bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of Bimaxillary Advancement Surgery on the Upper Airway and on Obstructive Sleep Apnea Syndrome: a Meta-Analysis
Authors: Rojo-Sanchis Carolina , Almerich-Silla José Manuel , Paredes-Gallardo Vanessa , Montiel-Company José María , Bellot-Arcís Carlos
Published: April 2018

Upper airway changes following bimaxillary advancement surgery to treat obstructive sleep apnea syndrome remain controversial. The main objective of this systematic review and meta-analysis was to investigate the effects of bimaxillary advancement surgery on the upper airway (UA) of obstructive sleep apnea syndrome patients through examining changes three-dimensionally in vertical and supine position and through changes in oximetric variables (AHI, RDI, O2 Sat) and in the quality of life measured by the Epworth sleepiness scale (ESS). A thorough search of the PubMed, Scopus, Embase and Cochrane databases and a grey literature search (Opengrey) were conducted. No limit was placed on publication year or language. The inclusion criteria were: adult obstructive sleep apnea patients who had undergone bimaxillary advancement surgery, three-dimensional CBCT or CT and oximetric measurements and at least six weeks follow-up. Sample sizes of under 10 patients were excluded. Finally, 26 articles were included in the qualitative review and 23 in the meta-analysis. Bimaxillary advancement surgery has been shown to be beneficial in terms of increased upper airway size, improved oximetric indicators and the quality of life measured on the Epworth sleepiness scale.
A Study on Micropipetting Detection Technology of Automatic Enzyme Immunoassay Analyzer
Authors: Shang Zhiwu , Zhou Xiangping , Li Cheng , Tsai Sang-Bing
Published: April 2018

In order to improve the accuracy and reliability of micropipetting, a method of micro-pipette detection and calibration combining the dynamic pressure monitoring in pipetting process and quantitative identification of pipette volume in image processing was proposed. Firstly, the normalized pressure model for the pipetting process was established with the kinematic model of the pipetting operation, and the pressure model is corrected by the experimental method. Through the pipetting process pressure and pressure of the first derivative of real-time monitoring, the use of segmentation of the double threshold method as pipetting fault evaluation criteria, and the pressure sensor data are processed by Kalman filtering, the accuracy of fault diagnosis is improved. When there is a fault, the pipette tip image is collected through the camera, extract the boundary of the liquid region by the background contrast method, and obtain the liquid volume in the tip according to the geometric characteristics of the pipette tip. The pipette deviation feedback to the automatic pipetting module and deviation correction is carried out. The titration test results show that the combination of the segmented pipetting kinematic model of the double threshold method of pressure monitoring, can effectively real-time judgment and classification of the pipette fault. The method of closed-loop adjustment of pipetting volume can effectively improve the accuracy and reliability of the pipetting system.
Extending a Gray Lattice Boltzmann Model for Simulating Fluid Flow in Multi-Scale Porous Media
Authors: Zhu Jiujiang , Ma Jingsheng
Published: April 2018

A gray lattice Boltzmann model has previously been developed by the authors of this article to simulate fluid flow in porous media that contain both resolved pores and grains as well as aggregates of unresolved smaller pores and grains. In this model, a single parameter is introduced to prescribe the amount of fluid to be bounced back at each aggregate cell. This model has been shown to recover Darcy-Brinkman flow but with effective viscosity and permeability correlated through the model parameter. In this paper, we prove that the model parameter relates to the fraction of the solid phase of a sub-pore system for a specific set of bounce-back conditions. We introduce an additional parameter to the model, and this enables flow simulation in which cases with variable effective viscosity and permeability can be specified by selecting the two parameters independently. We verify and validate the model for layered channel cases and mathematically analyze fluid momentum and energy losses for the single- and two-parameter models to explain the roles of the parameters in their conservation. We introduce a strategy to upgrade our model to an isotropic version. We discuss the fundamental differences between our model and the Brinkman body-force LBM scheme.
Quantitative Methods to Monitor RNA Biomarkers in Myotonic Dystrophy
Authors: Wojciechowska Marzena , Sobczak Krzysztof , Kozlowski Piotr , Sedehizadeh Saam , Wojtkowiak-Szlachcic Agnieszka , Czubak Karol , Markus Robert , Lusakowska Anna , Kaminska Anna , Brook J. David
Published: April 2018

Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are human neuromuscular disorders associated with mutations of simple repetitive sequences in affected genes. The abnormal expansion of CTG repeats in the 3′-UTR of the DMPK gene elicits DM1, whereas elongated CCTG repeats in intron 1 of ZNF9/CNBP triggers DM2. Pathogenesis of both disorders is manifested by nuclear retention of expanded repeat-containing RNAs and aberrant alternative splicing. The precise determination of absolute numbers of mutant RNA molecules is important for a better understanding of disease complexity and for accurate evaluation of the efficacy of therapeutic drugs. We present two quantitative methods, Multiplex Ligation-Dependent Probe Amplification and droplet digital PCR, for studying the mutant DMPK transcript (DMPKexpRNA) and the aberrant alternative splicing in DM1 and DM2 human tissues and cells. We demonstrate that in DM1, the DMPKexpRNA is detected in higher copy number than its normal counterpart. Moreover, the absolute number of the mutant transcript indicates its low abundance with only a few copies per cell in DM1 fibroblasts. Most importantly, in conjunction with fluorescence in-situ hybridization experiments, our results suggest that in DM1 fibroblasts, the vast majority of nuclear RNA foci consist of a few molecules of DMPKexpRNA.
Association between fasting Triglyceride levels and the Prevalence of Asymptomatic Intracranial Arterial Stenosis in a Chinese Community-based Study
Authors: Wu Jianwei , Wang Yu , Wang Anxin , Xie Jian , Zhao Xingquan
Published: April 2018

The aim of this study was to assess the association between fasting triglyceride (FTG) levels and the prevalence of asymptomatic intracranial arterial stenosis (ICAS). The Asymptomatic Polyvascular Abnormalities Community (APAC) study is a sub-population of the Kailuan study which targeting on the epidemiology of asymptomatic polyvascular abnormalities in Chinese adults. A total number of 5345 participants, aged ≥40, and without history of stroke, transient ischemic attack, and coronary heart disease were enrolled in this study. Transcranial Doppler Ultrasonography was performed for the detection of ICAS presence. Out of 5345 participants, 698 subjects diagnosed ICAS (13.1%). In univariate analysis, the association between fasting TG (FTG) levels and asymptomatic ICAS didn’t reach statistical significance (OR: 0.99, 95% CI: 0.89–1.09; P = 0.79), the same conclusion was reached in multivariate analysis, after adjustment for age, sex (OR: 1.05, 95% CI: 0.95–1.17) and age, sex, current smoking status, hypertension, diabetes, body mass index, estimated glomerular filtration rate, total cholesterol, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol (OR: 0.95, 95% CI: 0.84–1.06), respectively. FTG failed to show any statistical significance on ICAS presence in the APAC study, but the TG actually plays an important role in the progression of atherosclerosis as a biomarker.
Spatial Encoding of Translational Optic Flow in Planar Scenes by Elementary Motion Detector Arrays
Authors: Lecoeur Julien , Baird Emily , Floreano Dario
Published: April 2018

Elementary Motion Detectors (EMD) are well-established models of visual motion estimation in insects. The response of EMDs are tuned to specific temporal and spatial frequencies of the input stimuli, which matches the behavioural response of insects to wide-field image rotation, called the optomotor response. However, other behaviours, such as speed and position control, cannot be fully accounted for by EMDs because these behaviours are largely unaffected by image properties and appear to be controlled by the ratio between the flight speed and the distance to an object, defined here as relative nearness. We present a method that resolves this inconsistency by extracting an unambiguous estimate of relative nearness from the output of an EMD array. Our method is suitable for estimation of relative nearness in planar scenes such as when flying above the ground or beside large flat objects. We demonstrate closed loop control of the lateral position and forward velocity of a simulated agent flying in a corridor. This finding may explain how insects can measure relative nearness and control their flight despite the frequency tuning of EMDs. Our method also provides engineers with a relative nearness estimation technique that benefits from the low computational cost of EMDs.
Chronic cigarette smoke exposure drives spiral ganglion neuron loss in mice
Authors: Paquette Stephen T. , Dawes Ryan P. , Sundar Isaac K. , Rahman Irfan , Brown Edward B. , White Patricia M.
Published: April 2018

Tobacco use is associated with an increased risk of hearing loss in older individuals, suggesting cigarette smoke (CS) exposure may target the peripheral auditory organs. However, the effects of CS exposure on general cochlear anatomy have not previously been explored. Here we compare control and chronic CS exposed cochleae from adult mice to assess changes in structure and cell survival. Two-photon imaging techniques, including the imaging of second harmonic generation (SHG) and two-photon excitation fluorescence (TPEF) from native molecules, were used to probe the whole cochlear organ for changes. We found evidence for fibrillar collagen accumulation in the spiral ganglion and organ of Corti, consistent with fibrosis. Quantitative TPEF indicated that basal CS-exposed spiral ganglion neurons experienced greater oxidative stress than control neurons, which was confirmed by histological staining for lipid peroxidation products. Cell counts confirmed that the CS-exposed spiral ganglion also contained fewer basal neurons. Taken together, these data support the premise that CS exposure induces oxidative stress in cochlear cells. They also indicate that two-photon techniques may screen cochlear tissues for oxidative stress.
Lithium diffusion in Li5FeO4
Authors: Kuganathan Navaratnarajah , Iyngaran Poobalasuntharam , Chroneos Alexander
Published: April 2018

