bluuebunny/crossref_metadata_2025 huggingface dataset:
Selective Inactivation of Intracellular BiP/GRP78 Attenuates Endothelial Inflammation and Permeability in Acute Lung Injury
Authors: Leonard Antony , Grose Valerie , Paton Adrienne W. , Paton James C. , Yule David I. , Rahman Arshad , Fazal Fabeha
Published: February 2019

The role of Endoplasmic Reticulum Chaperone and Signaling Regulator BiP/GRP78 in acute inflammatory injury, particularly in the context of lung endothelium, is poorly defined. In his study, we monitored the effect of SubAB, a holoenzyme that cleaves and specifically inactivates BiP/GRP78 and its inactive mutant SubAA272B on lung inflammatory injury in an aerosolized LPS inhalation mouse model of acute lung injury (ALI). Analysis of lung homogenates and bronchoalveolar lavage (BAL) fluid showed that LPS-induced lung inflammation and injury were significantly inhibited in SubAB- but not in SubAA272B-treated mice. SubAB-treated mice were also protected from LPS-induced decrease in lung compliance. Gene transfer of dominant negative mutant of BiP in the lung endothelium protected against LPS-induced lung inflammatory responses. Consistent with this, stimulation of endothelial cells (EC) with thrombin caused an increase in BiP/GRP78 levels and inhibition of ER stress with 4-phenylbutyric acid (4-PBA) prevented this response as well as increase in VCAM-1, ICAM-1, IL-6, and IL-8 levels. Importantly, thrombin-induced Ca2+ signaling and EC permeability were also prevented upon BiP/GRP78 inactivation. The above EC responses are mediated by intracellular BiP/GRP78 and not by cell surface BiP/GRP78. Together, these data identify intracellular BiP/GRP78 as a novel regulator of endothelial dysfunction associated with ALI.
Fibrin glue as a local drug-delivery system for bacteriophage PA5
Authors: Rubalskii Evgenii , Ruemke Stefan , Salmoukas Christina , Aleshkin Andrey , Bochkareva Svetlana , Modin Evgeny , Mashaqi Bakr , Boyle Erin C. , Boethig Dietmar , Rubalsky Maxim , Zulkarneev Eldar , Kuehn Christian , Haverich Axel
Published: February 2019

Fibrin glue has been used clinically for decades in a wide variety of surgical specialties and is now being investigated as a medium for local, prolonged drug delivery. Effective local delivery of antibacterial substances is important perioperatively in patients with implanted medical devices or postoperatively for deep wounds. However, prolonged local application of antibiotics is often not possible or simply inadequate. Biofilm formation and antibiotic resistance are also major obstacles to antibacterial therapy. In this paper we test the biocompatibility of bacteriophages incorporated within fibrin glue, track the release of bacteriophages from fibrin scaffolds, and measure the antibacterial activity of released bacteriophages. Fibrin glue polymerized in the presence of the PA5 bacteriophage released high titers of bacteriophages during 11 days of incubation in liquid medium. Released PA5 bacteriophages were effective in killing Pseudomonas aeruginosa PA01. Overall, our results show that fibrin glue can be used for sustained delivery of bacteriophages and this strategy holds promise for many antibacterial applications.
Improving solutions by embedding larger subproblems in a D-Wave quantum annealer
Authors: Okada Shuntaro , Ohzeki Masayuki , Terabe Masayoshi , Taguchi Shinichiro
Published: February 2019

Quantum annealing is a heuristic algorithm that solves combinatorial optimization problems, and D-Wave Systems Inc. has developed hardware implementation of this algorithm. However, in general, we cannot embed all the logical variables of a large-scale problem, since the number of available qubits is limited. In order to handle a large problem, has been proposed as a method for partitioning the original large problem into subproblems that are embeddable in the D-Wave quantum annealer, and it then iteratively optimizes the subproblems using the quantum annealer. Multiple logical variables in the subproblem are simultaneously updated in this iterative solver, and using this approach we expect to obtain better solutions than can be obtained by conventional local search algorithms. Although embedding of large subproblems is essential for improving the accuracy of solutions in this scheme, the size of the subproblems are small in since the subproblems are basically embedded by using an embedding of a complete graph even for sparse problem graphs. This means that the resource of the D-Wave quantum annealer is not exploited efficiently. In this paper, we propose a fast algorithm for embedding larger subproblems, and we show that better solutions are obtained efficiently by embedding larger subproblems.
Propagation and self-healing properties of Bessel-Gaussian beam carrying orbital angular momentum in an underwater environment
Authors: Zhao Shengmei , Zhang Wenhao , Wang Le , Li Wei , Gong Longyan , Cheng Weiwen , Chen Hanwu , Gruska Jozef
Published: February 2019

In this paper, we report on experimental demonstration of the propagation and self-healing property of Bessel-Gaussian (BG) beam carrying orbital angular momentum (OAM) in an underwater environment. Especially, the effects of topological charge, temperature gradient, and salinity on the transmission and self-reconstruction of BG beam in underwater turbulence are analyzed. The results show that the detection probabilities both for propagation and self-healing greatly decrease with temperature gradient, and gradually decrease with salinity. BG beam has a self-healing property in the underwater environment when the obstruction is quite small. The detection probability greatly decreases with obstruction size, while it gradually decreases with salinity fluctuations for different obstruction sizes. For the same blockage ratio, the smaller topological charge of BG beam is, the better self-healing characteristics the BG beam has.
Litter removal reduced soil nitrogen mineralization in repeated freeze-thaw cycles
Authors: Yang Yulian , Zhang Li , Wei Xinyu , Chen Ya , Yang Wanqin , Tan Bo , Yue Kai , Ni Xiangyin , Wu Fuzhong
Published: February 2019

