bluuebunny/crossref_metadata_2025 huggingface dataset:
Meta-analysis identifies five novel loci associated with endometriosis highlighting key genes involved in hormone metabolism
Authors: Sapkota Yadav , Steinthorsdottir Valgerdur , Morris Andrew P. , Fassbender Amelie , Rahmioglu Nilufer , De Vivo Immaculata , Buring Julie E. , Zhang Futao , Edwards Todd L. , Jones Sarah , O Dorien , Peterse Daniëlle , Rexrode Kathryn M. , Ridker Paul M. , Schork Andrew J. , MacGregor Stuart , Martin Nicholas G. , Becker Christian M. , Adachi Sosuke , Yoshihara Kosuke , Enomoto Takayuki , Takahashi Atsushi , Kamatani Yoichiro , Matsuda Koichi , Kubo Michiaki , Thorleifsson Gudmar , Geirsson Reynir T. , Thorsteinsdottir Unnur , Wallace Leanne M. ,   iPSYCH-SSI-Broad Group, Werge Thomas M. , Thompson Wesley K. , Yang Jian , Velez Edwards Digna R. , Nyegaard Mette , Low Siew-Kee , Zondervan Krina T. , Missmer Stacey A. , D'Hooghe Thomas , Montgomery Grant W. , Chasman Daniel I. , Stefansson Kari , Tung Joyce Y. , Nyholt Dale R.
Published: May 2017

Endometriosis is a heritable hormone-dependent gynecological disorder, associated with severe pelvic pain and reduced fertility; however, its molecular mechanisms remain largely unknown. Here we perform a meta-analysis of 11 genome-wide association case-control data sets, totalling 17,045 endometriosis cases and 191,596 controls. In addition to replicating previously reported loci, we identify five novel loci significantly associated with endometriosis risk (P<5 × 10−8), implicating genes involved in sex steroid hormone pathways (FN1, CCDC170, ESR1, SYNE1 and FSHB). Conditional analysis identified five secondary association signals, including two at the ESR1 locus, resulting in 19 independent single nucleotide polymorphisms (SNPs) robustly associated with endometriosis, which together explain up to 5.19% of variance in endometriosis. These results highlight novel variants in or near specific genes with important roles in sex steroid hormone signalling and function, and offer unique opportunities for more targeted functional research efforts.
The interfacial structure of water droplets in a hydrophobic liquid
Authors: Smolentsev Nikolay , Smit Wilbert J. , Bakker Huib J. , Roke Sylvie
Published: May 2017

Nanoscopic and microscopic water droplets and ice crystals embedded in liquid hydrophobic surroundings are key components of aerosols, rocks, oil fields and the human body. The chemical properties of such droplets critically depend on the interfacial structure of the water droplet. Here we report the surface structure of 200 nm-sized water droplets in mixtures of hydrophobic oils and surfactants as obtained from vibrational sum frequency scattering measurements. The interface of a water droplet shows significantly stronger hydrogen bonds than the air/water or hexane/water interface and previously reported planar liquid hydrophobic/water interfaces at room temperature. The observed spectral difference is similar to that of a planar air/water surface at a temperature that is ∼50 K lower. Supercooling the droplets to 263 K does not change the surface structure. Below the homogeneous ice nucleation temperature, a single vibrational mode is present with a similar mean hydrogen-bond strength as for a planar ice/air interface.
Correction: Corrigendum: Superfast assembly and synthesis of gold nanostructures using nanosecond low-temperature compression via magnetic pulsed power
Authors: Li Binsong , Bian Kaifu , Lane J. Matthew D. , Salerno K. Michael , Grest Gary S. , Ao Tommy , Hickman Randy , Wise Jack , Wang Zhongwu , Fan Hongyou
Published: May 2017

Nature Communications 8: Article number: 14778 (2017); Published: 16 March 2017; Updated: 24 May 2017 In Fig. 5 of this Article, the image in the centre column for [111] incorrectly replicates the image above. The correct version of Fig. 5 appears below as Fig. 1.
The mobility of small vacancy/helium complexes in tungsten and its impact on retention in fusion-relevant conditions
Authors: Perez Danny , Sandoval Luis , Blondel Sophie , Wirth Brian D. , Uberuaga Blas P. , Voter Arthur F.
Published: May 2017

Tungsten is a promising plasma facing material for fusion reactors. Despite many favorable properties, helium ions incoming from the plasma are known to dramatically affect the microstructure of tungsten, leading to bubble growth, blistering, and/or to the formation of fuzz. In order to develop mitigation strategies, it is essential to understand the atomistic processes that lead to bubble formation and subsequent microstructural changes. In this work, we use large-scale Accelerated Molecular Dynamics simulations to investigate small (N = 1,2) V
N
He
M
vacancy/helium complexes, which serve as the nuclei for larger helium bubble growth, over timescales reaching into the milliseconds under conditions typical of the operation of fusion reactors. These complexes can interconvert between different I
L
V
N+L
He
M
variants via Frenkel pair nucleation (leading to the creation of a additional vacancy/interstitial pair) and annihilation events; sequences of these events can lead to net migration of these embryonic bubbles. The competition between nucleation and annihilation produces a very complex dependence of the diffusivity on the number of heliums. Finally, through cluster dynamics simulations, we show that diffusion of these complexes provides an efficient pathway for helium release at fluxes expected in fusion reactors, and hence that accounting for the mobility of these complexes is crucial.
Mathematical Analysis of Glioma Growth in a Murine Model
Authors: Rutter Erica M. , Stepien Tracy L. , Anderies Barrett J. , Plasencia Jonathan D. , Woolf Eric C. , Scheck Adrienne C. , Turner Gregory H. , Liu Qingwei , Frakes David , Kodibagkar Vikram , Kuang Yang , Preul Mark C. , Kostelich Eric J.
Published: May 2017