The anti-fluorite type Li5FeO4 has attracted significant interest as a potential cathode material for Li ion batteries due to its high Li content and electrochemical performance. Atomic scale simulation techniques have been employed to study the defects and Li ion migration in Li5FeO4. The calculations suggest that the most favorable intrinsic defect type is calculated to be the cation anti-site defect, in which Li+ and Fe3+ ions exchange positions. Li Frenkel is also found to be lower in this material (0.85 eV/defect). Long range lithium diffusion paths were constructed in Li5FeO4 and it is confirmed that the lower migration paths are three dimensional with the lowest activation energy of migration at 0.45 eV. Here we show that doping by Si on the Fe site is energetically favourable and an efficient way to introduce a high concentration of lithium vacancies. The introduction of Si increases the migration energy barrier of Li in the vicinity of the dopant to 0.59 eV. Nevertheless, the introduction of Si is positive for the diffusivity as the migration energy barrier increase is lower less than that of the lithium Frenkel process, therefore the activation energy of Li diffusion.
Author Correction: Disturbance Regimes Drive The Diversity of Regional Floristic Pools Across Guianan Rainforest Landscapes
Authors: Guitet Stéphane , Sabatier Daniel , Brunaux Olivier , Couteron Pierre , Denis Thomas , Freycon Vincent , Gonzalez Sophie , Hérault Bruno , Jaouen Gaëlle , Molino Jean-François , Pélissier Raphaël , Richard-Hansen Cécile , Vincent Grégoire
Published: April 2018

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
Embryonic Exposure to Valproic Acid Impairs Social Predispositions of Newly-Hatched Chicks
Authors: Sgadò Paola , Rosa-Salva Orsola , Versace Elisabetta , Vallortigara Giorgio
Published: April 2018

Biological predispositions to attend to visual cues, such as those associated with face-like stimuli or with biological motion, guide social behavior from the first moments of life and have been documented in human neonates, infant monkeys and domestic chicks. Impairments of social predispositions have been recently reported in neonates at high familial risk of Autism Spectrum Disorder (ASD). Using embryonic exposure to valproic acid (VPA), an anticonvulsant associated to increased risk of developing ASD, we modeled ASD behavioral deficits in domestic chicks. We then assessed their spontaneous social predispositions by comparing approach responses to a stimulus containing a face configuration, a stuffed hen, vs. a scrambled version of it. We found that this social predisposition was abolished in VPA-treated chicks, whereas experience-dependent mechanisms associated with filial imprinting were not affected. Our results suggest a specific effect of VPA on the development of biologically-predisposed social orienting mechanisms, opening new perspectives to investigate the neurobiological mechanisms involved in early ASD symptoms.
A Bowman-Birk type chymotrypsin inhibitor peptide from the amphibian, Hylarana erythraea
Authors: Zhang Luyao , Chen Xiaoling , Wu Yue , Zhou Mei , Ma Chengbang , Xi Xinping , Chen Tianbao , Walker Brian , Shaw Chris , Wang Lei
Published: April 2018

The first amphibian skin secretion-derived Bowman-Birk type chymotrypsin inhibitor is described here from the Asian green frog, Hylarana erythraea, and was identified by use of molecular cloning and tandem mass spectrometric amino acid sequencing. It was named Hylarana erythraea chymotrypsin inhibitor (HECI) and in addition to inhibition of chymotrypsin (Ki = 3.92 ± 0.35 μM), the peptide also inhibited the 20 S proteasome (Ki = 8.55 ± 1.84  μM). Additionally, an analogue of HECI, named K9-HECI, in which Phe9 was substituted by Lys9 at the P1 position, was functional as a trypsin inhibitor. Both peptides exhibited anti-proliferation activity against the human cancer cell lines, H157, PC-3 and MCF-7, up to a concentration of 1 mM and possessed a low degree of cytotoxicity on normal cells, HMEC-1. However, HECI exhibited higher anti-proliferative potency against H157. The results indicate that HECI, inhibiting chymotryptic-like activity of proteasome, could provide new insights in treatment of lung cancer.
Impact of a vegan diet on the human salivary microbiota
Authors: Hansen Tue H. , Kern Timo , Bak Emilie G. , Kashani Alireza , Allin Kristine H. , Nielsen Trine , Hansen Torben , Pedersen Oluf
Published: April 2018

Little is known about the effect of long-term diet patterns on the composition and functional potential of the human salivary microbiota. In the present study, we sought to contribute to the ongoing elucidation of dietary effects on the oral microbial community by examining the diversity, composition and functional potential of the salivary microbiota in 160 healthy vegans and omnivores using 16S rRNA gene amplicon sequencing. We further sought to identify bacterial taxa in saliva associated with host inflammatory markers. We show that compositional differences in the salivary microbiota of vegans and omnivores is present at all taxonomic levels below phylum level and includes upper respiratory tract commensals (e.g. Neisseria subflava, Haemophilus parainfluenzae, and Rothia mucilaginosa) and species associated with periodontal disease (e.g. Campylobacter rectus and Porphyromonas endodontalis). Dietary intake of medium chain fatty acids, piscine mono- and polyunsaturated fatty acids, and dietary fibre was associated with bacterial diversity, community structure, as well as relative abundance of several species-level operational taxonomic units. Analysis of imputed genomic potential revealed several metabolic pathways differentially abundant in vegans and omnivores indicating possible effects of macro- and micro-nutrient intake. We also show that certain oral bacteria are associated with the systemic inflammatory state of the host.
Disposable all-printed electronic biosensor for instantaneous detection and classification of pathogens
Authors: Ali Shawkat , Hassan Arshad , Hassan Gul , Eun Chang-Ho , Bae Jinho , Lee Chong Hyun , Kim In-Jung
Published: April 2018