Repeated freeze-thaw cycles (FTCs) can alter the relationships between plant litter and soil nitrogen (N) mineralization in subalpine ecosystems, but little information is available about the underlying mechanisms. Therefore, a controlled soil incubation experiment was carried out to study the effects of litter removal on soil N mineralization during FTCs, and the results indicated that FTCs promoted soil N mineralization more than the continuously frozen or nonfrozen condition did. Litter removal promoted soil ammonium N (NH4+-N) and dissolved organic N (DON) as well as the cumulative N mineralization (CNM) and ammonification, but it reduced the soil microbial biomass N (MBN) in the early stage of FTCs. With an increasing number of FTCs, litter removal significantly reduced the CNM but increased the soil MBN. The modified first-order kinetics model was verified under incubation conditions and predicted a lower soil N mineralization rate in FTCs with litter removal. In addition, the dominant factor impacting soil N mineralization was soil NO3−-N, and soil MBN had a greater influence on soil N mineralization when litter remained than when it was removed. These results further clarify the mechanism driving the effect of plant residues on soil N cycling.
The role of diffusion-driven pure climb creep on the rheology of bridgmanite under lower mantle conditions
Authors: Reali Riccardo , Van Orman James A. , Pigott Jeffrey S. , Jackson Jennifer M. , Boioli Francesca , Carrez Philippe , Cordier Patrick
Published: February 2019

The viscosity of Earth’s lower mantle is poorly constrained due to the lack of knowledge on some fundamental variables that affect the deformation behaviour of its main mineral phases. This study focuses on bridgmanite, the main lower mantle constituent, and assesses its rheology by developing an approach based on mineral physics. Following and revising the recent advances in this field, pure climb creep controlled by diffusion is identified as the key mechanism driving deformation in bridgmanite. The strain rates of this phase under lower mantle pressures, temperatures and stresses are thus calculated by constraining diffusion and implementing a creep theoretical model. The viscosity of MgSiO3 bridgmanite resulting from pure climb creep is consequently evaluated and compared with the viscosity profiles available from the literature. We show that the inferred variability of viscosity in these profiles can be fully accounted for with the chosen variables of our calculation, e.g., diffusion coefficients, vacancy concentrations and applied stresses. A refinement of these variables is advocated in order to further constrain viscosity and match the observables.
Carbide-free one-zone sulfurization method grows thin MoS2 layers on polycrystalline CVD diamond
Authors: Sojková Michaela , Siffalovic Peter , Babchenko Oleg , Vanko Gabriel , Dobročka Edmund , Hagara Jakub , Mrkyvkova Nada , Majková Eva , Ižák Tibor , Kromka Alexander , Hulman Martin
Published: February 2019

The last few decades faced on the fabrication of advanced engineering materials involving also different composites. Here, we report on the fabrication of few-layer molybdenum disulfide on top of thin polycrystalline diamond substrates with a high specific surface area. In the method, pre-deposited molybdenum coatings were sulfurized in a one-zone furnace at ambient pressure. As-prepared MoS2 layers were characterized by several techniques including grazing-incidence wide-angle X-ray scattering, atomic force microscopy, scanning electron microscopy, Raman spectroscopy and X-ray photoelectron spectroscopy. We found out that the initial thickness of Mo films determined the final c-axis crystallographic orientation of MoS2 layer as previously observed on other substrates. Even though it is well-known that Mo diffuses into diamond at elevated temperatures, the competing sulfurization applied effectively suppressed the diffusion and a chemical reaction between molybdenum and diamond. In particular, a Mo2C layer does not form at the interface between the Mo film and diamond substrate. The combination of diamond high specific surface area along with a controllable layer orientation might be attractive for applications, such as water splitting or water disinfection.
Towards calibration-invariant spectroscopy using deep learning
Authors: Chatzidakis M. , Botton G. A.
Published: February 2019

The interaction between matter and electromagnetic radiation provides a rich understanding of what the matter is composed of and how it can be quantified using spectrometers. In many cases, however, the calibration of the spectrometer changes as a function of time (such as in electron spectrometers), or the absolute calibration may be different between different instruments. Calibration differences cause difficulties in comparing the absolute position of measured emission or absorption peaks between different instruments and even different measurements taken at different times on the same instrument. Present methods of avoiding this issue involve manual feature extraction of the original signal or qualitative analysis. Here we propose automated feature extraction using deep convolutional neural networks to determine the class of compound given only the shape of the spectrum. We classify three unique electronic environments of manganese (being relevant to many battery materials applications) in electron energy loss spectroscopy using 2001 spectra we collected in addition to testing on spectra from different instruments. We test a variety of commonly used neural network architectures found in the literature and propose a new fully convolutional architecture with improved translation-invariance which is immune to calibration differences.
Serotonin Transporter Deficiency is Associated with Dysbiosis and Changes in Metabolic Function of the Mouse Intestinal Microbiome
Authors: Singhal Megha , Turturice Benjamin A. , Manzella Christopher R. , Ranjan Ravi , Metwally Ahmed A. , Theorell Juliana , Huang Yue , Alrefai Waddah A. , Dudeja Pradeep K. , Finn Patricia W. , Perkins David L. , Gill Ravinder K.
Published: February 2019