Five immunocompetent C57BL/6-cBrd/cBrd/Cr (albino C57BL/6) mice were injected with GL261-luc2 cells, a cell line sharing characteristics of human glioblastoma multiforme (GBM). The mice were imaged using magnetic resonance (MR) at five separate time points to characterize growth and development of the tumor. After 25 days, the final tumor volumes of the mice varied from 12 mm3 to 62 mm3, even though mice were inoculated from the same tumor cell line under carefully controlled conditions. We generated hypotheses to explore large variances in final tumor size and tested them with our simple reaction-diffusion model in both a 3-dimensional (3D) finite difference method and a 2-dimensional (2D) level set method. The parameters obtained from a best-fit procedure, designed to yield simulated tumors as close as possible to the observed ones, vary by an order of magnitude between the three mice analyzed in detail. These differences may reflect morphological and biological variability in tumor growth, as well as errors in the mathematical model, perhaps from an oversimplification of the tumor dynamics or nonidentifiability of parameters. Our results generate parameters that match other experimental in vitro and in vivo measurements. Additionally, we calculate wave speed, which matches with other rat and human measurements.
Insights into the complexation of N-Allyl-4-(4-(N-phenylureido)benzylamino)-1,8-naphthalimide with various anions
Authors: Blok Andrew J. , Johnston Martin R. , Lenehan Claire E.
Published: May 2017

A new urea functionalised 4-amino-1,8-naphthalimide based fluorescent anion sensor was synthesised in 64% yield over three steps. Fluorescence and 1H NMR titrations showed that the sensor complexes strongly with acetate and dihydrogen phosphate and to a lesser extent bromide. The corresponding binding stoichiometries were examined using 1H NMR titrations. Results show that the sensor molecule initially forms 1:1 complexes through hydrogen bonding to the urea moiety, followed by secondary complexation to form higher order host:guest stoichiometries. Specifically, oxyanions complex to the sensor via hydrogen bonding through synergistic aryl C-H and N-H anion interactions in a 1:2 sensor:oxyanion arrangement. Furthermore, 2:1 sensor:oxyanion complexes are formed through an oxyanion linkage between two urea functionalities on different host molecules. This contrasts the majority of previous reports for similar hosts, which indicate 1:1 binding stoichiometry.
Inclusions properties at 1673 K and room temperature with Ce addition in SS400 steel
Authors: Pan Fei , Chen Hao-Long , Su Yen-Hsun , Su Yen-Hao , Hwang Weng-Sing
Published: May 2017

Inclusion species formed in SS400 steel with Ce-addition was predicted by thermodynamic calculation. The analysis of the inclusion morphology and size distribution was carried out by applying Scanning Electron Microscopy (SEM) and Transmission Electron Microscope (TEM). Nano-Fe3O4 particles were also found in cerium-deoxidized and -desulfurized steel and their shapes were nearly spherical. The complex Ce2O3 inclusions covering a layer of 218 nm composed by several MnS particles with similar diffraction pattern. Most importantly, the complex Ce2O3 characterized by using TEM diffraction is amorphous in the steel, indicating that Ce2O3 formed in the liquid iron and then MnS segregated cling to it.
Mutation Spectrum in the CACNA1A Gene in 49 Patients with Episodic Ataxia
Authors: Sintas Cèlia , Carreño Oriel , Fernàndez-Castillo Noèlia , Corominas Roser , Vila-Pueyo Marta , Toma Claudio , Cuenca-León Ester , Barroeta Isabel , Roig Carles , Volpini Víctor , Macaya Alfons , Cormand Bru
Published: May 2017

Episodic ataxia is an autosomal dominant ion channel disorder characterized by episodes of imbalance and incoordination. The disease is genetically heterogeneous and is classified as episodic ataxia type 2 (EA2) when it is caused by a mutation in the CACNA1A gene, encoding the α1A subunit of the P/Q-type voltage-gated calcium channel Cav2.1. The vast majority of EA2 disease-causing variants are loss-of-function (LoF) point changes leading to decreased channel currents. CACNA1A exonic deletions have also been reported in EA2 using quantitative approaches. We performed a mutational screening of the CACNA1A gene, including the promoter and 3′UTR regions, in 49 unrelated patients diagnosed with episodic ataxia. When pathogenic variants were not found by sequencing, we performed a copy number variant (CNV) analysis to screen for duplications or deletions. Overall, sequencing screening allowed identification of six different point variants (three nonsense and three missense changes) and two coding indels, one of them found in two unrelated patients. Additionally, CNV analysis identified a deletion in a patient spanning exon 35 as a result of a recombination event between flanking intronic Alu sequences. This study allowed identification of potentially pathogenic alterations in our sample, five of them novel, which cover 20% of the patients (10/49). Our data suggest that most of these variants are disease-causing, although functional studies are required.
An integrated analysis revealed different microRNA-mRNA profiles during skeletal muscle development between Landrace and Lantang pigs
Authors: Xie Shuihua , Chen Luxi , Zhang Xumeng , Liu Xiaohong , Chen Yaosheng , Mo Delin
Published: May 2017