A novel disposable all-printed electronic biosensor is proposed for a fast detection and classification of bacteria. This biosensor is applied to classify three types of popular pathogens: Salmonella typhimurium, and the Escherichia coli strains JM109 and DH5-α. The proposed sensor consists of inter-digital silver electrodes fabricated through an inkjet material printer and silver nanowires uniformly decorated on the electrodes through the electrohydrodynamic technique on a polyamide based polyethylene terephthalate substrate. The best sensitivity of the proposed sensor is achieved at 200 µm teeth spaces of the inter-digital electrodes along the density of the silver nanowires at 30 × 103/mm2. The biosensor operates on ±2.5 V and gives the impedance value against each bacteria type in 8 min after sample injection. The sample data are measured through an impedance analyzer and analyzed through pattern recognition methods such as linear discriminate analysis, maximum likelihood, and back propagation artificial neural network to classify each type of bacteria. A perfect classification and cross-validation is achieved by using the unique fingerprints extracted from the proposed biosensor through all the applied classifiers. The overall experimental results demonstrate that the proposed disposable all-printed biosensor is applicable for the rapid detection and classification of pathogens.
Bacterial Pore-Forming Toxins Promote the Activation of Caspases in Parallel to Necroptosis to Enhance Alarmin Release and Inflammation During Pneumonia
Authors: Gonzalez-Juarbe Norberto , Bradley Kelley M. , Riegler Ashleigh N. , Reyes Luis F. , Brissac Terry , Park Sang-Sang , Restrepo Marcos I. , Orihuela Carlos J.
Published: April 2018

Pore-forming toxins are the most common virulence factor in pathogenic bacteria. They lead to membrane permeabilization and cell death. Herein, we show that respiratory epithelial cells (REC) undergoing bacterial pore-forming toxin (PFT)-induced necroptosis simultaneously experienced caspase activation independently of RIPK3. MLKL deficient REC treated with a pan-caspase inhibitor were protected in an additive manner against PFT-induced death. Subsequently, cleaved versions of caspases-2, -4 and -10 were detected within REC undergoing necroptosis by immunoblots and monoclonal antibody staining. Caspase activation was observed in lung samples from mice and non-human primates experiencing Gram-negative and Gram-positive bacterial pneumonia, respectively. During apoptosis, caspase activation normally leads to cell shrinkage, nuclear condensation, and immunoquiescent death. In contrast, caspase activity during PFT-induced necroptosis increased the release of alarmins to the extracellular milieu. Caspase-mediated alarmin release was found sufficient to activate resting macrophages, leading to Interleukin-6 production. In a mouse model of Gram-negative pneumonia, deletion of caspases -2 and -11, the mouse orthologue of caspase-4, reduced pulmonary inflammation, immune cell infiltration and lung damage. Thus, our study describes a previously unrecognized role for caspase activation in parallel to necroptosis, and indicates that their activity plays a critical pro-inflammatory role during bacterial pneumonia.
A mega-analysis of expression quantitative trait loci (eQTL) provides insight into the regulatory architecture of gene expression variation in liver
Authors: Strunz Tobias , Grassmann Felix , Gayán Javier , Nahkuri Satu , Souza-Costa Debora , Maugeais Cyrille , Fauser Sascha , Nogoceke Everson , Weber Bernhard H. F.
Published: April 2018

Genome-wide association studies (GWAS) have identified numerous genetic variants in the human genome associated with diseases and traits. Nevertheless, for most loci the causative variant is still unknown. Expression quantitative trait loci (eQTL) in disease relevant tissues is an excellent approach to correlate genetic association with gene expression. While liver is the primary site of gene transcription for two pathways relevant to age-related macular degeneration (AMD), namely the complement system and cholesterol metabolism, we explored the contribution of AMD associated variants to modulate liver gene expression. We extracted publicly available data and computed the largest eQTL data set for liver tissue to date. Genotypes and expression data from all studies underwent rigorous quality control. Subsequently, Matrix eQTL was used to identify significant local eQTL. In total, liver samples from 588 individuals revealed 202,489 significant eQTL variants affecting 1,959 genes (Q-Value < 0.001). In addition, a further 101 independent eQTL signals were identified in 93 of the 1,959 eQTL genes. Importantly, our results independently reinforce the notion that high density lipoprotein metabolism plays a role in AMD pathogenesis. Taken together, our study generated a first comprehensive map reflecting the genetic regulatory landscape of gene expression in liver.
Pro-inflammatory cytokines activate hypoxia-inducible factor 3α via epigenetic changes in mesenchymal stromal/stem cells
Authors: Cuomo Francesca , Coppola Antonietta , Botti Chiara , Maione Ciro , Forte Amalia , Scisciola Lucia , Liguori Giuseppina , Caiafa Ilaria , Ursini Matilde Valeria , Galderisi Umberto , Cipollaro Marilena , Altucci Lucia , Cobellis Gilda
Published: April 2018