Serotonin transporter (SERT) plays a critical role in regulating extracellular availability of serotonin (5-HT) in the gut and brain. Mice with deletion of SERT develop metabolic syndrome as they age. Changes in the gut microbiota are being increasingly implicated in Metabolic Syndrome and Diabetes. To investigate the relationship between the gut microbiome and SERT, this study assessed the fecal and cecal microbiome profile of 11 to 12 week-old SERT+/+ and SERT−/− mice. Microbial DNA was isolated, processed for metagenomics shotgun sequencing, and taxonomic and functional profiles were assessed. 34 differentially abundant bacterial species were identified between SERT+/+ and SERT−/−. SERT−/− mice displayed higher abundances of Bacilli species including genera Lactobacillus, Streptococcus, Enterococcus, and Listeria. Furthermore, SERT−/− mice exhibited significantly lower abundances of Bifidobacterium species and Akkermansia muciniphilia. Bacterial community structure was altered in SERT−/− mice. Differential abundance of bacteria was correlated with changes in host gene expression. Bifidobacterium and Bacilli species exhibited significant associations with host genes involved in lipid metabolism pathways. Our results show that SERT deletion is associated with dysbiosis similar to that observed in obesity. This study contributes to the understanding as to how changes in gut microbiota are associated with metabolic phenotype seen in SERT deficiency.
Real-time imaging of senescence in tumors with DNA damage
Authors: Wang Ying , Liu Jun , Ma Xiaowei , Cui Chao , Deenik Philip R. , Henderson Paul K. P. , Sigler Ashton L. , Cui Lina
Published: February 2019

Detection of cellular senescence is important not only in the study of senescence in various biological systems, but also in various practical applications such as image-guided surgical removal of senescent cells, as well as the monitoring of drug-responsiveness during cancer therapies. Due to the lack of suitable imaging probes for senescence detection, particularly in living subjects, we have developed an activatable near-infrared (NIR) molecular probe with far-red excitation, NIR emission, and high “turn-on” ratio upon senescence-associated β-galactosidase (SABG) activation. We present here the first successful demonstration of NIR imaging of DNA damage-induced senescence both in vitro and in human tumor xenograft models.
Positive and negative contexts predict duration of pig vocalisations
Authors: Friel Mary , Kunc Hansjoerg P. , Griffin Kym , Asher Lucy , Collins Lisa M.
Published: February 2019

Emotions are mental states occurring in response to external and internal stimuli and thus form an integral part of an animal’s behaviour. Emotions can be mapped in two dimensions based on their arousal and valence. Whilst good indicators of arousal exist, clear indicators of emotional valence, particularly positive valence, are still rare. However, positively valenced emotions may play a crucial role in social interactions in many species and thus, an understanding of how emotional valence is expressed is needed. Vocalisations are a potential indicator of emotional valence as they can reflect the internal state of the caller. We experimentally manipulated valence, using positive and negative cognitive bias trials, to quantify changes in pig vocalisations. We found that grunts were shorter in positive trials than in negative trials. Interestingly, we did not find differences in the other measured acoustic parameters between the positive and negative contexts as reported in previous studies. These differences in results suggest that acoustic parameters may differ in their sensitivity as indicators of emotial valence. However, it is important to understand how similar contexts are, in terms of their valence, to be able to fully understand how and when acoustic parameters reflect emotional states.
High sensitivity detection of extracellular vesicles immune-captured from urine by conventional flow cytometry
Authors: Campos-Silva Carmen , Suárez Henar , Jara-Acevedo Ricardo , Linares-Espinós Estefanía , Martinez-Piñeiro Luis , Yáñez-Mó María , Valés-Gómez Mar
Published: February 2019

Extracellular vesicles (EVs) provide an invaluable tool to analyse physiological processes because they transport, in biological fluids, biomolecules secreted from diverse tissues of an individual. EV biomarker detection requires highly sensitive techniques able to identify individual molecules. However, the lack of widespread, affordable methodologies for high-throughput EV analyses means that studies on biomarkers have not been done in large patient cohorts. To develop tools for EV analysis in biological samples, we evaluated here the critical parameters to optimise an assay based on immunocapture of EVs followed by flow cytometry. We describe a straightforward method for EV detection using general EV markers like the tetraspanins CD9, CD63 and CD81, that allowed highly sensitive detection of urinary EVs without prior enrichment. In proof-of-concept experiments, an epithelial marker enriched in carcinoma cells, EpCAM, was identified in EVs from cell lines and directly in urine samples. However, whereas EVs isolated from 5–10 ml of urine were required for western blot detection of EpCAM, only 500 μl of urine were sufficient to visualise EpCAM expression by flow cytometry. This method has the potential to allow any laboratory with access to conventional flow cytometry to identify surface markers on EVs, even non-abundant proteins, using minimally processed biological samples.
Understanding the role of distance, direction and cue salience in an associative model of landmark learning
Authors: Commins Sean , Fey Dirk
Published: February 2019