Pigs supply vital dietary proteins for human consumption, and their economic value depends largely on muscle production. MicroRNAs are known to play important roles in skeletal muscle development. However, their relationship to distinct muscle production between pig breeds remains unknown. Here, we performed an integrated analysis of microRNA-mRNA expression profiles for Landrace (LR, lean) pigs and the Chinese indigenous Lantang pig (LT, lard-type) during 8 stages of skeletal muscle developmental, including at 35, 49, 63, 77 dpc (days post coitum) and 2, 28, 90, 180 dpn (days postnatal). As differentially expressed-miRNA expression profiles can be well classified into two clusters by PCA analysis, we grouped the embryonic stages as G1 and the postnatal stages as G2. A total of 203 genes were predicted miRNA targets, and a STEM analysis showed distinct expression patterns between G1 and G2 in both breeds based on their transcriptomic data. Furthermore, a STRING analysis predicted interactions between 22 genes and 35 miRNAs, including some crucial myogenic factors and myofibrillar genes. Thus, it can be reasonably speculated that myogenic miRNAs may regulate myofibrillar genes in myofiber formation during embryonic stages and muscle hypertrophy during postnatal stages, leading to distinct differences in muscle production between breeds.
Difference in Cerebral Circulation Time between Subtypes of Moyamoya Disease and Moyamoya Syndrome
Authors: Kang Kaijiang , Lu Jingjing , Zhang Dong , Li Youxiang , Wang Dandan , Liu Peng , Li Bohong , Ju Yi , Zhao Xingquan
Published: May 2017

In this study, we evaluated the differences in hemodynamics between hemorrhagic and non-hemorrhagic moyamoya disease (MMD) and moyamoya syndrome (MMS) by measuring cerebral circulation time (CCT). This case-control study included 136 patients with MMD or MMS diagnosed between April 2015 and July 2016 at Beijing Tian Tan Hospital. Each hemisphere was analyzed separately. The difference in clinical, radiological characteristics and CCT between subtypes of MMD and MMS were analyzed statistically. The results showed that total CCT between hemorrhagic and non-hemorrhagic sides was not statistically different (16.55 s vs. 16.06 s, P = 0.562). The cerebral filling circulation time (CFCT) of hemorrhagic sides was significantly shorter than that of non-hemorrhagic sides (4.52 s vs. 5.41 s, P < 0.001), and the cerebral venous circulation time (CVCT) of hemorrhagic sides was significantly longer than that of non-hemorrhagic sides (12.02 s, vs. 10.64 s, P < 0.001). The ratio of CFCT to CVCT (F-V ratio) was inversely correlated with the possibility of hemorrhagic stroke. Therefore, we conclude that the rapid filling and poor venous drainage of cerebral circulation are likely risk factors of hemorrhagic stroke secondary to MMD or MMS. The F-V ratio can be used to identify individuals at high risk of hemorrhagic stroke.
Community and species-specific responses of plant traits to 23 years of experimental warming across subarctic tundra plant communities
Authors: Baruah Gaurav , Molau Ulf , Bai Yang , Alatalo Juha M.
Published: May 2017

To improve understanding of how global warming may affect competitive interactions among plants, information on the responses of plant functional traits across species to long-term warming is needed. Here we report the effect of 23 years of experimental warming on plant traits across four different alpine subarctic plant communities: tussock tundra, Dryas heath, dry heath and wet meadow. Open-top chambers (OTCs) were used to passively warm the vegetation by 1.5–3 °C. Changes in leaf width, leaf length and plant height of 22 vascular plant species were measured. Long-term warming significantly affected all plant traits. Overall, plant species were taller, with longer and wider leaves, compared with control plots, indicating an increase in biomass in warmed plots, with 13 species having significant increases in at least one trait and only three species having negative responses. The response varied among species and plant community in which the species was sampled, indicating community-warming interactions. Thus, plant trait responses are both species- and community-specific. Importantly, we show that there is likely to be great variation between plant species in their ability to maintain positive growth responses over the longer term, which might cause shifts in their relative competitive ability.
Interaction processes of ciprofloxacin with graphene oxide and reduced graphene oxide in the presence of montmorillonite in simulated gastrointestinal fluids
Authors: Ma Shuai , Si Yang , Wang Fei , Su Lei , Xia CongCong , Yao Jun , Chen Huilun , Liu Xingyu
Published: May 2017

This study investigated the interaction processes of ciprofloxacin (CIP) with graphene oxide (GO) and reduced GO (rGO) in presence of montmorillonite (Mont) in simulated gastrointestinal fluids. The order of CIP adsorption affinity was rGO+Mont > GO+Mont > rGO+Mont+pepsin > rGO > GO+Mont+pepsin > Mont > Mont+pepsin > GO > rGO+pepsin > GO+pepsin in simulated gastric fluid. Mont enhanced the adsorption of CIP on GO and rGO due to hydrated Si species coating on GO and rGO in the simulated gastric fluid. Meanwhile, π–π interaction between CIP and graphene caused the great shift of two cyclopropyl CH2 and one cyclopropyl in CIP molecules. And GO, rGO, and Mont interacted mainly with CIP by COOH groups. CIP and pepsin molecules could intercalate and increase the basal spacing of Mont as well. After the various interaction systems of adsorbent-adsorbate transferring to the simulated intestinal fluid, CIP was continuously adsorbed by GO and rGO. In addition, adsorbed CIP was released from Mont into the solution through electrostatic repulsion. The decrease ratio of CIP was the lowest in the GO/rGO+Mont+pepsin systems. Therefore, the mixture of Mont and GO/rGO decreased the CIP concentration in gastrointestinal fluid to weaken further antibiotic activity of CIP.
Pilot Study of 64Cu(I) for PET Imaging of Melanoma
Authors: Jiang Lei , Tu Yingfeng , Hu Xiang , Bao Ande , Chen Hao , Ma Xiaowei , Doyle Tim , Shi Hongcheng , Cheng Zhen
Published: May 2017

