bluuebunny/crossref_metadata_2025_split huggingface dataset:
Independent losses of a xenobiotic receptor across teleost evolution
Authors: Eide Marta , Rydbeck Halfdan , Tørresen Ole K. , Lille-Langøy Roger , Puntervoll Pål , Goldstone Jared V. , Jakobsen Kjetill S. , Stegeman John , Goksøyr Anders , Karlsen Odd A. 
Published: July 2018

AbstractSensitivity to environmental stressors largely depend on the genetic complement of the organism. Recent sequencing and assembly of teleost fish genomes enable us to trace the evolution of defense genes in the largest and most diverse group of vertebrates. Through genomic searches and in-depth analysis of gene loci in 76 teleost genomes, we show here that the xenosensor pregnane X receptor (Pxr, Nr1i2) is absent in more than half of these species. Notably, out of the 27 genome assemblies that belong to the Gadiformes order, the pxr gene was only retained in the Merluccidae family (hakes) and Pelagic cod (Melanonus zugmayeri). As an important receptor for a wide range of drugs and environmental pollutants, vertebrate PXR regulate the transcription of a number of genes involved in the biotransformation of xenobiotics, including cytochrome P450 enzymes (CYP). In the absence of Pxr, we suggest that the aryl hydrocarbon receptor (Ahr) have evolved an extended regulatory role by governing the expression of certain Pxr target genes, such as cyp3a, in Atlantic cod (Gadus morhua). However, as several independent losses of pxr have occurred during teleost evolution, other lineages and species may have adapted alternative compensating mechanisms for controlling crucial cellular defense mechanisms.
Radiobrominated benzimidazole-quinoline derivatives as Platelet-derived growth factor receptor beta (PDGFRβ) imaging probes
Authors: Effendi Nurmaya , Mishiro Kenji , Takarada Takeshi , Makino Akira , Yamada Daisuke , Kitamura Yoji , Shiba Kazuhiro , Kiyono Yasushi , Odani Akira , Ogawa Kazuma 
Published: July 2018

AbstractPlatelet-derived growth factor receptor beta (PDGFRβ) affects in numerous human cancers and has been recognized as a promising molecular target for cancer therapies. The overexpression of PDGFRβ could be a biomarker for cancer diagnosis. Radiolabeled ligands having high affinity for the molecular target could be useful tools for the imaging of overexpressed receptors in tumors. In this study, we aimed to develop radiobrominated PDGFRβ ligands and evaluate their effectiveness as PDGFRβ imaging probes. The radiolabeled ligands were designed by modification of 1-{2-[5-(2-methoxyethoxy)-1H- benzo[d]imidazol-1-yl]quinolin-8-yl}piperidin-4-amine (1), which shows selective inhibition profile toward PDGFRβ. The bromine atom was introduced directly into C-5 of the quinoline group of 1, or indirectly by the conjugation of 1 with the 3-bromo benzoyl group. [77Br]1-{5-Bromo-2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinoline-8-yl}piperidin-4-amine ([77Br]2) and [77Br]-N-3-bromobenzoyl-1-{2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinolin-8-yl}-piperidin-4-amine ([77Br]3) were prepared using a bromodestannylation reaction. In a cellular uptake study, [77Br]2 and [77Br]3 more highly accumulatd in BxPC3-luc cells (PDGFRβ-positive) than in MCF7 cells (PDGFRβ-negative), and their accumulation was significantly reduced by pretreatment with inhibitors. In biodistribution experiments, [77Br]2 accumulation was higher than [77Br]3 accumulation at 1 h postinjection. These findings suggest that [76Br]2 is more promising for positron emission tomography (PET) imaging of PDGFRβ than [76Br]3.
Water Pharmacophore: Designing Ligands using Molecular Dynamics Simulations with Water
Authors: Jung Sang Won , Kim Minsup , Ramsey Steven , Kurtzman Tom , Cho Art E. 
Published: July 2018