Navigation and spatial memory relies on the ability to use and recall environmental landmarks relative to important locations. Such learning is thought to result from the strengthening of associations between the goal location and environmental cues. Factors that contribute to the strength of this association include cue stability, saliency and cue location. Here we combine an autoregressive random walk model, that describes goal-directed swimming behaviour, with an associative learning model to provide an integrated model of landmark learning, using the water maze task. The model allows for the contribution of each cue, the salience and the vector information provided (both distance and directional) to be separately analysed. The model suggests that direction and distance information are independent components and can influence searching patterns. Importantly, the model can also be used to simulate various experimental scenarios to understand what has been learnt in relation to the cues, thereby offering new insights into how animals navigate.
Dissecting quantitative resistance to Xanthomonas campestris pv. campestris in leaves of Brassica oleracea by QTL analysis
Authors: Iglesias-Bernabé Laura , Madloo Pari , Rodríguez Víctor Manuel , Francisco Marta , Soengas Pilar
Published: February 2019

Black rot, caused by the bacterium Xanthomonas campestris pv. campestris (Xcc), produces important economic losses in crops of Brassica oleracea worldwide. Resistance to race 1, the most virulent and widespread in B. oleracea, is under quantitative control. Knowledge about the genetics of this resistance would help in designing strategies to control initial stages of invasion and development of the disease. QTL analysis of the resistance in the BolTBDH mapping population was performed. Resistance was measured with five traits related to initial stages of the invasion, success of infection and spread of the pathogen. Four single-trait QTLs of resistance were found, from which one represent novel variation. After performing multi-trait QTL, we concluded that spread of Xcc is related to the size of the leaf. Individuals from the mapping population follow two different strategies to cope with the spread of the disease: reducing lesion size or maintain more area of the leaf photosynthetically active, being more tolerant to Xcc invasion. Mechanisms underlying variation for resistance may be related to different aspects of plant immunity, including the synthesis of glucosinolates and phenolics.
X-ray induced damage of B4C-coated bilayer materials under various irradiation conditions
Authors: Follath Rolf , Koyama Takahisa , Lipp Vladimir , Medvedev Nikita , Tono Kensuke , Ohashi Haruhiko , Patthey Luc , Yabashi Makina , Ziaja Beata
Published: February 2019

In this report, we analyse X-ray induced damage of B4C-coated bilayer materials under various irradiation geometries, following the conditions of our experiment performed at the free-electron-laser facility SACLA. We start with the discussion of structural damage in solids and damage threshold doses for the experimental system components: B4C, SiC, Mo and Si. Later, we analyze the irradiation of the experimentally tested coated bilayer systems under two different incidence conditions of a linearly polarized X-ray pulse: (i) grazing incidence, and (ii) normal incidence, in order to compare quantitatively the effect of the pulse incidence on the radiation tolerance of both systems. For that purpose, we propose a simple theoretical model utilizing properties of hard X-ray propagation and absorption in irradiated materials and of the following electron transport. With this model, we overcome the bottleneck problem of large spatial scales, inaccessible for any existing first-principle-based simulation tools due to their computational limitations for large systems. Predictions for damage thresholds obtained with the model agree well with the available experimental data. In particular, they confirm that two coatings tested: 15 nm B4C/20 nm Mo on silicon wafer and 15 nm B4C/50 nm SiC on silicon wafer can sustain X-ray irradiation at the fluences up to ~10 μJ/μm2, when exposed to linearly polarized 10 keV X-ray pulse at a grazing incidence angle of 3 mrad. Below we present the corresponding theoretical analysis. Potential applications of our approach for design and radiation tolerance tests of multilayer components within X-ray free-electron-laser optics are indicated.
Experimental Tracheal Replacement Using 3-dimensional Bioprinted Artificial Trachea with Autologous Epithelial Cells and Chondrocytes
Authors: Park Jae-Hyun , Yoon Jeong-Kee , Lee Jung Bok , Shin Young Min , Lee Kang-Woog , Bae Sang-Woo , Lee JunHee , Yu JunJie , Jung Cho-Rok , Youn Young-Nam , Kim Hwi-Yool , Kim Dae-Hyun
Published: February 2019

Various treatment methods for tracheal defects have been attempted, such as artificial implants, allografts, autogenous grafts, and tissue engineering; however, no perfect method has been established. We attempted to create an effective artificial trachea via a tissue engineering method using 3D bio-printing. A multi-layered scaffold was fabricated using a 3D printer. Polycaprolactone (PCL) and hydrogel were used with nasal epithelial and auricular cartilage cells in the printing process. An artificial trachea was transplanted into 15 rabbits and a PCL scaffold without the addition of cells was transplanted into 6 rabbits (controls). All animals were followed up with radiography, CT, and endoscopy at 3, 6, and 12 months. In the control group, 3 out of 6 rabbits died from respiratory symptoms. Surviving rabbits in control group had narrowed tracheas due to the formation of granulation tissue and absence of epithelium regeneration. In the experimental group, 13 of 15 animals survived, and the histologic examination confirmed the regeneration of epithelial cells. Neonatal cartilage was also confirmed at 6 and 12 months. Our artificial trachea was effective in the regeneration of respiratory epithelium, but not in cartilage regeneration. Additional studies are needed to promote cartilage regeneration and improve implant stability.
Silver diamine fluoride versus sodium fluoride for arresting dentine caries in children: a systematic review and meta-analysis
Authors: Trieu Alice , Mohamed Ahmed , Lynch Edward
Published: February 2019