At present,64Cu(II) labeled tracers including64CuCl2have been widely applied in the research of molecular imaging and therapy. Human copper transporter 1 (hCTR1) is the major high affinity copper influx transporter in mammalian cells, and specially responsible for the transportation of Cu(I) not Cu(II). Thus, we investigated the feasible application of64Cu(I) for PET imaging.64Cu(II) was reduced to64Cu(I) with the existence of sodium L-ascorbate, DL-Dithiothreitol or cysteine. Cell uptake and efflux assay was investigated using B16F10 and A375 cell lines, respectively. Small animal PET and biodistribution studies were performed in both B16F10 and A375 tumor-bearing mice. Compared with64Cu(II),64Cu(I) exhibited higher cellular uptake by melanoma, which testified CTR1 specially influx of Cu(I). However, due to oxidation reactionin vivo, no significant difference between64Cu(I) and64Cu(II) was observed through PET images and biodistribution. Additionally, radiation absorbed doses for major tissues of human were calculated based on the mouse biodistribution. Radiodosimetry calculations for64/67Cu(I) and64/67Cu(II) were similar, which suggested that although melanoma were with high radiation absorbed doses, high radioactivity accumulation by liver and kidney should be noticed for the further application. Thus,64Cu(I) should be further studied to evaluate it as a PET imaging radiotracer.
Urban eddy covariance measurements reveal significant missing NOx emissions in Central Europe
Authors: Karl T. , Graus M. , Striednig M. , Lamprecht C. , Hammerle A. , Wohlfahrt G. , Held A. , von der Heyden L. , Deventer M. J. , Krismer A. , Haun C. , Feichter R. , Lee J.
Published: May 2017

Nitrogen oxide (NOx) pollution is emerging as a primary environmental concern across Europe. While some large European metropolitan areas are already in breach of EU safety limits for NO2, this phenomenon does not seem to be only restricted to large industrialized areas anymore. Many smaller scale populated agglomerations including their surrounding rural areas are seeing frequent NO2 concentration violations. The question of a quantitative understanding of different NOx emission sources is therefore of immanent relevance for climate and air chemistry models as well as air pollution management and health. Here we report simultaneous eddy covariance flux measurements of NOx, CO2, CO and non methane volatile organic compound tracers in a city that might be considered representative for Central Europe and the greater Alpine region. Our data show that NOx fluxes are largely at variance with modelled emission projections, suggesting an appreciable underestimation of the traffic related atmospheric NOx input in Europe, comparable to the weekend-weekday effect, which locally changes ozone production rates by 40%.
Down-regulated GATA-1 up-regulates interferon regulatory factor 3 in lung adenocarcinoma
Authors: Wang Lu-Lu , Chen Zheng-Sen , Zhou Wen-Di , Shu Jin , Wang Xiao-Hua , Jin Rui , Zhuang Li-Li , Hoda Mir Alireza , Zhang Hao , Zhou Guo-Ping
Published: May 2017

Interferon regulatory factor 3 (IRF-3) is widely known for its prompt response against viral infection by activating the interferon system. We previously reported that E2F1, Sp1 and Sp3 regulated transcriptional activity of IRF-3. Recently, different expression patterns of IRF-3 were found in lung cancer, leading to the alternation of the immunomodulatory function in tumorigenesis. However, the mechanism of transcriptional regulation of IRF-3 in lung cancer has not been extensively studied. Here, we investigated the characterization of IRF-3 promoter and found that GATA-1 bound to a specific domain of IRF-3 promoter in vitro and in vivo. We found elevated IRF-3 and decreased GATA-1 gene expression in lung adenocarcinoma in Oncomine database. Additionally, higher IRF-3 gene expression was observed in human lung adenocarcinoma, accompanied by aberrant GATA-1 protein expression. We further analyzed the relationship of GATA-1 and IRF-3 expression in lung adenocarcinoma cell lines and found that inhibition of GATA-1 by siRNA increased the promoter activity, mRNA and protein levels of IRF-3, while over-expression of GATA-1 down-regulated IRF-3 gene expression. Taken together, we conclude that reduced GATA-1 could be responsible for the upregulation of IRF-3 in lung adenocarcinoma cells through binding with a specific domain of IRF-3 promoter.
Metabolomic profiling in a Hedgehog Interacting Protein (Hhip) murine model of chronic obstructive pulmonary disease
Authors: Wan Emily S. , Li Yan , Lao Taotao , Qiu Weiliang , Jiang Zhiqiang , Mancini John D. , Owen Caroline A. , Clish Clary , DeMeo Dawn L. , Silverman Edwin K. , Zhou Xiaobo
Published: May 2017

Genetic variants annotated to the hedgehog interacting protein (HHIP) are robustly associated with chronic obstructive pulmonary disease (COPD). Hhip haploinsufficiency in mice leads to increased susceptibility towards the development of emphysema following exposure to chronic cigarette smoke (CS). To explore the molecular pathways which contribute to increased susceptibility, we performed metabolomic profiling using high performance liquid chromatography tandem mass spectroscopy (LC/MS-MS) on plasma, urine, and lung tissue of Hhip+/− heterozygotes and wild type (Hhip+/+) C57/BL6 mice exposed to either room-air or CS for six months. Univariate comparisons between groups were made with a combined fold change ≥2 and Student’s t-test p-value < 0.05 to denote significance; associations with mean alveolar chord length (MACL), a quantitative measure of emphysema, and gene-by-environment interactions were examined using empiric Bayes-mediated linear models. Decreased urinary excretion of cotinine despite comparable plasma levels was observed in Hhip+/− heterozygotes; a strong gene-by-smoking association was also observed. Correlations between MACL and markers of oxidative stress such as urinary methionine sulfoxide were observed in Hhip+/− but not in Hhip+/+ mice. Metabolite set enrichment analyses suggest reduced antioxidant capacity and alterations in macronutrient metabolism contribute to increased susceptibility to chronic CS-induced oxidative stress in Hhip haploinsufficiency states.
Controlling Light Transmission Through Highly Scattering Media Using Semi-Definite Programming as a Phase Retrieval Computation Method
Authors: N’Gom Moussa , Lien Miao-Bin , Estakhri Nooshin M. , Norris Theodore B. , Michielssen Eric , Nadakuditi Raj Rao
Published: May 2017