AbstractIn this study, we demonstrate a method to construct a water-based pharmacophore model which can be utilized in the absence of known ligands. This method utilizes waters found in the binding pocket, sampled through molecular dynamics. Screening of compound databases against this water-based pharmacophore model reveals that this approach can successfully identify known binders to a target protein. The method was tested by enrichment studies of 7 therapeutically important targets and compared favourably to screening-by-docking with Glide. Our results suggest that even without experimentally known binders, pharmacophore models can be generated using molecular dynamics with waters and used for virtual screening.
NaV1.4 DI-S4 periodic paralysis mutation R222W enhances inactivation and promotes leak current to attenuate action potentials and depolarize muscle fibers
Authors: Bayless-Edwards Landon , Winston Vern , Lehmann-Horn Frank , Arinze Paula , Groome James R. , Jurkat-Rott Karin 
Published: July 2018

AbstractHypokalemic periodic paralysis is a skeletal muscle disease characterized by episodic weakness associated with low serum potassium. We compared clinical and biophysical effects of R222W, the first hNaV1.4 domain I mutation linked to this disease. R222W patients exhibited a higher density of fibers with depolarized resting membrane potentials and produced action potentials that were attenuated compared to controls. Functional characterization of the R222W mutation in heterologous expression included the inactivation deficient IFM/QQQ background to isolate activation. R222W decreased sodium current and slowed activation without affecting probability. Consistent with the phenotype of muscle weakness, R222W shifted fast inactivation to hyperpolarized potentials, promoted more rapid entry, and slowed recovery. R222W increased the extent of slow inactivation and slowed its recovery. A two-compartment skeletal muscle fiber model revealed that defects in fast inactivation sufficiently explain action potential attenuation in patients. Molecular dynamics simulations showed that R222W disrupted electrostatic interactions within the gating pore, supporting the observation that R222W promotes omega current at hyperpolarized potentials. Sodium channel inactivation defects produced by R222W are the primary driver of skeletal muscle fiber action potential attenuation, while hyperpolarization-induced omega current produced by that mutation promotes muscle fiber depolarization.
Oxidative degradation of polyamines by serum supplement causes cytotoxicity on cultured cells
Authors: Wang Linlin , Liu Ying , Qi Cui , Shen Luyao , Wang Junyan , Liu Xiangjun , Zhang Nan , Bing Tao , Shangguan Dihua 
Published: July 2018

AbstractSerum is a common supplement for cell culture due to it containing the essential active components for the growth and maintenance of cells. However, the knowledges of the active components in serum are incomplete. Apart from the direct influence of serum components on cultured cells, the reaction of serum components with tested drugs cannot be ignored, which usually results in the false conclusion on the activity of the tested drugs. Here we report the toxicity effect of polyamines (spermidine and spermine) on cultured cells, especially on drug-resistant cancer cell lines, which resulted from the oxidative degradation of polyamines by amine oxidases in serum supplement. Upon adding spermidine or spermine, high concentration of H2O2, an enzyme oxidation product of polyamines, was generated in culture media containing ruminant serum, such as fetal bovine serum (FBS), calf serum, bovine serum, goat serum or horse serum, but not in the media containing human serum. Drug-resistant cancer cell lines showed much higher sensitivity to the oxidation products of polyamines (H2O2 and acrolein) than their wild cell lines, which was due to their low antioxidative capacity.
Cellomics approach for high-throughput functional annotation of Caenorhabditis elegans neural network
Authors: Aoki Wataru , Matsukura Hidenori , Yamauchi Yuji , Yokoyama Haruki , Hasegawa Koichi , Shinya Ryoji , Ueda Mitsuyoshi 
Published: July 2018

AbstractIn Caenorhabditis elegans, which has only 302 neurons, relationships between behaviors and neural networks are not easily elucidated. In this study, we proposed a novel cellomics approach enabling high-throughput and comprehensive exploration of the functions of a single neuron or a subset of neurons in a complex neural network on a particular behavior. To realize this, we combined optogenetics and Brainbow technologies. Using these technologies, we established a C. elegans library where opsin is labeled in a randomized pattern. Behavioral analysis on this library under light illumination enabled high-throughput annotation of neurons affecting target behaviors. We applied this approach to the egg-laying behavior of C. elegans and succeeded in high-throughput confirmation that hermaphrodite-specific neurons play an important role in the egg-laying behavior. This cellomics approach will lead to the accumulation of neurophysiological and behavioral data of the C. elegans neural network, which is necessary for constructing neuroanatomically grounded models of behavior.
A profiling analysis of contributions of cigarette smoking, dietary calcium intakes, and physical activity to fragility fracture in the elderly
Authors: Pham Thuy T. , Nguyen Diep N. , Dutkiewicz Eryk , Center Jacqueline R. , Eisman John A. , Nguyen Tuan V. 
Published: July 2018

