bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association and cis-mQTL analysis of variants in CHRNA3-A5, CHRNA7, CHRNB2, and CHRNB4 in relation to nicotine dependence in a Chinese Han population
Authors: Liu Qiang , Han Haijun , Wang Maiqiu , Yao Yinghao , Wen Li , Jiang Keran , Ma Yunlong , Fan Rongli , Chen Jiali , Su Kunkai , Yang Zhongli , Cui Wenyan , Yuan Wenji , Jiang Xianzhong , Li Jingjing , Payne Thomas J. , Wang Jundong , Li Ming D. 
Published: April 2018

AbstractNicotine dependence (ND) is a worldwide health problem. Numerous genetic studies have demonstrated a significant association of variants in nicotinic acetylcholine receptors (nAChRs) with smoking behaviors. However, most of these studies enrolled only subjects of European or African ancestry. In addition, although an increasing body of evidence implies a causal connection of single-nucleotide polymorphisms (SNPs) and epigenetic regulation of gene expression, few studies of this issue have been reported. In this study, we performed both association and interaction analysis for 67 SNPs inCHRNA3-A5, CHRNA7, CHRNB2, andCHRNB4with ND in a Chinese Han population (N = 5055). We further analyzedcis-mQTL for the three most significant SNPs and 5580 potential methylation loci within these target gene regions. Our results indicated that the SNPs rs1948 and rs7178270 inCHRNB4and rs3743075 inCHRNA3were significantly associated with the Fagerström Test for Nicotine Dependence (FTND) score (p = 6.6 × 10−5;p = 2.0 × 10−4, andp = 7.0 × 10−4, respectively). Haplotype-based association analysis revealed that two major haplotypes, T-G and C-A, formed by rs3743075–rs3743074 inCHRNA3, and other two major haplotypes, A-G-C and G-C-C, formed by rs1948–rs7178270–rs17487223 inCHRNB4, were significantly associated with the FTND score (p ≤ 8.0 × 10−4). Further, we found evidence for the presence of significant interaction among variants withinCHRNA3/B4/A5, CHRNA4/B2/A5, andCHRNA7in affecting ND, with correspondingpvalues of 5.8 × 10−6, 8.0 × 10−5, and 0.012, respectively. Finally, we identified two CpG sites (CpG_2975 and CpG_3007) inCHRNA3that are significantly associated with threecis-mQTL SNPs (rs1948, rs7178270, rs3743075) in theCHRNA5/A3/B4cluster (p ≤ 1.9 × 10−6), which formed four significant CpG–SNP pairs in our sample. Together, we revealed at least three novel SNPs inCHRNA3andCHRNB4to be significantly associated with the FTND score. Further, we showed that these significant variants contribute to ND via two methylated sites, and we demonstrated significant interaction affecting ND among variants inCHRNA5/A3/B4,CHRNA7, andCHRNA4/B2/A5. In sum, these findings provide robust evidence that SNPs in nAChR genes convey a risk of ND in the Chinese Han population.
Signaling pathways responsible for the rapid antidepressant-like effects of a GluN2A-preferring NMDA receptor antagonist
Authors: Gordillo-Salas Marta , Pilar-Cuéllar Fuencisla , Auberson Yves P. , Adell Albert 
Published: April 2018

AbstractIn a previous study we found that the preferring GluN2A receptor antagonist, NVP-AAM077, elicited rapid antidepressant-like effects in the forced swim test that was related to the release of glutamate and serotonin in the medial prefrontal cortex. In the present work we sought to examine the duration of this behavioral effect as well as the molecular readouts involved. Our results showed that NVP-AAM077 reduced the immobility in the forced swim test 30 min and 24 h after its administration. However, this effect waned 7 days later. The rapid antidepressant-like response seems to be associated with increases in the GluA1 subunit of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, mammalian target of rapamycin (mTOR) signaling, glia markers such as glial fibrillary acidic protein (GFAP) and excitatory amino acid transporter 1 (EAAT1), and a rapid mobilization of intracellular stores of brain-derived neurotrophic factor (BDNF) in the medial prefrontal cortex.
Altered function and maturation of primary cortical neurons from a 22q11.2 deletion mouse model of schizophrenia
Authors: Sun Ziyi , Williams Damian J. , Xu Bin , Gogos Joseph A. 
Published: April 2018