Complex Semi-Definite Programming (SDP) is introduced as a novel approach to phase retrieval enabled control of monochromatic light transmission through highly scattering media. In a simple optical setup, a spatial light modulator is used to generate a random sequence of phase-modulated wavefronts, and the resulting intensity speckle patterns in the transmitted light are acquired on a camera. The SDP algorithm allows computation of the complex transmission matrix of the system from this sequence of intensity-only measurements, without need for a reference beam. Once the transmission matrix is determined, optimal wavefronts are computed that focus the incident beam to any position or sequence of positions on the far side of the scattering medium, without the need for any subsequent measurements or wavefront shaping iterations. The number of measurements required and the degree of enhancement of the intensity at focus is determined by the number of pixels controlled by the spatial light modulator.
Reverse Anti-solvent Crystallization Process for the Facile Synthesis of Zinc Tetra(4-pyridyl)porphyrin Single Crystalline Cubes
Authors: Park Yohwan , Hong Misun , Koo Jin Young , Lee Minkyung , Lee Jinho , Moon Dae Jun , Sohn So Hyeong , Joo Taiha , Lim Woo Taik , Lim Hyunseob , Choi Hee Cheul
Published: May 2017

Synthesis of morphologically well-defined crystals of metalloporphyrin by direct crystallization based on conventional anti-solvent crystallization method without using any additives has been rarely reported. Herein, we demonstrate an unconventional and additive-free synthetic method named reverse anti-solvent crystallization method to achieve well-defined zinc-porphyrin cube crystals by reversing the order of the addition of solvents. The extended first solvation shell effect mechanism is therefore suggested to support the synthetic process by providing a novel kinetic route for reaching the local supersaturation environment depending on the order of addition of solvents, which turned out to be critical to achieve clean cube morphology of the crystal. We believe that our work not only extends fundamental knowledge about the kinetic process in binary solvent systems, but also enables great opportunities for shape-directing crystallization of various organic and organometallic compounds.
Comparison of pediatric and adult lymphomas involving the mediastinum characterized by distinctive clinicopathological and radiological features
Authors: Chen Lei , Wang Mingsong , Fan Hua , Hu Fengqing , Liu Tingting
Published: May 2017

Lymphomas involving the mediastinum occur in a wide age range and represent heterogeneous histological subtypes with various clinical symptoms and complex radiological findings. However, studies that describe the clinical and radiological features of different subtypes among Chinese pediatric and adult patients are limited. We analyzed the clinical, radiological and pathological features of 31 pediatric lymphomas involving the mediastinum, and compared them to the features of 21 adult patients. Although several histological subtypes were identified in adults, pediatric patients presented with T-cell lymphoblastic lymphoma/T-cell acute lymphoblastic leukemia (T-LBL/T-ALL) and classical Hodgkin lymphomas (CHL) in 24 and 7 cases, respectively. Compared to adults, pediatric patients were more likely to be male (P = 0.089) and showed a higher incidence of T-LBL/T-ALL (P = 0.001), prevalence of dyspnea (P = 0.001), frequency of stage IV tumors (P = 0.008), and ratio of tumor diameter to maximum transthoracic diameter (P = 0.015). T-LBL/T-ALL patients presented with a higher frequency with stage IV disease (P = 0.000 and P = 0.001), compression of the blood vessels (P = 0.005 and P = 0.017), and pleural effusions (P = 0.001, for both) than CHL and PMBL patients. Compared to adults, pediatric patients with mediastinal lymphomas presented with exclusive histological subtypes of T-LBL/T-ALL and CHL, which showed distinctive characteristics of histological distribution, clinical presentation and radiological assessments.
The role of flavin-containing enzymes in mitochondrial membrane hyperpolarization and ROS production in respiring Saccharomyces cerevisiae cells under heat-shock conditions
Authors: Fedoseeva Irina V. , Pyatrikas Darya V. , Stepanov Alexei V. , Fedyaeva Anna V. , Varakina Nina N. , Rusaleva Tatyana M. , Borovskii Gennadii B. , Rikhvanov Eugene G.
Published: May 2017

Heat shock is known to accelerate mitochondrial ROS production in Saccharomyces cerevisiae cells. But how yeast mitochondria produce ROS under heat-shock condition is not completely clear. Previously, it was shown that ROS production in heat-stressed fermenting yeast cells was accompanied by mitochondrial membrane potential (MMP) increase. In the current investigation the relationship between ROS production and MMP was studied in respiring yeast cells in stationary phase, using diphenyleneiodonium chloride (DPI), an inhibitor of flavin-containing proteins, as well as the mutants deleted for NDE1, NDE2 and NDI1 genes, encoding flavin-containing external and internal NADH dehydrogenases. It was shown that heat shock induced a transient burst in mitochondrial ROS production, which was paralleled by MMP rise. ROS production and MMP was significantly suppressed by DPI addition and deletion of NDE1. The effect of DPI on ROS production and MMP rise was specific for respiring cells. The results obtained suggest that the functioning of mitochondrial flavin-binding enzymes, Nde1p for instance, is required for the hyperpolarization of inner mitochondrial membrane and ROS production in respiring S. cerevisiae cells under heat-shock conditions.
MRI tracking of autologous pancreatic progenitor-derived insulin-producing cells in monkeys
Authors: Zou Chunlin , Lu Yi , Teng Xiahong , Wang Shuyan , Sun Xiaoting , Huang Fen , Shu Guannan , Huang Xin , Guo Hongwei , Chen Zhiguo , Zhang Jian , Zhang Yu Alex
Published: May 2017