AbstractFragility fracture and bone mineral density (BMD) are influenced by common and modifiable lifestyle factors. In this study, we sought to define the contribution of lifestyle factors to fracture risk by using a profiling approach. The study involved 1683 women and 1010 men (50+ years old, followed up for up to 20 years). The incidence of new fractures was ascertained by X-ray reports. A “lifestyle risk score” (LRS) was derived as the weighted sum of effects of dietary calcium intake, physical activity index, and cigarette smoking. Each individual had a unique LRS, with higher scores being associated with a healthier lifestyle. Baseline values of lifestyle factors were assessed. In either men or women, individuals with a fracture had a significantly lower age-adjusted LRS than those without a fracture. In men, each unit lower in LRS was associated with a 66% increase in the risk of total fracture (non-adjusted hazard ratio [HR] 1.66; 95% CI, 1.26 to 2.20) and still significant after adjusting for age, weight or BMD. However, in women, the association was uncertain (HR 1.30; 95% CI, 1.11 to 1.53). These data suggest that unhealthy lifestyle habits are associated with an increased risk of fracture in men, but not in women, and that the association is mediated by BMD.
Power-law relationship in the long-tailed sections of proton dose distributions
Authors: Jiang Bo , Wang Xiaochun , Zhang Yang , Guan Fada , Li Yupeng , Wang Xianliang , Zhu Ronald X. , Zhang Xiaodong 
Published: July 2018

AbstractThe halo portion of a proton therapy dose creates a long tail in proton dose distributions, but so far study of this phenomenon has been limited. We used statistical methods and mathematical models to confirm that the long-tailed portion of proton dose distributions exhibits a power-law relationship. By analyzing 299 measured dose profiles, we found that all proton lateral dose distributions had a significant power-law scaling correlation with a high correlation coefficient in the tail. We set up a dual-mechanism model, containing both direct and indirect impact mechanisms. In the direct impact mechanism, the proximal dose deposition is mainly due to the direct impact of a proton on a particle. In the indirect mechanism, the impact of a proton on a given particle is considered in terms of the proton’s impact on a neighboring particle that then impacts the given particle. We found that the indirect impact mechanism led to a tail in the distribution exhibiting a power-law relationship because the probability of the indirect impacts was proportional to the distance; i.e., the longer the distance, the larger the indirect impact probability. Upon analyzing the experimental data, we observed that the power-law exponent increased with proton energy.
Volumetric, Nanoscale Optical Imaging of Mouse and Human Kidney via Expansion Microscopy
Authors: Chozinski Tyler J. , Mao Chenyi , Halpern Aaron R. , Pippin Jeffrey W. , Shankland Stuart J. , Alpers Charles E. , Najafian Behzad , Vaughan Joshua C. 
Published: July 2018

AbstractAlthough light microscopy is a powerful tool for the assessment of kidney physiology and pathology, it has traditionally been unable to resolve structures separated by less than the ~250 nm diffraction limit of visible light. Here, we report on the optimization, validation, and application of a recently developed super-resolution fluorescence microscopy method, called expansion microscopy (ExM), for volumetric interrogation of mouse and human kidney tissue with 70–75 nm lateral and ~250 nm axial spatial resolution. Using ExM with a standard confocal microscope, we resolve fine details of structures that have traditionally required visualization by electron microscopy, including podocyte foot processes, the glomerular basement membrane, and the cytoskeleton. This inexpensive and accessible approach to volumetric, nanoscale imaging enables visualization of fine structural details of kidney tissues that were previously difficult or impossible to measure by conventional methodologies.
Whole-genome sequencing reveals selection signatures associated with important traits in six goat breeds
Authors: Guo Jiazhong , Tao Haixi , Li Pengfei , Li Li , Zhong Tao , Wang Linjie , Ma Jinying , Chen Xiaoying , Song Tianzeng , Zhang Hongping 
Published: July 2018