AbstractGiven its high penetrance, clearly delineated and evolutionary conserved genomic structure, mouse models of the 22q11.2 deletion provide an ideal organism-based and cell-based model of this well-established disease mutation for schizophrenia. In this study we examined the development of changes in intrinsic properties, action potential firing and synaptic transmission using whole-cell patch-clamp recordings of cultured embryonic cortical neurons fromDf(16)A+/−and WT mice at DIV7 and DIV14, respectively. Compared to neurons from the WT littermates, significantly increased input resistance and decreased rising rate of action potential was observed inDf(16)A+/−mice at DIV7 but not at DIV14 indicative of delayed neuronal maturation. Neurons fromDf(16)A+/−mice also showed significantly higher cellular excitability at both DIV7 and DIV14. Evaluation of Ca2+homeostasis perturbation caused by 22q11.2 deletion using calcium imaging revealed a significantly lower amplitude of calcium elevation and a smaller area under the curve after depolarization in neurons fromDf(16)A+/−mice at both DIV7 and DIV14. Furthermore, the properties of inhibitory synaptic events were significantly altered inDf(16)A+/−mice. We identified changes in mRNA expression profiles, especially in ion channels, receptors, and transporters that may underlie the neurophysiological effects of this mutation. Overall, we show a number of alterations in electrophysiological and calcium homeostatic properties of embryonic cortical neurons from a 22q11.2 deletion mouse model at different culture times and provide valuable insights towards revealing disease mechanisms and discovery of new therapeutic compounds.
Heterogeneous Fe3 single-cluster catalyst for ammonia synthesis via an associative mechanism
Authors: Liu Jin-Cheng , Ma Xue-Lu , Li Yong , Wang Yang-Gang , Xiao Hai , Li Jun 
Published: April 2018

AbstractThe current industrial ammonia synthesis relies on Haber–Bosch process that is initiated by the dissociative mechanism, in which the adsorbed N2dissociates directly, and thus is limited by Brønsted–Evans–Polanyi (BEP) relation. Here we propose a new strategy that an anchored Fe3cluster on the θ-Al2O3(010) surface as a heterogeneous catalyst for ammonia synthesis from first-principles theoretical study and microkinetic analysis. We have studied the whole catalytic mechanism for conversion of N2to NH3on Fe3/θ-Al2O3(010), and find that an associative mechanism, in which the adsorbed N2is first hydrogenated to NNH, dominates over the dissociative mechanism, which we attribute to the large spin polarization, low oxidation state of iron, and multi-step redox capability of Fe3cluster. The associative mechanism liberates the turnover frequency (TOF) for ammonia production from the limitation due to the BEP relation, and the calculated TOF on Fe3/θ-Al2O3(010) is comparable to Ru B5 site.
Gauging force by tapping tendons
Authors: Martin Jack A. , Brandon Scott C. E. , Keuler Emily M. , Hermus James R. , Ehlers Alexander C. , Segalman Daniel J. , Allen Matthew S. , Thelen Darryl G. 
Published: April 2018

AbstractMuscles are the actuators that drive human movement. However, despite many decades of work, we still cannot readily assess the forces that muscles transmit during human movement. Direct measurements of muscle–tendon loads are invasive and modeling approaches require many assumptions. Here, we introduce a non-invasive approach to assess tendon loads by tracking vibrational behavior. We first show that the speed of shear wave propagation in tendon increases with the square root of axial stress. We then introduce a remarkably simple shear wave tensiometer that uses micron-scale taps and skin-mounted accelerometers to track tendon wave speeds in vivo. Tendon wave speeds are shown to modulate in phase with active joint torques during isometric exertions, walking, and running. The capacity to non-invasively assess muscle–tendon loading can provide new insights into the motor control and biomechanics underlying movement, and could lead to enhanced clinical treatment of musculoskeletal injuries and diseases.
Placental miR-340 mediates vulnerability to activity based anorexia in mice
Authors: Schroeder Mariana , Jakovcevski Mira , Polacheck Tamar , Drori Yonat , Luoni Alessia , Röh Simone , Zaugg Jonas , Ben-Dor Shifra , Albrecht Christiane , Chen Alon 
Published: April 2018