Insulin-producing cells (IPCs) derived from a patient’s own stem cells offer great potential for autologous transplantation in diabetic patients. However, the limited survival of engrafted cells remains a bottleneck in the application of this strategy. The present study aimed to investigate whether nanoparticle-based magnetic resonance (MR) tracking can be used to detect the loss of grafted stem cell-derived IPCs in a sensitive and timely manner in a diabetic monkey model. Pancreatic progenitor cells (PPCs) were isolated from diabetic monkeys and labeled with superparamagnetic iron oxide nanoparticles (SPIONs). The SPION-labeled cells presented as hypointense signals on MR imaging (MRI). The labeling procedure did not affect the viability or IPC differentiation of PPCs. Importantly, the total area of the hypointense signal caused by SPION-labeled IPCs on liver MRI decreased before the decline in C-peptide levels after autotransplantation. Histological analysis revealed no detectable immune response to the grafts and many surviving insulin- and Prussian blue-positive cell clusters on liver sections at one year post-transplantation. Collectively, this study demonstrates that SPIO nanoparticles can be used to label stem cells for noninvasive, sensitive, longitudinal monitoring of stem cell-derived IPCs in large animal models using a conventional MR imager.
All-fiber spatial rotation manipulation for radially asymmetric modes
Authors: Mo Qi , Hong Zhikun , Yu Dawei , Fu Songnian , Wang Liang , Oh Kyunghwan , Tang Ming , Liu Deming
Published: May 2017

We propose and experimentally demonstrate spatial rotation manipulation for radially asymmetric modes based on two kinds of polarization maintaining few-mode fibers (PM-FMFs). Theoretical finding shows that due to successful suppression of both polarization and spatial mode coupling, the spatial rotation of radially asymmetric modes has an excellent linear relationship with the twist angle of PM-FMF. Both elliptical core and panda type FMFs are fabricated, in order to realize manageable spatial rotation of LP11 mode within ±360° range. Finally, we characterize individual PM-FMF based spatial orientation rotator and present comprehensive performance comparison between two PM-FMFs in terms of insertion loss, temperature sensitivity, linear polarization maintenance, and mode scalability.
Serum miRNA signature diagnoses and discriminates murine colitis subtypes and predicts ulcerative colitis in humans
Authors: Viennois Emilie , Zhao Yuan , Han Moon Kwon , Xiao Bo , Zhang Mingzhen , Prasad Meena , Wang Lixin , Merlin Didier
Published: May 2017

Inflammatory bowel disease (IBD) is difficult to diagnose due to nonspecific and variable symptoms, and lack of reliable diagnostic tests. Current methods are invasive, non-sensitive, non-predictive, and do not easily discriminate between its two main forms. Consequently, there remains a great need for reliable serum markers for IBD. Here, using a longitudinal study of various mouse models of colitis, we identified a serum miRNA signature that indicated the development of colitis and discriminated between inflammations of various origins (colitis from arthritis). Unlike the existing biomarkers, the newly identified signature also serves to distinguish individuals at risk, predict the type of inflammation, and evaluate the response to therapeutics. Moreover, the miRNA signature identified in mice predicted ulcerative colitis with 83.3% accuracy. In future, the signature identified herein could play a central role in monitoring inflammatory disorders and therapeutic responses in patients, thereby paving the way for personalized medicine.
The structural and magnetic properties of dual phase cobalt ferrite
Authors: Gore Shyam K. , Jadhav Santosh S. , Jadhav Vijaykumar V. , Patange S. M. , Naushad Mu. , Mane Rajaram S. , Kim Kwang Ho
Published: May 2017

The bismuth (Bi3+)-doped cobalt ferrite nanostructures with dual phase, i.e. cubic spinel with space group Fd3m and perovskite with space group R3c, have been successfully engineered via self-ignited sol-gel combustion route. To obtain information about the phase analysis and structural parameters, like lattice constant, Rietveld refinement process is applied. The replacement of divalent Co2+ by trivalent Bi3+ cations have been confirmed from energy dispersive analysis of the ferrite samples. The micro-structural evolution of cobalt ferrite powders at room temperature under various Bi3+ doping levels have been identified from the digital photoimages recorded using scanning electron microscopy. The hyperfine interactions, like isomer shift, quadrupole splitting and magnetic hyperfine fields, and cation distribution are confirmed from the Mossbauer spectra. Saturation magnetization is increased with Bi3+-addition up to x = 0.15 and then is decreased when x = 0.2. The coercivity is increased from 1457 to 2277 G with increasing Bi3+-doping level. The saturation magnetization, coercivity and remanent ratio for x = 0.15 sample is found to be the highest, indicating the potential of Bi3+-doping in enhancing the magnetic properties of cobalt ferrite.
Exosomes derived from human umbilical cord mesenchymal stem cells protect against cisplatin-induced ovarian granulosa cell stress and apoptosis in vitro
Authors: Sun Liping , Li Dong , Song Kun , Wei Jianlu , Yao Shu , Li Zhao , Su Xuantao , Ju Xiuli , Chao Lan , Deng Xiaohui , Kong Beihua , Li Li
Published: May 2017

Human umbilical cord mesenchymal stem cells (huMSCs) can treat primary ovarian insufficiency (POI) related to ovarian granulosa cell (OGC) apoptosis caused by cisplatin chemotherapy. Exosomes are a class of membranous vesicles with diameters of 30–200 nm that are constitutively released by eukaryotic cells. Exosomes mediate local cell-to-cell communication by transferring microRNAs and proteins. In the present study, we demonstrated the effects of exosomes derived from huMSCs (huMSC-EXOs) on a cisplatin-induced OGC model in vitro and discussed the preliminary mechanisms involved in these effects. We successfully extracted huMSC-EXOs from huMSC culture supernatant and observed the effective uptake of exosomes by cells with fluorescent staining. Using flow cytometry (with annexin-V/PI labelling), we found that huMSC-EXOs increased the number of living cells. Western blotting showed that the expression of Bcl-2 and caspase-3 were upregulated, whilst the expression of Bax, cleaved caspase-3 and cleaved PARP were downregulated to protect OGCs. These results suggest that huMSC-EXOs can be used to prevent and treat chemotherapy-induced OGC apoptosis in vitro. Therefore, this work provides insight and further evidence of stem cell function and indicates that huMSC-EXOs protect OGCs from cisplatin-induced injury in vitro.
A novel CXCR4-targeted near-infrared (NIR) fluorescent probe (Peptide R-NIR750) specifically detects CXCR4 expressing tumors
Authors: Santagata Sara , Portella Luigi , Napolitano Maria , Greco Adelaide , D’Alterio Crescenzo , Barone Maria Vittoria , Luciano Antonio , Gramanzini Matteo , Auletta Luigi , Arra Claudio , Zannetti Antonella , Scala Stefania
Published: May 2017