Dental caries can compromise quality of life and is associated with demineralization of tooth structure by organic acids produced by microorganisms. This study systematically reviewed the dentine caries arrest capabilities of silver diamine fluoride (SDF) and sodium fluoride (NaF). A comprehensive search strategy was developed to identify the relevant publications in electronic databases and hand searched journals and reviews (to March 2018). By applying strict inclusion and exclusion criteria, only six papers (two randomized controlled trials, two follow-up articles and two secondary statistical analysis studies) were considered for full text qualitative and quantitative assessment. The included studies were critically appraised and statistically evaluated. Only four articles were considered for meta-analysis, as the other two were secondary analyses of included studies. When comparing the caries arrest lesions of SDF and NaF, SDF was found to be statistically more effective in dentine caries arrest of primary teeth during the 18 and 30 month clinical examinations. The weighted total effect size of the differences between SDF and NaF regarding arrested caries surfaces was calculated and showed nearly double the effectiveness of SDF to NaF at 30 months. Therefore, SDF is a more effective caries management reagent than NaF. Further clinical research is needed to consolidate the findings of this systematic review.
Oncostatin M exerts a protective effect against excessive scarring by counteracting the inductive effect of TGFβ1 on fibrosis markers
Authors: Huguier Vincent , Giot Jean-Philippe , Simonneau Marie , Levillain Pierre , Charreau Sandrine , Garcia Martine , Jégou Jean-François , Bodet Charles , Morel Franck , Lecron Jean-Claude , Favot Laure
Published: February 2019

Wound healing is a complex physiological process that repairs a skin lesion and produces fibrous tissue. In some cases, this process can lead to hypertrophic scars (HS) or keloid scars (KS), for which the pathophysiology remains poorly understood. Previous studies have reported the presence of oncostatin M (OSM) during the wound healing process; however, the role of OSM in pathological scarring remains to be precisely elucidated. This study aims to analyse the presence and involvement of OSM in the pathological scarring process. It was conducted with 18 patients, including 9 patients with hypertrophic scarring and 9 patients with keloid scarring. Histological tissue analysis of HS and KS showed minor differences in the organization of the extracellular matrix, the inflammatory infiltrate and the keratinocyte phenotype. Transcriptomic analysis showed increased expression levels of fibronectin, collagen I, TGFβ1, β-defensin-2 and S100A7 in both pathological samples. OSM expression levels were greater in HS than in KS and control skin. In vitro, OSM inhibited TGFβ1-induced secretion of components of the extracellular matrix by normal and pathological fibroblasts. Overall, we suggest that OSM is involved in pathological wound healing processes by inhibiting the evolution of HS towards KS by controlling the fibrotic effect of TGFβ1.
Targeting Epidermal Growth Factor Receptor (EGFR) and Human Epidermal Growth Factor Receptor 2 (HER2) Expressing Bladder Cancer Using Combination Photoimmunotherapy (PIT)
Authors: Siddiqui Mohammad R. , Railkar Reema , Sanford Thomas , Crooks Daniel R. , Eckhaus Michael A. , Haines Diana , Choyke Peter L. , Kobayashi Hisataka , Agarwal Piyush K.
Published: February 2019

Bladder cancer (BC) is heterogeneous and expresses various cell surface targets. Photoimmunotherapy (PIT) involves monoclonal antibodies (MAbs) conjugated to a photoabsorber (PA), IR Dye 700Dx, and then activated by near infra-red light (NIR) to specifically target tumors. We have demonstrated that tumors expressing EGFR can be targeted with PIT. However, PIT may be less effective when a tumor lacks “overwhelming” expression of a single target such as EGFR. We present a combinatorial PIT approach for targeting BC expressing EGFR and HER2, using PA- labeled panitumumab (pan) and trastuzumab (tra), respectively. Human BC tissues and cell lines were analyzed for EGFR and HER2 expression. Efficacy of PA-labeled MAbs singly and in combination was analyzed. About 45% of BC tissues stain for both EGFR and HER2. In vitro, the combination of pan IR700 and tra IR700 with NIR was more efficacious than either agent alone. Tumor xenografts treated with combination PIT showed significant tumor growth retardation. Combination PIT is a promising approach for treating BC with low/moderate expression of surface receptors. In addition, given the molecular heterogeneity of bladder cancer, targeting more than one surface receptor may allow for more effective cell death across different bladder tumors.
Association between DNA methylation in obesity-related genes and body mass index percentile in adolescents
Authors: He Fan , Berg Arthur , Imamura Kawasawa Yuka , Bixler Edward O. , Fernandez-Mendoza Julio , Whitsel Eric A. , Liao Duanping
Published: February 2019