Human mesenchymal stromal/stem cells (hMSCs) emerged as a promising therapeutic tool for ischemic disorders, due to their ability to regenerate damaged tissues, promote angiogenesis and reduce inflammation, leading to encouraging, but still limited results. The outcomes in clinical trials exploring hMSC therapy are influenced by low cell retention and survival in affected tissues, partially influenced by lesion’s microenvironment, where low oxygen conditions (i.e. hypoxia) and inflammation coexist. Hypoxia and inflammation are pathophysiological stresses, sharing common activators, such as hypoxia-inducible factors (HIFs) and NF-κB. HIF1α and HIF2α respond essentially to hypoxia, activating pathways involved in tissue repair. Little is known about the regulation of HIF3α. Here we investigated the role of HIF3α in vitro and in vivo. Human MSCs expressed HIF3α, differentially regulated by pro-inflammatory cytokines in an oxygen-independent manner, a novel and still uncharacterized mechanism, where NF-κB is critical for its expression. We investigated if epigenetic modifications are involved in HIF3α expression by methylation-specific PCR and histone modifications. Robust hypermethylation of histone H3 was observed across HIF3A locus driven by pro-inflammatory cytokines. Experiments in a murine model of arteriotomy highlighted the activation of Hif3α expression in infiltrated inflammatory cells, suggesting a new role for Hif3α in inflammation in vivo.
Switching between individual and collective motility in B lymphocytes is controlled by cell-matrix adhesion and inter-cellular interactions
Authors: Rey-Barroso Javier , Calovi Daniel S. , Combe Maud , German Yolla , Moreau Mathieu , Canivet Astrid , Wang Xiaobo , Sire Clément , Theraulaz Guy , Dupré Loïc
Published: April 2018

Lymphocytes alternate between phases of individual migration across tissues and phases of clustering during activation and function. The range of lymphocyte motility behaviors and the identity of the factors that govern them remain elusive. To explore this point, we here collected unprecedented statistics pertaining to cell displacements, cell:matrix and cell:cell interactions using a model B cell line as well as primary human B lymphocytes. At low cell density, individual B lymphocytes displayed a high heterogeneity in their speed and diffusivity. Beyond this intrinsic variability, B lymphocytes adapted their motility to the composition of extra-cellular matrix, adopting slow persistent walks over collagen IV and quick Brownian walks over fibronectin. At high cell density, collagen IV favored the self-assembly of B lymphocytes into clusters endowed with collective coordination, while fibronectin stimulated individual motility. We show that this behavioral plasticity is controlled by acto-myosin dependent adhesive and Arp2/3-dependent protrusive actin pools, respectively. Our study reveals the adaptive nature of B lymphocyte motility and group dynamics, which are shaped by an interplay between and cell:matrix and cell:cell interactions.
Mucin gel assembly is controlled by a collective action of non-mucin proteins, disulfide bridges, Ca2+-mediated links, and hydrogen bonding
Authors: Meldrum Oliver W. , Yakubov Gleb E. , Bonilla Mauricio R. , Deshmukh Omkar , McGuckin Michael A. , Gidley Michael J.
Published: April 2018

Mucus is characterized by multiple levels of assembly at different length scales which result in a unique set of rheological (flow) and mechanical properties. These physical properties determine its biological function as a highly selective barrier for transport of water and nutrients, while blocking penetration of pathogens and foreign particles. Altered integrity of the mucus layer in the small intestine has been associated with a number of gastrointestinal tract pathologies such as Crohn’s disease and cystic fibrosis. In this work, we uncover an intricate hierarchy of intestinal mucin (Muc2) assembly and show how complex rheological properties emerge from synergistic interactions between mucin glycoproteins, non-mucin proteins, and Ca2+. Using a novel method of mucus purification, we demonstrate the mechanism of assembly of Muc2 oligomers into viscoelastic microscale domains formed via hydrogen bonding and Ca2+-mediated links, which require the joint presence of Ca2+ ions and non-mucin proteins. These microscale domains aggregate to form a heterogeneous yield stress gel-like fluid, the macroscopic rheological properties of which are virtually identical to that of native intestinal mucus. Through proteomic analysis, we short-list potential protein candidates implicated in mucin assembly, thus paving the way for identifying the molecules responsible for the physiologically critical biophysical properties of mucus.
Unraveling the compromised biomechanical performance of type 2 diabetes- and Roux-en-Y gastric bypass bone by linking mechanical-structural and physico-chemical properties
Authors: Marin Carlos , Papantonakis Georgios , Sels Kathleen , van Lenthe G. Harry , Falgayrac Guillaume , Vangoitsenhoven Roman , Van der Schueren Bart , Penel Guillaume , Luyten Frank , Vandamme Katleen , Kerckhofs Greet
Published: April 2018