AbstractComparative population genomics analysis is an effective approach to identify selection signatures in farm animals. In this study, we systematically investigated the selection signatures in six phenotypically diverse goat breeds using SNPs obtained from pooled whole-genome resequencing data. More than 95.5% of 446–642 million clean reads were mapped to the latest reference goat genome, which generated a sequencing depth ranging from 22.30 to 31.75-fold for each breed. A total of 5,802,307, 6,794,020, 7,562,312, 5,325,119, 8,764,136, and 9,488,057 putative SNPs were detected in Boer, Meigu, Jintang Black, Nanjiang Yellow, Tibetan, and Tibetan cashmere goats, respectively. Based on the genome-wide FST and expected heterozygosity scores along 100-kb sliding windows, 68, 89, 44, 44, 19, and 35 outlier windows were deemed as the selection signatures in the six goat breeds. After genome annotation, several genes within the selection signals were found to be possibly associated with important traits in goats, such as coat color (IRF4, EXOC2, RALY, EIF2S2, and KITLG), high-altitude adaptation (EPAS1), growth (LDB2), and reproduction traits (KHDRBS2). In summary, we provide an improved understanding of the genetic diversity and the genomic footprints under positive selection or the adaptations to the local environments in the domestic goat genome.
Circadian challenge of astronauts’ unconscious mind adapting to microgravity in space, estimated by heart rate variability
Authors: Otsuka Kuniaki , Cornelissen Germaine , Kubo Yutaka , Shibata Koichi , Hayashi Mitsutoshi , Mizuno Koh , Ohshima Hiroshi , Furukawa Satoshi , Mukai Chiaki 
Published: July 2018

AbstractIt is critical that the regulatory system functions well in space’s microgravity. However, the “intrinsic” cardiovascular regulatory system (β), estimated by the fractal scaling of heart rate variability (HRV) (0.0001–0.01 Hz), does not adapt to the space environment during long-duration (6-month) space flights. Neuroimaging studies suggest that the default mode network (DMN) serves a broad adaptive purpose, its topology changing over time in association with different brain states of adaptive behavior. Hypothesizing that HRV varies in concert with changes in brain’s functional connectivity, we analyzed 24-hour HRV records from 8 healthy astronauts (51.8 ± 3.7 years; 6 men) on long (174.5 ± 13.8 days) space missions, obtained before launch, after about 21 (ISS01), 73 (ISS02), and 156 (ISS03) days in space, and after return to Earth. Spectral power in 8 frequency regions reflecting activity in different brain regions was computed by maximal entropy. Improved β (p < 0.05) found in 4 astronauts with a positive activation in the “HRV slow-frequency oscillation” (0.10–0.20 Hz) occurred even in the absence of consciousness. The adaptive response was stronger in the evening and early sleep compared to morning (p = 0.039). Brain functional networks, the DMN in particular, can help adapt to microgravity in space with help from the circadian clock.
Systematic RNA-interference in primary human monocyte-derived macrophages: A high-throughput platform to study foam cell formation
Authors: Domschke Gabriele , Linden Fabian , Pawig Lukas , Hafner Anna , Akhavanpoor Mohammadreza , Reymann Jürgen , Doesch Andreas O. , Erbel Christian , Weber Christian , Katus Hugo A. , Noels Heidi , Erfle Holger , Gleissner Christian A. , Runz Heiko 
Published: July 2018

AbstractMacrophage-derived foam cells are key regulators of atherogenesis. They accumulate in atherosclerotic plaques and support inflammatory processes by producing cytokines and chemokines. Identifying factors that regulate macrophage lipid uptake may reveal therapeutic targets for coronary artery disease (CAD). Here, we establish a high-throughput screening workflow to systematically identify genes that impact the uptake of DiI-labeled low-density lipoprotein (LDL) into monocyte-derived primary human macrophages. For this, monocytes isolated from peripheral blood were seeded onto 384-well plates, solid-phase transfected with siRNAs, differentiated in vitro into macrophages, and LDL-uptake per cell was measured by automated microscopy and quantitative image analysis. We applied this workflow to study how silencing of 89 genes impacts LDL-uptake into cells from 16 patients with CAD and 16 age-matched controls. Silencing of four novel genes (APOC1, CMTM6, FABP4, WBP5) reduced macrophage LDL-uptake. Additionally, knockdown of the chemokine receptor CXCR4 reduced LDL-uptake, most likely through a G-protein coupled mechanism that involves the CXCR4 ligand macrophage-induced factor (MIF), but is independent of CXCL12. We introduce a high-throughput strategy to systematically study gene function directly in primary CAD-patient cells. Our results propose a function for the MIF/CXCR4 signaling pathway, as well as several novel candidate genes impacting lipid uptake into human macrophages.
Diffusion weighted MRI as an early predictor of tumor response to hypofractionated stereotactic boost for prostate cancer
Authors: Pasquier David , Hadj Henni Abderraouf , Escande Alexandre , Tresch Emmanuelle , Reynaert Nick , Colot Olivier , Lartigau Eric , Betrouni Nacim 
Published: July 2018