C-X-C chemokine receptor 4 (CXCR4) is over-expressed in multiple human cancers and correlates with tumor aggressiveness, poor prognosis and increased risk for distant metastases. Imaging agents for CXCR4 are thus highly desirable. We developed a novel CXCR4-targeted near-infrared (NIR) fluorescent probe (Peptide R-NIR750) conjugating the new developed CXCR4 peptidic antagonist Peptide R with the NIR fluorescent dye VivoTag-S750. Specific CXCR4 binding was obtained in cells overexpressing human CXCR4 (B16-hCXCR4 and human melanoma cells PES43), but not in CXCR4 low expressing cells (FB-1). Ex vivo evaluation demonstrated that PepR-NIR750 specifically detects B16-hCXCR4-derived subcutaneous tumors and lung metastases. Fluorescence Molecular Tomography (FMT) in vivo imaging was performed on mice carrying subcutaneous CHO and CHO-CXCR4 tumors. PepR-NIR750 accumulates only in CXCR4-positive expressing subcutaneous tumors. Additionally, an intense NIR fluorescence signal was detected in PES43-derived lung metastases of nude mice injected with PepR-NIR750 versus mice injected with VivoTag-S750. With a therapeutic intent, mice bearing PES43-derived lung metastases were treated with Peptide R. A the dramatic reduction in PES43-derived lung metastases was detected through a decrease of the PepR-NIR750 signal. PepR-NIR750 is a specific probe for non-invasive detection of human high CXCR4-expressing tumors and metastatic lesion and thus a valuable tool for cancer molecular imaging.
Chronic Alcohol Consumption Promotes Diethylnitrosamine-Induced Hepatocarcinogenesis via Immune Disturbances
Authors: Yan Guoxiu , Wang Xuefu , Sun Cheng , Zheng Xiaodong , Wei Haiming , Tian Zhigang , Sun Rui
Published: May 2017

Chronic alcohol consumption increases the risk of hepatocellular carcinoma (HCC). However, little is known about the potential immunological mechanisms by which ethanol affects tumor progression. Here, adult male mice were administered multiple doses of diethylnitrosamine (DEN). Four and a half months later, the DEN-treated mice were placed on a liquid Lieber-DeCarli control diet or diet containing 5% ethanol for 2.5 months. At the end of the study, liver tissue samples were obtained to analyze pathology, gene expression, and hepatic mononuclear cells (MNCs). Results showed that ethanol feeding exacerbates the progression of hepatic tumors (characterized by the ratio of liver weight to body weight, and the tumor volume and diameter) in DEN-treated mice. Mechanistically, chronic alcohol consumption decreased the number of antitumor CD8+ T cells but increased the number of tumor-associated macrophages (TAMs) in the liver in DEN-initiated tumorigenesis. Besides, TAMs were prone to be M2 phenotype after alcohol consumption. Moreover, chronic alcohol consumption aggravated inflammation, fibrosis, and epithelial-mesenchymal transition (EMT) in the pathological process of HCC. These data demonstrate that chronic alcohol consumption exacerbates DEN-induced hepatocarcinogenesis by enhancing protumor immunity, impairing antitumor immunity and aggravating hepatic pathological injury. Targeting the immune system is a potential therapeutic regimen for alcohol-promoted HCC.
Colitis promotes neuronal differentiation of Sox2+ and PLP1+ enteric cells
Authors: Belkind-Gerson Jaime , Graham Hannah K. , Reynolds Justin , Hotta Ryo , Nagy Nandor , Cheng Lily , Kamionek Michal , Shi Hai Ning , Aherne Carol M. , Goldstein Allan M.
Published: May 2017

Mechanisms mediating adult enteric neurogenesis are largely unknown. Using inflammation-associated neurogenesis models and a transgenic approach, we aimed to understand the cell-source for new neurons in infectious and inflammatory colitis. Dextran sodium sulfate (DSS) and Citrobacter rodentium colitis (CC) was induced in adult mice and colonic neurons were quantified. Sox2GFP and PLP1GFP mice confirmed the cell-type specificity of these markers. Sox2CreER:YFP and PLP1creER:tdT mice were used to determine the fate of these cells after colitis. Sox2 expression was investigated in colonic neurons of human patients with Clostridium difficile or ulcerative colitis. Both DSS and CC led to increased colonic neurons. Following colitis in adult Sox2CreER:YFP mice, YFP initially expressed predominantly by glia becomes expressed by neurons following colitis, without observable DNA replication. Similarly in PLP1CreER:tdT mice, PLP1 cells that co-express S100b but not RET also give rise to neurons following colitis. In human colitis, Sox2-expressing neurons increase from 1–2% to an average 14% in colitis. The new neurons predominantly express calretinin, thus appear to be excitatory. These results suggest that colitis promotes rapid enteric neurogenesis in adult mice and humans through differentiation of Sox2- and PLP1-expressing cells, which represent enteric glia and/or neural progenitors. Further defining neurogenesis will improve understanding and treatment of injury-associated intestinal motility/sensory disorders.
Pharmacokinetic Evaluation of Empagliflozin in Healthy Egyptian Volunteers Using LC-MS/MS and Comparison with Other Ethnic Populations
Authors: Ayoub Bassam M. , Mowaka Shereen , Elzanfaly Eman S. , Ashoush Nermeen , Elmazar Mohamed M. , Mousa Shaker A.
Published: May 2017