Type 2 diabetes mellitus (T2DM) is a metabolic disorder associated with obesity and hyperglycemia. Roux-en-Y gastric bypass (RYGB) surgery is a common treatment for severely obese patients and T2DM. Both RYGB and T2DM are linked to increased skeletal fragility, though the exact mechanisms are poorly understood. Our aim was to characterize the structural, mechanical and compositional properties of bones from diet-induced obese and RYGB-treated obese (bypass) mice to elucidate which the exact factors are contributing to the increased skeletal fragility. To achieve this, a combinatory approach including microfocus X-ray computed tomography, 3-point bending, finite element modeling and Raman spectroscopy, was used. Compared to aged-matched lean controls, the obese mice displayed decreased cortical thickness, trabecular bone loss, decreased stiffness and increased Young’s modulus. For the bypass mice, these alterations were even more pronounced, and additionally they showed low mineral-to-matrix ratio in the cortical endosteal area. Accumulation of the advanced glycation end-product (AGE) pentosidine was found in the cortex of obese and bypass groups and this accumulation was correlated with an increased Young’s modulus. In conclusion, we found that the increased fracture risk in T2DM- and post-RYGB bones is mainly driven by accumulation of AGEs and macro-structural alterations, generating biomechanical dysfunctionality.
A standardized flow cytometry network study for the assessment of circulating endothelial cell physiological ranges
Authors: Lanuti Paola , Simeone Pasquale , Rotta Gianluca , Almici Camillo , Avvisati Giuseppe , Azzaro Rosa , Bologna Giuseppina , Budillon Alfredo , Di Cerbo Melania , Di Gennaro Elena , Di Martino Maria Luisa , Diodato Annamaria , Doretto Paolo , Ercolino Eva , Falda Alessandra , Gregorj Chiara , Leone Alessandra , Losa Francesca , Malara Natalia , Marini Mirella , Mastroroberto Pasquale , Mollace Vincenzo , Morelli Michele , Muggianu Emma , Musolino Giuseppe , Neva Arabella , Pierdomenico Laura , Pinna Silvia , Piovani Giovanna , Roca Maria Serena , Russo Domenico , Scotti Lorenza , Tirindelli Maria Cristina , Trunzo Valentina , Venturella Roberta , Vitagliano Carlo , Zullo Fulvio , Marchisio Marco , Miscia Sebastiano
Published: April 2018

Circulating endothelial cells (CEC) represent a restricted peripheral blood (PB) cell subpopulation with high potential diagnostic value in many endothelium-involving diseases. However, whereas the interest in CEC studies has grown, the standardization level of their detection has not. Here, we undertook the task to align CEC phenotypes and counts, by standardizing a novel flow cytometry approach, within a network of six laboratories. CEC were identified as alive/nucleated/CD45negative/CD34bright/CD146positive events and enumerated in 269 healthy PB samples. Standardization was demonstrated by the achievement of low inter-laboratory Coefficients of Variation (CVL), calculated on the basis of Median Fluorescence Intensity values of the most stable antigens that allowed CEC identification and count (CVL of CD34bright on CEC ~ 30%; CVL of CD45 on Lymphocytes ~ 20%). By aggregating data acquired from all sites, CEC numbers in the healthy population were captured (medianfemale = 9.31 CEC/mL; medianmale = 11.55 CEC/mL). CEC count biological variability and method specificity were finally assessed. Results, obtained on a large population of donors, demonstrate that the established procedure might be adopted as standardized method for CEC analysis in clinical and in research settings, providing a CEC physiological baseline range, useful as starting point for their clinical monitoring in endothelial dysfunctions.
1.5 °C carbon budget dependent on carbon cycle uncertainty and future non-CO2 forcing
Authors: Mengis Nadine , Partanen Antti-Ilari , Jalbert Jonathan , Matthews H. Damon
Published: April 2018

Estimates of the 1.5 °C carbon budget vary widely among recent studies, emphasizing the need to better understand and quantify key sources of uncertainty. Here we quantify the impact of carbon cycle uncertainty and non-CO2 forcing on the 1.5 °C carbon budget in the context of a prescribed 1.5 °C temperature stabilization scenario. We use Bayes theorem to weight members of a perturbed parameter ensemble with varying land and ocean carbon uptake, to derive an estimate for the fossil fuel (FF) carbon budget of 469 PgC since 1850, with a 95% likelihood range of (411,528) PgC. CO2 emissions from land-use change (LUC) add about 230 PgC. Our best estimate of the total (FF + LUC) carbon budget for 1.5 °C is therefore 699 PgC, which corresponds to about 11 years of current emissions. Non-CO2 greenhouse gas and aerosol emissions represent equivalent cumulative CO2 emissions of about 510 PgC and −180 PgC for 1.5 °C, respectively. The increased LUC, high non-CO2 emissions and decreased aerosols in our scenario, cause the long-term FF carbon budget to decrease following temperature stabilization. In this scenario, negative emissions would be required to compensate not only for the increasing non-CO2 climate forcing, but also for the declining natural carbon sinks.
Accurate estimation of 5-methylcytosine in mammalian mitochondrial DNA
Authors: Matsuda Shigeru , Yasukawa Takehiro , Sakaguchi Yuriko , Ichiyanagi Kenji , Unoki Motoko , Gotoh Kazuhito , Fukuda Kei , Sasaki Hiroyuki , Suzuki Tsutomu , Kang Dongchon
Published: April 2018