Childhood obesity remains an epidemic in the U.S. and worldwide. However, little is understood regarding the epigenetic basis of obesity in adolescents. To investigate the cross-sectional association between DNA methylation level in obesity-related genes and body mass index (BMI) percentile, data from 263 adolescents in the population-based Penn State Child Cohort follow-up exam was analysed. Using DNA extracted from peripheral leukocytes, epigenome-wide single nucleotide resolution of DNA methylation in cytosine-phosphate-guanine (CpG) sites and surrounding regions was obtained. We used multivariable-adjusted linear regression models to assess the association between site-specific methylation level and age- and sex-specific BMI percentile. Hypergeometric and permutation tests were used to determine if obesity-related genes were significantly enriched among all intragenic sites that achieved a p < 0.05 throughout the epigenome. Among the 5,669 sites related to BMI percentile with p < 0.05, 28 were identified within obesity-related genes. Obesity-related genes were significantly enriched among 103,466 intragenic sites (Phypergeometric = 0.006; Ppermutation = 0.006). Moreover, increased methylation on one site within SIM1 was significantly related to higher BMI percentile (P = 4.2E-05). If externally validated, our data would suggest that DNA methylation in obesity-related genes may relate to obesity risk in adolescents.
Ex vivo organotypic culture system of precision-cut slices of human pancreatic ductal adenocarcinoma
Authors: Misra Sougat , Moro Carlos F. , Del Chiaro Marco , Pouso Soledad , Sebestyén Anna , Löhr Matthias , Björnstedt Mikael , Verbeke Caroline S.
Published: February 2019

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, which is mainly due to late diagnosis and profound resistance to treatment. The latter is to a large extent attributed to the tumor stroma that is exceedingly prominent in PDAC and engages in complex interactions with the cancer cells. Hence, relevant preclinical models of PDAC should also include the tumor stroma. We herein describe the establishment and functional validation of an ex vivo organotypic culture of human PDAC that is based on precision-cut tissue slices from surgical specimens and reproducibly recapitulates the complex cellular and acellular composition of PDAC, including its microenvironment. The cancer cells, tumor microenvironment and interspersed remnants of nonneoplastic pancreas contained in these 350 µm thick slices maintained their structural integrity, phenotypic characteristics and functional activity when in culture for at least 4 days. In particular, tumor cell proliferation persisted and the grade of differentiation and morphological phenotype remained unaltered. Cultured tissue slices were metabolically active and responsive to rapamycin, an mTOR inhibitor. This culture system is to date the closest surrogate to the parent carcinoma and harbors great potential as a drug sensitivity testing system for the personalized treatment of PDAC.
The long non-coding RNA Meg3 is dispensable for hematopoietic stem cells
Authors: Sommerkamp Pia , Renders Simon , Ladel Luisa , Hotz-Wagenblatt Agnes , Schönberger Katharina , Zeisberger Petra , Przybylla Adriana , Sohn Markus , Zhou Yunli , Klibanski Anne , Cabezas-Wallscheid Nina , Trumpp Andreas
Published: February 2019

The long non-coding RNA (lncRNA) Maternally Expressed Gene 3 (Meg3) is encoded within the imprinted Dlk1-Meg3 gene locus and is only maternally expressed. Meg3 has been shown to play an important role in the regulation of cellular proliferation and functions as a tumor suppressor in numerous tissues. Meg3 is highly expressed in mouse adult hematopoietic stem cells (HSCs) and strongly down-regulated in early progenitors. To address its functional role in HSCs, we used MxCre to conditionally delete Meg3 in the adult bone marrow of Meg3mat-flox/pat-wt mice. We performed extensive in vitro and in vivo analyses of mice carrying a Meg3 deficient blood system, but neither observed impaired hematopoiesis during homeostatic conditions nor upon serial transplantation. Furthermore, we analyzed VavCre Meg3mat-flox/pat-wt mice, in which Meg3 was deleted in the embryonic hematopoietic system and unexpectedly this did neither generate any hematopoietic defects. In response to interferon-mediated stimulation, Meg3 deficient adult HSCs responded highly similar compared to controls. Taken together, we report the finding, that the highly expressed imprinted lncRNA Meg3 is dispensable for the function of HSCs during homeostasis and in response to stress mediators as well as for serial reconstitution of the blood system in vivo.
A Monte Carlo feasibility study for neutron based real-time range verification in proton therapy
Authors: Ytre-Hauge Kristian Smeland , Skjerdal Kyrre , Mattingly John , Meric Ilker
Published: February 2019

Uncertainties in the proton range in tissue during proton therapy limit the precision in treatment delivery. These uncertainties result in expanded treatment margins, thereby increasing radiation dose to healthy tissue. Real-time range verification techniques aim to reduce these uncertainties in order to take full advantage of the finite range of the primary protons. In this paper, we propose a novel concept for real-time range verification based on detection of secondary neutrons produced in nuclear interactions during proton therapy. The proposed detector concept is simple; consisting of a hydrogen-rich converter material followed by two charged particle tracking detectors, mimicking a proton recoil telescopic arrangement. Neutrons incident on the converter material are converted into protons through elastic and inelastic (n,p) interactions. The protons are subsequently detected in the tracking detectors. The information on the direction and position of these protons is then utilized in a new reconstruction algorithm to estimate the depth distribution of neutron production by the proton beam, which in turn is correlated with the primary proton range. In this paper, we present the results of a Monte Carlo feasibility study and show that the proposed concept could be used for real-time range verification with millimetric precision in proton therapy.
Intravital imaging of glioma border morphology reveals distinctive cellular dynamics and contribution to tumor cell invasion
Authors: Alieva Maria , Leidgens Verena , Riemenschneider Markus J. , Klein Christoph A. , Hau Peter , van Rheenen Jacco
Published: February 2019