AbstractAnorexia nervosa (AN) is a devastating eating disorder characterized by self-starvation that mainly affects women. Its etiology is unknown, which impedes successful treatment options leading to a limited chance of full recovery. Here, we show that gestation is a vulnerable window that can influence the predisposition to AN. By screening placental microRNA expression of naive and prenatally stressed (PNS) fetuses and assessing vulnerability to activity-based anorexia (ABA), we identify miR-340 as a sexually dimorphic regulator involved in prenatal programming of ABA. PNS caused gene-body hypermethylation of placental miR-340, which is associated with reduced miR-340 expression and increased protein levels of several target transcripts, GR, Cry2 and H3F3b. MiR-340 is linked to the expression of several nutrient transporters both in mice and human placentas. Using placenta-specific lentiviral transgenes and embryo transfer, we demonstrate the key role miR-340 plays in the mechanism involved in early life programming of ABA.
Multi-faceted immunomodulatory and tissue-tropic clinical bacterial isolate potentiates prostate cancer immunotherapy
Authors: Anker Jonathan F. , Naseem Anum F. , Mok Hanlin , Schaeffer Anthony J. , Abdulkadir Sarki A. , Thumbikat Praveen 
Published: April 2018

AbstractImmune checkpoint inhibitors have not been effective for immunologically “cold” tumors, such as prostate cancer, which contain scarce tumor infiltrating lymphocytes. We hypothesized that select tissue-specific and immunostimulatory bacteria can potentiate these immunotherapies. Here we show that a patient-derived prostate-specific microbe, CP1, in combination with anti-PD-1 immunotherapy, increases survival and decreases tumor burden in orthotopic MYC- and PTEN-mutant prostate cancer models. CP1 administered intra-urethrally specifically homes to and colonizes tumors without causing any systemic toxicities. CP1 increases immunogenic cell death of cancer cells, T cell cytotoxicity, and tumor infiltration by activated CD8 T cells, Th17 T cells, mature dendritic cells, M1 macrophages, and NK cells. CP1 also decreases intra-tumoral regulatory T cells and VEGF. Mechanistically, blocking CP1-recruited T cells from infiltrating the tumor inhibits its therapeutic efficacy. CP1 is an immunotherapeutic tool demonstrating how a tissue-specific microbe can increase tumor immunogenicity and sensitize an otherwise resistant cancer type to immunotherapy.
True equilibrium measurement of transcription factor-DNA binding affinities using automated polarization microscopy
Authors: Jung Christophe , Bandilla Peter , von Reutern Marc , Schnepf Max , Rieder Susanne , Unnerstall Ulrich , Gaul Ulrike 
Published: April 2018

AbstractThe complex patterns of gene expression in metazoans are controlled by selective binding of transcription factors (TFs) to regulatory DNA. To improve the quantitative understanding of this process, we have developed a novel method that uses fluorescence anisotropy measurements in a controlled delivery system to determine TF-DNA binding energies in solution with high sensitivity and throughput. Owing to its large dynamic range, the method, named high performance fluorescence anisotropy (HiP-FA), allows for reliable quantification of both weak and strong binding; binding specificities are calculated on the basis of equilibrium constant measurements for mutational DNA variants. We determine the binding preference landscapes for 26 TFs and measure high absolute affinities, but mostly lower binding specificities than reported by other methods. The revised binding preferences give rise to improved predictions of in vivo TF occupancy and enhancer expression. Our approach provides a powerful new tool for the systems-biological analysis of gene regulation.
Anthropogenic combustion iron as a complex climate forcer
Authors: Matsui Hitoshi , Mahowald Natalie M. , Moteki Nobuhiro , Hamilton Douglas S. , Ohata Sho , Yoshida Atsushi , Koike Makoto , Scanza Rachel A. , Flanner Mark G. 
Published: April 2018

AbstractAtmospheric iron affects the global carbon cycle by modulating ocean biogeochemistry through the deposition of soluble iron to the ocean. Iron emitted by anthropogenic (fossil fuel) combustion is a source of soluble iron that is currently considered less important than other soluble iron sources, such as mineral dust and biomass burning. Here we show that the atmospheric burden of anthropogenic combustion iron is 8 times greater than previous estimates by incorporating recent measurements of anthropogenic magnetite into a global aerosol model. This new estimation increases the total deposition flux of soluble iron to southern oceans (30–90 °S) by 52%, with a larger contribution of anthropogenic combustion iron than dust and biomass burning sources. The direct radiative forcing of anthropogenic magnetite is estimated to be 0.021 W m−2 globally and 0.22 W m−2 over East Asia. Our results demonstrate that anthropogenic combustion iron is a larger and more complex climate forcer than previously thought, and therefore plays a key role in the Earth system.
Evolution of high-level resistance during low-level antibiotic exposure
Authors: Wistrand-Yuen Erik , Knopp Michael , Hjort Karin , Koskiniemi Sanna , Berg Otto G. , Andersson Dan I. 
Published: April 2018