Whilst 5-methylcytosine (5mC) is a major epigenetic mark in the nuclear DNA in mammals, whether or not mitochondrial DNA (mtDNA) receives 5mC modification remains controversial. Herein, we exhaustively analysed mouse mtDNA using three methods that are based upon different principles for detecting 5mC. Next-generation bisulfite sequencing did not give any significant signatures of methylation in mtDNAs of liver, brain and embryonic stem cells (ESCs). Also, treatment with methylated cytosine-sensitive endonuclease McrBC resulted in no substantial decrease of mtDNA band intensities in Southern hybridisation. Furthermore, mass spectrometric nucleoside analyses of highly purified liver mtDNA preparations did not detect 5-methyldeoxycytidine at the levels found in the nuclear DNA but at a range of only 0.3–0.5% of deoxycytidine. Taken together, we propose that 5mC is not present at any specific region(s) of mtDNA and that levels of the methylated cytosine are fairly low, provided the modification occurs. It is thus unlikely that 5mC plays a universal role in mtDNA gene expression or mitochondrial metabolism.
Snf1/AMPK is involved in the mitotic spindle alignment in Saccharomyces cerevisiae
Authors: Tripodi Farida , Fraschini Roberta , Zocchi Monica , Reghellin Veronica , Coccetti Paola
Published: April 2018

Before anaphase onset, budding yeast cells must align the mitotic spindle parallel to the mother-bud axis to ensure proper chromosome segregation. The protein kinase Snf1/AMPK is a highly conserved energy sensor, essential for adaptation to glucose limitation and in response to cellular stresses. However, recent findings indicate that it plays important functions also in non-limiting glucose conditions. Here we report a novel role of Snf1/AMPK in the progression through mitosis in glucose-repressing condition. We show that active Snf1 is localized to the bud neck from bud emergence to cytokinesis in a septin-dependent manner. In addition, loss of Snf1 induces a delay of the metaphase to anaphase transition that is due to a defect in the correct alignment of the mitotic spindle. In particular, genetic data indicate that Snf1 promotes spindle orientation acting in parallel with Dyn1 and in concert with Kar9. Altogether this study describes a new role for Snf1 in mitosis and connects cellular metabolism to mitosis progression.
Proteomic profiling of human cancer pseudopodia for the identification of anti-metastatic drug candidates
Authors: Choi Sunkyu , Bhagwat Aditya M. , Al Mismar Rasha , Goswami Neha , Ben Hamidane Hisham , Sun Lu , Graumann Johannes
Published: April 2018

Cancer metastasis causes approximately 90% of all cancer-related death and independent of the advancement of cancer therapy, a majority of late stage patients suffers from metastatic cancer. Metastasis implies cancer cell migration and invasion throughout the body. Migration requires the formation of pseudopodia in the direction of movement, but a detailed understanding of this process and accordingly strategies of prevention remain elusive. Here, we use quantitative proteomic profiling of human cancer pseudopodia to examine this mechanisms essential to metastasis formation, and identify potential candidates for pharmacological interference with the process. We demonstrate that Prohibitins (PHBs) are significantly enriched in the pseudopodia fraction derived from cancer cells, and knockdown of PHBs, as well as their chemical inhibition through Rocaglamide (Roc-A), efficiently reduces cancer cell migration.
Phylogeny, biogeography and methodology: a meta-analytic perspective on heterogeneity in adult marine turtle survival rates
Authors: Pfaller Joseph B. , Chaloupka Milani , Bolten Alan B. , Bjorndal Karen A.
Published: April 2018

Comparative syntheses of key demographic parameters are critical not only for identifying data gaps, but also for evaluating sources of heterogeneity among estimates. Because demographic studies frequently exhibit heterogeneity, evaluating sources of heterogeneity among estimates can inform biological patterns and conservation actions more broadly. To better understand adult survival in marine turtles and avoid drawing inaccurate conclusions from current estimates, we conducted a comprehensive meta-analysis to test how heterogeneity among estimates was partitioned among phylogenetic, biogeographic and methodological factors. Fifty-nine studies from five marine turtle species met the minimum selection criteria for inclusion in our meta-analysis. Heterogeneity among survival estimates was first partitioned between differences in ocean basin (Indo-PacificversusAtlantic), then by differences among family/tribe within the Indo-Pacific (CheloniniversusCarettini and Dermochelidae). However, apparent differences attributed to biogeography (ocean basin effect) and phylogeny (family/tribe effect) were highly correlated with methodological differences in tag type, model type, habitat type and study duration, thereby confounding biological interpretations and complicating efforts to use many current survival estimates in population assessments. Our results highlight the importance of evaluating sources of heterogeneity when interpreting patterns among similar demographic studies and directly inform efforts to identify research priorities for marine turtles globally.
Recurrent Neural Networks for Multivariate Time Series with Missing Values
Authors: Che Zhengping , Purushotham Sanjay , Cho Kyunghyun , Sontag David , Liu Yan
Published: April 2018