AbstractWe evaluated the feasibility of using the kinetic of diffusion-weighted MRI (DWI) and the normalized apparent coefficient diffusion (ADC) map value as an early biomarker in patients treated by external beam radiotherapy (EBRT). Twelve patients were included within the frame of a multicenter phase II trial and treated for intermediate risk prostate cancer (PCa). Multiparametric MRI was performed before treatment (M0) and every 6 months until M24. Association between nADC and PSA or PSA kinetic was evaluated using the test of nullity of the Spearman correlation coefficient. The median rates of PSA at the time of diagnosis, two years and four years after EBRT were 9.29 ng/ml (range from 5.26 to 17.67), 0.68 ng/ml (0.07–2.7), 0.47 ng/ml (0.09–1.39), respectively. Median nADC increased from 1.14 × 10−3 mm2/s to 1.59 × 10−3 mm2/s between M0 and M24. Only one patient presented a decrease of nADC (1.35 × 10−3 mm2/s and 1.11 × 10−3 mm2/s at M0 and M12 respectively). The increase in nADC at M6 was correlated with PSA decrease at M18, M24 and M30 (p < 0.05). The increase in nADc at M12 was correlated with PSA decrease at M36 (p = 0.019). Early nADC variation were correlated with late PSA decrease for patients with PCa treated by EBRT.
Meta-proteomics of rumen microbiota indicates niche compartmentalisation and functional dominance in a limited number of metabolic pathways between abundant bacteria
Authors: Hart E. H. , Creevey C. J. , Hitch T. , Kingston-Smith A. H. 
Published: July 2018

AbstractThe rumen is a complex ecosystem. It is the primary site for microbial fermentation of ingested feed allowing conversion of a low nutritional feed source into high quality meat and milk products. However, digestive inefficiencies lead to production of high amounts of environmental pollutants; methane and nitrogenous waste. These inefficiencies could be overcome by development of forages which better match the requirements of the rumen microbial population. Although challenging, the application of meta-proteomics has potential for a more complete understanding of the rumen ecosystem than sequencing approaches alone. Here, we have implemented a meta-proteomic approach to determine the association between taxonomies of microbial sources of the most abundant proteins in the rumens of forage-fed dairy cows, with taxonomic abundances typical of those previously described by metagenomics. Reproducible proteome profiles were generated from rumen samples. The most highly abundant taxonomic phyla in the proteome were Bacteriodetes, Firmicutes and Proteobacteria, which corresponded with the most abundant taxonomic phyla determined from 16S rRNA studies. Meta-proteome data indicated differentiation between metabolic pathways of the most abundant phyla, which is in agreement with the concept of diversified niches within the rumen microbiota.
Effective Resistivity in Collisionless Magnetic Reconnection
Authors: Ma Z. W. , Chen T. , Zhang H. W. , Yu M. Y. 
Published: July 2018

AbstractAn effective resistivity relevant to collisionless magnetic reconnection (MR) in plasma is presented. It is based on the argument that pitch angle scattering of electrons in the small electron diffusion region around the X line can lead to an effective, resistivity in collisionless plasma. The effective resistivity so obtained is in the form of a power law of the local plasma and magnetic field parameters. Its validity is confirmed by direct collisionless particle-in-cell (PIC) simulation. The result agrees very well with the resistivity (obtained from available data) of a large number of environments susceptible to MR: from the intergalactic and interstellar to solar and terrestrial to laboratory fusion plasmas. The scaling law can readily be incorporated into existing collisional magnetohydrodynamic simulation codes to investigate collisionless MR, as well as serve as a guide to ab initio theoretical investigations of the collisionless MR process.