 30–60 min. Although optimized for copper and copper alloy surfaces and E. coli, the method can be extended to other types of metallic surfaces and bacterial strains.
One-way edge modes in a photonic crystal of semiconductor at terahertz frequencies
Authors: He Lingjuan , Shen Qian , Xu Jie , You Yun , Yu Tianbao , Shen Linfang , Deng Xiaohua 
Published: May 2018

AbstractElectromagnetic edge mode in a photonic crystal (PhC), which is a square array of semiconductor rods in air, is theoretically investigated for terahertz frequencies. In the PhC, gyroelectric anisotropy is introduced in the semiconductor rods by applying an external magnetic field and consequently, a degeneracy point, at which two dispersion surfaces intersect, is lifted and a new band gap is created. The edge mode sustained by the PhC possesses the character of one-way propagation, and it even can be immune to backscattering at large defect on the wavelength scale and 90° sharp bend. The properties of the one-way mode are closely dependent on the cladding layer structure of the PhC.
The neurotrophic tyrosine kinase receptor TrkA and its ligand NGF are increased in squamous cell carcinomas of the lung
Authors: Gao Fangfang , Griffin Nathan , Faulkner Sam , Rowe Christopher W. , Williams Lily , Roselli Severine , Thorne Rick F. , Ferdoushi Aysha , Jobling Phillip , Walker Marjorie M. , Hondermarck Hubert 
Published: May 2018

AbstractThe neurotrophic tyrosine kinase receptor TrkA (NTRK1) and its ligand nerve growth factor (NGF) are emerging promoters of tumor progression. In lung cancer, drugs targeting TrkA are in clinical trials, but the clinicopathological significance of TrkA and NGF, as well as that of the precursor proNGF, the neurotrophin co-receptor p75NTR and the proneurotrophin co-receptor sortilin, remains unclear. In the present study, analysis of these proteins was conducted by immunohistochemistry and digital quantification in a series of 204 lung cancers of different histological subtypes versus 121 normal lung tissues. TrkA immunoreactivity was increased in squamous cell carcinoma compared with benign and other malignant lung cancer histological subtypes (p < 0.0001). NGF and proNGF were also increased in squamous cell carcinoma, as well as in adenocarcinoma (p < 0.0001). In contrast, p75NTR was increased across all lung cancer histological subtypes compared to normal lung (p < 0.0001). Sortilin was higher in adenocarcinoma and small cell carcinoma (p < 0.0001). Nerves in the tumor microenvironment were negative for TrkA, NGF, proNGF, p75NTR and sortilin. In conclusion, these data suggest a preferential therapeutic value of targeting the NGF-TrkA axis in squamous cell carcinomas of the lung.