The pathogenesis of glioblastoma (GBM) is characterized by highly invasive behavior allowing dissemination and progression. A conclusive image of the invasive process is not available. The aim of this work was to study invasion dynamics in GBM using an innovative in vivo imaging approach. Primary brain tumor initiating cell lines from IDH-wild type GBM stably expressing H2B-Dendra2 were implanted orthotopically in the brains of SCID mice. Using high-resolution time-lapse intravital imaging, tumor cell migration in the tumor core, border and invasive front was recorded. Tumor cell dynamics at different border configurations were analyzed and multivariate linear modelling of tumor cell spreading was performed. We found tumor border configurations, recapitulating human tumor border morphologies. Not only tumor borders but also the tumor core was composed of highly dynamic cells, with no clear correlation to the ability to spread into the brain. Two types of border configurations contributed to tumor cell spreading through distinct invasion patterns: an invasive margin that executes slow but directed invasion, and a diffuse infiltration margin with fast but less directed movement. By providing a more detailed view on glioma invasion patterns, our study may improve accuracy of prognosis and serve as a basis for personalized therapeutic approaches.
Exquisitely-preserved, high-definition skin traces in diminutive theropod tracks from the Cretaceous of Korea
Authors: Kim Kyung Soo , Lockley Martin G. , Lim Jong Deock , Xing Lida
Published: February 2019

Small theropod tracks, ichnogenus Minisauripus, from the Jinju Formation (Cretaceous) of Korea reveal exquisitely preserved skin texture impressions. This is the first report for any dinosaur of skin traces that cover entire footprints, and every footprint in a trackway. Special sedimentological conditions allowed footprint registration without smearing of skin texture patterns which consist of densely-packed, reticulate arrays of small (<0.5 mm) polygons, preserved as both impressions and casts, the latter essentially foot replicas. The skin texture resembles that reported for two Lower Cretaceous avian theropods (birds) from China which had quite different foot morphologies. This is also the oldest report of Minisauripus from Korea predating five reports from the Haman Formation of inferred Albian age. Minisauripus is now known from six Korean and three Chinese localities, all from the Lower Cretaceous. This gives a total sample of ~95 tracks representing ~54 trackways. With >80% of tracks <3.0 cm long, Minisauripus is pivotal in debates over whether small tracks represent small species, as the database suggests, or juveniles of large species.
Annual change in FEV1 in elderly 10-year survivors with established chronic obstructive pulmonary disease
Authors: Suzuki Masaru , Makita Hironi , Konno Satoshi , Shimizu Kaoruko , Nasuhara Yasuyuki , Nagai Katsura , Akiyama Yasushi , Fuke Satoshi , Saito Hiroshi , Igarashi Takeshi , Takeyabu Kimihiro , Nishimura Masaharu
Published: February 2019

Long-term decline in lung function is generally considered to be progressive in individuals with established chronic obstructive pulmonary disease (COPD), despite the presence of intersubject variation. We hypothesized that the annualized rate of decline in forced expiratory volume in 1 second (FEV1) would not be constant among different time periods in the natural history of established COPD. We compared the annual change rates in FEV1 during the first 5 years and the last 5 years, estimated separately using a linear mixed-effects model in 10-year survivors (n = 110). The subjects were classified into three FEV1 decline groups, based on the 25th and 75th percentile values in each time period. The rates of FEV1 changes, calculated from the first 5 years and the last 5 years, did not correlate with each other among 10-year survivors; the subjects of each FEV1 decline group during the first 5 years did not consistently remain in the same FEV1 decline group during the last 5 years. Smoking status and exacerbation frequency were not associated with decline in FEV1. In conclusion, the disease activity, which is often expressed as annualized change in FEV1, might be changeable either way over years in patients with established COPD.
Stress-induced mast cell activation contributes to atherosclerotic plaque destabilization
Authors: Lagraauw H. Maxime , Wezel Anouk , van der Velden Daniël , Kuiper Johan , Bot Ilze
Published: February 2019

Mast cells accumulate in the perivascular tissue during atherosclerotic plaque progression and contribute to plaque destabilization. However, the specific triggers for mast cell activation in atherosclerosis remain unresolved. We hypothesized that psychological stress-induced activation of mast cells may contribute to plaque destabilization. To investigate this, apoE−/− mice on Western-type diet were exposed to 120′ restraint stress. A single episode of restraint caused a significant increase in mast cell activation in the heart. In addition to a rise in serum corticosterone and changes in circulating leukocyte populations, we observed an increase in the circulating pro-inflammatory cytokine interleukin (IL)-6 in the stressed mice. Subsequent characterization of the atherosclerotic plaques revealed a high incidence and larger size of intraplaque hemorrhages in stressed mice. In mast cell-deficient apoE−/− mice, restraint stress affected circulating leukocyte levels, but did not increase plasma IL-6 levels. Furthermore, we did not observe any intraplaque hemorrhages in these mice upon stress, strongly indicating the involvement of a mast cell-dependent response to stress in atherosclerotic plaque destabilization. In conclusion, we demonstrate that acute stress activates mast cells, which induces the incidence of intraplaque hemorrhage in vivo, identifying acute stress as a risk factor for atherosclerotic plaque destabilization.
Unexpected population fragmentation in an endangered seabird: the case of the Peruvian diving-petrel
Authors: Cristofari Robin , Plaza Paula , Fernández Claudia E. , Trucchi Emiliano , Gouin Nicolas , Le Bohec Céline , Zavalaga Carlos , Alfaro-Shigueto Joanna , Luna-Jorquera Guillermo
Published: February 2019