The present study considered the pharmacokinetic evaluation of empagliflozin after administration to Egyptian volunteers, and the results were compared with other ethnic populations. The FDA recognizes that standard methods of defining racial subgroups are necessary to compare results across pharmacokinetic studies and to assess potential subgroup differences. The design of the study was as an open labeled, randomized, one treatment, one period, single dose pharmacokinetic study. The main pharmacokinetic parameters estimated were Cmax, Tmax, t1/2, elimination rate constant, AUC0-t and AUC0-inf. The insignificant difference in pharmacokinetic parameters between Egyptians and white German subjects suggests that no dose adjustment should be considered with administration of 25 mg empagliflozin to Egyptian population. A new LC-MS/MS method was developed and validated, allowing sensitive estimation of empagliflozin (25–600 ng mL−1) in human plasma using dapagliflozin as an internal standard (IS). The method was applied successfully on the underlying pharmacokinetic study with enhanced sample preparation that involved liquid-liquid extraction. Multiple Reaction Monitoring (MRM) of the transition pairs of m/z 449.01 to 371.21 for empagliflozin and m/z 407.00 to 328.81 for dapagliflozin (IS) was employed utilizing negative mode Electro Spray Ionization (ESI). The validated LC-MS/MS method is suitable for further toxicodynamic and bioequivalence studies.
Proof-of-Concept Gene Editing for the Murine Model of Inducible Arginase-1 Deficiency
Authors: Sin Yuan Yan , Price Phillipe R. , Ballantyne Laurel L. , Funk Colin D.
Published: May 2017

Arginase-1 deficiency in humans is a rare genetic disorder of metabolism resulting from a loss of arginase-1, leading to impaired ureagenesis, hyperargininemia and neurological deficits. Previously, we generated a tamoxifen-inducible arginase-1 deficient mouse model harboring a deletion ofArg1exons 7 and 8 that leads to similar biochemical defects, along with a wasting phenotype and death within two weeks. Here, we report a strategy utilizing theClustered,RegularlyInterspaced,ShortPalindromicRepeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system in conjunction withpiggyBactechnology to target and reincorporate exons 7 and 8 at the specificArg1locus in attempts to restore the function of arginase-1 in induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells (iHLCs) and macrophagesin vitro. While successful gene targeted repair was achieved, minimal urea cycle function was observed in the targeted iHLCs compared to adult hepatocytes likely due to inadequate maturation of the cells. On the other hand, iPSC-derived macrophages expressed substantial amounts of “repaired” arginase. Our studies provide proof-of-concept for gene-editing at theArg1locus and highlight the challenges that lie ahead to restore sufficient liver-based urea cycle function in patients with urea cycle disorders.
Platelet-rich plasma respectively reduces and promotes adipogenic and myofibroblastic differentiation of human adipose-derived stromal cells via the TGFβ signalling pathway
Authors: Chignon-Sicard Bérengère , Kouidhi Magali , Yao Xi , Delerue-Audegond Audrey , Villageois Phi , Peraldi Pascal , Ferrari Patricia , Rival Yves , Piwnica David , Aubert Jérôme , Dani Christian
Published: June 2017

Autologous fat grafting is a gold standard therapy for soft tissue defects, but is hampered by unpredictable postoperative outcomes. Fat graft enrichment with adipose-derived stromal cell (ASCs) was recently reported to enhance graft survival. Platelet-rich plasma (PRP) has also emerged as a biologic scaffold that promotes fat graft viability. Combined ASC/PRP fat grafting enrichment is thus a promising new regenerative medicine approach. The effects of PRP on ASC proliferation are well documented, but the impact of PRP on ASC differentiation has yet to be investigated in depth to further elucidate the PRP clinical effects. Here we analyzed the human ASC fate upon PRP treatment. PRP was found to sharply reduce the potential of ASCs to undergo differentiation into adipocytes. Interestingly, the PRP anti-adipogenic effect was accompanied by the generation of myofibroblast-like cells. Among the various factors released from PRP, TGFβ pathway activators played a critical role in both the anti-adipogenic and pro-myofibroblastic PRP effects. Overall, these data suggest that PRP participates in maintaining a pool of ASCs and in the repair process by promoting ASC differentiation into myofibroblast-like cells. TGFβ may provide an important target pathway to improve PRP clinical outcomes.
Physiological mechanisms of drought-induced tree die-off in relation to carbon, hydraulic and respiratory stress in a drought-tolerant woody plant
Authors: Saiki Shin-Taro , Ishida Atsushi , Yoshimura Kenichi , Yazaki Kenichi
Published: June 2017

Drought-induced tree die-off related to climate change is occurring worldwide and affects the carbon stocks and biodiversity in forest ecosystems. Hydraulic failure and carbon starvation are two commonly proposed mechanisms for drought-induced tree die-off. Here, we show that inhibited branchlet respiration and soil-to-leaf hydraulic conductance, likely caused by cell damage, occur prior to hydraulic failure (xylem embolism) and carbon starvation (exhaustion of stored carbon in sapwood) in a drought-tolerant woody species, Rhaphiolepis wrightiana Maxim. The ratio of the total leaf area to the twig sap area was used as a health indicator after drought damage. Six adult trees with different levels of tree health and one dead adult tree were selected. Two individuals having the worst and second worst health among the six live trees died three months after our study was conducted. Soil-to-leaf hydraulic conductance and leaf gas exchange rates decreased linearly as tree health declined, whereas xylem cavitation and total non-structural carbon remained unchanged in the branchlets except in the dead and most unhealthy trees. Respiration rates and the number of living cells in the sapwood decreased linearly as tree health declined. This study is the first report on the importance of dehydration tolerance and respiration maintenance in living cells.