AbstractIt has become increasingly clear that low levels of antibiotics present in many environments can select for resistant bacteria, yet the evolutionary pathways for resistance development during exposure to low amounts of antibiotics remain poorly defined. Here we show that Salmonella enterica exposed to sub-MIC levels of streptomycin evolved high-level resistance via novel mechanisms that are different from those observed during lethal selections. During lethal selection only rpsL mutations are found, whereas at sub-MIC selection resistance is generated by several small-effect resistance mutations that combined confer high-level resistance via three different mechanisms: (i) alteration of the ribosomal RNA target (gidB mutations), (ii) reduction in aminoglycoside uptake (cyoB, nuoG, and trkH mutations), and (iii) induction of the aminoglycoside-modifying enzyme AadA (znuA mutations). These results demonstrate how the strength of the selective pressure influences evolutionary trajectories and that even weak selective pressures can cause evolution of high-level resistance.
Vibrio vulnificus quorum-sensing molecule cyclo(Phe-Pro) inhibits RIG-I-mediated antiviral innate immunity
Authors: Lee Wooseong , Lee Seung-Hoon , Kim Minwoo , Moon Jae-Su , Kim Geon-Woo , Jung Hae-Gwang , Kim In Hwang , Oh Ji Eun , Jung Hi Eun , Lee Heung Kyu , Ku Keun Bon , Ahn Dae-Gyun , Kim Seong-Jun , Kim Kun-Soo , Oh Jong-Won 
Published: April 2018

AbstractThe recognition of pathogen-derived ligands by pattern recognition receptors activates the innate immune response, but the potential interaction of quorum-sensing (QS) signaling molecules with host anti-viral defenses remains largely unknown. Here we show that the Vibrio vulnificus QS molecule cyclo(Phe-Pro) (cFP) inhibits interferon (IFN)-β production by interfering with retinoic-acid-inducible gene-I (RIG-I) activation. Binding of cFP to the RIG-I 2CARD domain induces a conformational change in RIG-I, preventing the TRIM25-mediated ubiquitination to abrogate IFN production. cFP enhances susceptibility to hepatitis C virus (HCV), as well as Sendai and influenza viruses, each known to be sensed by RIG-I but did not affect the melanoma-differentiation-associated gene 5 (MDA5)-recognition of norovirus. Our results reveal an inter-kingdom network between bacteria, viruses and host that dysregulates host innate responses via a microbial quorum-sensing molecule modulating the response to viral infection.
A mobile endocytic network connects clathrin-independent receptor endocytosis to recycling and promotes T cell activation
Authors: Compeer Ewoud B. , Kraus Felix , Ecker Manuela , Redpath Gregory , Amiezer Mayan , Rother Nils , Nicovich Philip R. , Kapoor-Kaushik Natasha , Deng Qiji , Samson Guerric P. B. , Yang Zhengmin , Lou Jieqiong , Carnell Michael , Vartoukian Haig , Gaus Katharina , Rossy Jérémie 
Published: April 2018

AbstractEndocytosis of surface receptors and their polarized recycling back to the plasma membrane are central to many cellular processes, such as cell migration, cytokinesis, basolateral polarity of epithelial cells and T cell activation. Little is known about the mechanisms that control the organization of recycling endosomes and how they connect to receptor endocytosis. Here, we follow the endocytic journey of the T cell receptor (TCR), from internalization at the plasma membrane to recycling back to the immunological synapse. We show that TCR triggering leads to its rapid uptake through a clathrin-independent pathway. Immediately after internalization, TCR is incorporated into a mobile and long-lived endocytic network demarked by the membrane-organizing proteins flotillins. Although flotillins are not required for TCR internalization, they are necessary for its recycling to the immunological synapse. We further show that flotillins are essential for T cell activation, supporting TCR nanoscale organization and signaling.
Curcumin interacts directly with the Cysteine 259 residue of STAT3 and induces apoptosis in H-Ras transformed human mammary epithelial cells
Authors: Hahn Young-Il , Kim Su-Jung , Choi Bu-Young , Cho Kyung-Cho , Bandu Raju , Kim Kwang Pyo , Kim Do-Hee , Kim Wonki , Park Joon Sung , Han Byung Woo , Lee Jeewoo , Na Hye-Kyung , Cha Young-Nam , Surh Young-Joon 
Published: April 2018