In less than one century, the once-abundant Peruvian diving petrel has become the first endangered seabird of the Humboldt Current System (HCS). This small endemic petrel of the South American Pacific coast is now an important indicator of ongoing habitat loss and of the success of local conservation policies in the HCS - an ecoregion designated as a priority for the conservation of global biodiversity. Yet so far, poorly understood life history traits such as philopatry or dispersal ability may strongly influence the species’ response to ecosystem changes, but also our capacity to assess and interpret this response. To address this question, we explore the range-wide population structure of the Peruvian diving petrel, and show that this small seabird exhibits extreme philopatric behavior at the island level. Mitochondrial DNA sequences and genome-wide SNP data reveal significant isolation and low migration at very short distances, and provide strong evidence for questioning the alleged recovery in the Peruvian and Chilean populations of this species. Importantly, the full demographic independence between colonies makes local population rescue through migration unlikely. As a consequence, the Peruvian diving petrel appears to be particularly vulnerable to ongoing anthropogenic pressure. By excluding immigration as a major factor of demographic recovery, our results highlight the unambiguously positive impact of local conservation measures on breeding populations; yet at the same time they also cast doubt on alleged range-wide positive population trends. Overall, the protection of independent breeding colonies, and not only of the species as a whole, remains a major element in the conservation strategy for endemic seabirds. Finally, we underline the importance of considering the philopatric behavior and demographic independence of breeding populations, even at very fine spatial scales, in spatial planning for marine coastal areas.
Unexpected rip currents induced by a meteotsunami
Authors: Linares Álvaro , Wu Chin H. , Bechle Adam J. , Anderson Eric J. , Kristovich David A. R.
Published: February 2019

A tragic drowning event occurred along southeastern beaches of Lake Michigan on a sunny and calm July 4, 2003, hours after a fast-moving convective storm had crossed the lake. Data forensics indicates that a moderate-height (~0.3 m) meteotsunami was generated by the fast-moving storm impacting the eastern coast of the lake. Detailed Nearshore Area (DNA) modeling forensics on a high-resolution spatial O(1 m) grid reveals that the meteotsunami wave generated unexpected rip currents, changing the nearshore condition from calm to hazardous in just a few minutes and lasting for several hours after the storm. Cross-comparison of rip current incidents and meteotsunami occurrence databases suggests that meteotsunamis present severe water safety hazards and high risks, more frequently than previously recognized. Overall, meteorological tsunamis are revealed as a new generation mechanism of rip currents, thus posing an unexpected beach hazard that, to date, has been ignored.
Seroprevalence of six pathogens transmitted by the Ixodes ricinus ticks in asymptomatic individuals with HIV infection and in blood donors
Authors: Pawełczyk Agnieszka , Bednarska Małgorzata , Kowalska Justyna D. , Uszyńska-Kałuża Beata , Radkowski Marek , Welc-Falęciak Renata
Published: February 2019

The objective of our study was to estimate the seroprevalence of six pathogens transmitted by ticks in HIV-infected persons and blood donors in Poland (B.burgdorferis.l.,A.phagocytophilum,Ehrlichiaspp.,Babesiaspp.,Rickettsiaspp.Bartonella henselae) to assess the frequency of exposure to such microorganisms in immunocompetent and immunocompromised individuals in endemic regions forI.ricinusticks. Serum samples were collected from 227 HIV-infected patients and 199 blood donors. All samples were analyzed for antibodies against six tick-borne pathogens and seroprevalence rates were statistically compared between two tested group as well as age, sex and lymphocyte T CD4+ level in HIV infected patients. The seroprevalence of tick-borne infections in HIV-infected patients is higher than that of the healthy population in Poland, although no association between serological status of patients and lymphocyte CD4+ T cell level has been observed. The frequency of tick-borne coinfections and doubtful results of serological tests were significantly higher in HIV-positive individuals. In Poland, the possibility of tick-borne diseases transmission with blood is rather negligible.
Curcumin and Quercetin as Potential Radioprotectors and/or Radiosensitizers for X-ray-based Sterilization of Male Navel Orangeworm Larvae
Authors: Liang Pei-Shih , Haff Ronald P. , Ovchinnikova Inna , Light Douglas M. , Mahoney Noreen E. , Kim Jong H.
Published: February 2019

Two natural compounds (quercetin and curcumin) were tested as sensitizing or protecting agents for Navel Orangeworm (NOW) larvae under x-ray sterilization, with the aim to reduce required doses and thus facilitate the substitution of x-ray for radioisotopes. The compounds were added to NOW diet at concentrations between 0 and 1.0 mmol kg−1 and subsequent reared male larvae were subjected to x-ray irradiation (90 keV, 9 mA) to doses up to 15 Gy. Upon emergence as adults, surviving male NOW were paired with colony virgin females and placed in isolation for observation of deformity, mortality, and fertility. Treatments included rearing larvae on infused diet before irradiation, after irradiation, and both. Results were tabulated as percentage of insects that were dead/deformed, infertile, or fertile and subjected to chi-squared analysis. While insect populations subjected to quercetin treatments were not found to be significantly different from control at any x-ray dose, all curcumin treatments yielded significant differences at an absorbed dose of 10 Gy, both in terms of decreased mortality and fertility. While none of the treatments resulted in acceptable mortality/deformity rates, the observed effects strongly support the need for continued testing of natural compounds for their efficacy to reduce required dose levels for sterilization.