AbstractSignal transducer and activator of transcription 3 (STAT3) is a transcription factor that is latent but constitutively activated in many types of cancers. It is well known that STAT3 plays a key role in inflammation-associated tumorigenesis. Curcumin is an anti-inflammatory natural compound isolated from the turmeric (Curcuma longaL., Zingiberaceae) that has been extensively used in a traditional medicine over the centuries. In the present study, we have found that curcumin inhibits STAT3 signaling that is persistently overactivated in H-Rastransformed breast epithelial cells (H-RasMCF10A). Specific cysteine residues present in STAT3 appear to be critical for the activity as well as conformation of this transcription factor. We identified the cysteine residue 259 of STAT3 as a putative site for curcumin binding. Site-directed mutation of this cysteine residue abolished curcumin-induced inactivation of STAT3 and apoptosis in H-RasMCF10A cells. The α,β-unsaturated carbonyl moiety of curcumin appears to be essential in its binding to STAT3 in H-RasMCF10A cells. Tetrahydrocurcumin that lacks such electrophilic moiety failed to interact with STAT3 and to induce apoptosis in the same cell line. Taken together, our findings suggest that curcumin can abrogate aberrant activation of STAT3 through direct interaction, thereby inhibiting STAT3-mediated mammary carcinogenesis.
Quantitative optical mapping of two-dimensional materials
Authors: Jessen Bjarke S. , Whelan Patrick R. , Mackenzie David M. A. , Luo Birong , Thomsen Joachim D. , Gammelgaard Lene , Booth Timothy J. , Bøggild Peter 
Published: April 2018

AbstractThe pace of two-dimensional materials (2DM) research has been greatly accelerated by the ability to identify exfoliated thicknesses down to a monolayer from their optical contrast. Since this process requires time-consuming and error-prone manual assignment to avoid false-positives from image features with similar contrast, efforts towards fast and reliable automated assignments schemes is essential. We show that by modelling the expected 2DM contrast in digitally captured images, we can automatically identify candidate regions of 2DM. More importantly, we show a computationally-light machine vision strategy for eliminating false-positives from this set of 2DM candidates through the combined use of binary thresholding, opening and closing filters, and shape-analysis from edge detection. Calculation of data pyramids for arbitrarily high-resolution optical coverage maps of two-dimensional materials produced in this way allows the real-time presentation and processing of this image data in a zoomable interface, enabling large datasets to be explored and analysed with ease. The result is that a standard optical microscope with CCD camera can be used as an analysis tool able to accurately determine the coverage, residue/contamination concentration, and layer number for a wide range of presented 2DMs.
A novel in vitro metric predicts in vivo efficacy of inhaled silver-based antimicrobials in a murine Pseudomonas aeruginosa pneumonia model
Authors: Shah Parth N. , Shah Kush N. , Smolen Justin A. , Tagaev Jasur A. , Torrealba Jose , Zhou Lan , Zhang Shiyi , Zhang Fuwu , Wagers Patrick O. , Panzner Matthew J. , Youngs Wiley J. , Wooley Karen L. , Cannon Carolyn L. 
Published: April 2018

AbstractTo address the escalating problem of antimicrobial resistance and the dwindling antimicrobial pipeline, we have developed a library of novel aerosolizable silver-based antimicrobials, particularly for the treatment of pulmonary infections. To rapidly screen this library and identify promising candidates, we have devised a novel in vitro metric, named the “drug efficacy metric” (DEM), which integrates both the antibacterial activity and the on-target, host cell cytotoxicity. DEMs calculated using an on-target human bronchial epithelial cell-line correlates well (R2 > 0.99) with in vivo efficacy, as measured by median survival hours in a Pseudomonas aeruginosa pneumonia mouse model following aerosolized antimicrobial treatment. In contrast, DEMs derived using off-target primary human dermal fibroblasts correlate poorly (R2 = 0.0595), which confirms our hypothesis. SCC1 and SCC22 have been identified as promising drug candidates through these studies, and SCC22 demonstrates a dose-dependent survival advantage compared to sham treatment. Finally, silver-bearing biodegradable nanoparticles were predicted to exhibit excellent in vivo efficacy based on its in vitro DEM value, which was confirmed in our mouse pneumonia model. Thus, the DEM successfully predicted the efficacy of various silver-based antimicrobials, and may serve as an excellent tool for the rapid screening of potential antimicrobial candidates without the need for extensive animal experimentation.