Multivariate time series data in practical applications, such as health care, geoscience, and biology, are characterized by a variety of missing values. In time series prediction and other related tasks, it has been noted that missing values and their missing patterns are often correlated with the target labels, a.k.a., informative missingness. There is very limited work on exploiting the missing patterns for effective imputation and improving prediction performance. In this paper, we develop novel deep learning models, namely GRU-D, as one of the early attempts. GRU-D is based on Gated Recurrent Unit (GRU), a state-of-the-art recurrent neural network. It takes two representations of missing patterns, i.e., masking and time interval, and effectively incorporates them into a deep model architecture so that it not only captures the long-term temporal dependencies in time series, but also utilizes the missing patterns to achieve better prediction results. Experiments of time series classification tasks on real-world clinical datasets (MIMIC-III, PhysioNet) and synthetic datasets demonstrate that our models achieve state-of-the-art performance and provide useful insights for better understanding and utilization of missing values in time series analysis.
Comparative biogeography of the gut microbiome between Jinhua and Landrace pigs
Authors: Xiao Yingping , Kong Fanli , Xiang Yun , Zhou Weidong , Wang Junjun , Yang Hua , Zhang Guolong , Zhao Jiangchao
Published: April 2018

The intestinal microbiome is critically important in shaping a variety of host physiological responses. However, it remains elusive on how gut microbiota impacts overall growth and more specifically, adipogenesis. Using the pig as an animal model, we compared the differences in bacterial community structure throughout the intestinal tract in two breeds (Landrace and Jinhua) of pigs with distinct phenotypes. The Landrace is a commercial purebred and the Jinhua is a Chinese indigenous, slow-growing breed with high propensity for fat deposition. Using 16S rRNA gene sequencing, we revealed that the bacterial communities are more diverse in the duodenum, jejunum, and cecum of Jinhua pigs than in those of Landrace pigs, whereas the ileal and colonic microbiota show a similar complexity between the two breeds. Furthermore, a number of bacterial taxa differentially exist in Jinhua and Landrace pigs throughout the entire intestinal tract, with the jejunal and ileal microbiome showing the greatest contrast. Functional prediction of the bacterial community suggested increased fatty acid biosynthesis in Jinghua pigs, which could partially explain their adiposity phenotype. Further studies are warranted to experimentally verify the relative contribution of each enriched bacterial species and their effect on adipogenesis and animal growth.
Low-level mitochondrial heteroplasmy modulates DNA replication, glucose metabolism and lifespan in mice
Authors: Hirose Misa , Schilf Paul , Gupta Yask , Zarse Kim , Künstner Axel , Fähnrich Anke , Busch Hauke , Yin Junping , Wright Marvin N. , Ziegler Andreas , Vallier Marie , Belheouane Meriem , Baines John F , Tautz Diethard , Johann Kornelia , Oelkrug Rebecca , Mittag Jens , Lehnert Hendrik , Othman Alaa , Jöhren Olaf , Schwaninger Markus , Prehn Cornelia , Adamski Jerzy , Shima Kensuke , Rupp Jan , Häsler Robert , Fuellen Georg , Köhling Rüdiger , Ristow Michael , Ibrahim Saleh M.
Published: April 2018

Mutations in mitochondrial DNA (mtDNA) lead to heteroplasmy, i.e., the intracellular coexistence of wild-type and mutant mtDNA strands, which impact a wide spectrum of diseases but also physiological processes, including endurance exercise performance in athletes. However, the phenotypic consequences of limited levels of naturally arising heteroplasmy have not been experimentally studied to date. We hence generated a conplastic mouse strain carrying the mitochondrial genome of an AKR/J mouse strain (B6-mtAKR) in a C57BL/6 J nuclear genomic background, leading to >20% heteroplasmy in the origin of light-strand DNA replication (OriL). These conplastic mice demonstrate a shorter lifespan as well as dysregulation of multiple metabolic pathways, culminating in impaired glucose metabolism, compared to that of wild-type C57BL/6 J mice carrying lower levels of heteroplasmy. Our results indicate that physiologically relevant differences in mtDNA heteroplasmy levels at a single, functionally important site impair the metabolic health and lifespan in mice.
The value of radial endobronchial ultrasound-guided bronchial brushing in peripheral non-squamous non-small cell lung cancer
Authors: Yu Kai-Lun , Tsai Tzu-Hsiu , Ho Chao-Chi , Liao Wei-Yu , Lin Ching-Kai , Hsu Chia-Lin , Shih Jin-Yuan
Published: April 2018

Radial endobronchial ultrasound (R-EBUS) is one important diagnostic approach in non-small cell lung cancers (NSCLC). However, the small samples obtained from R-EBUS-guided transbronchial biopsies are sometimes insufficient for pathological and molecular diagnosis. Herein, we investigated the suitability of R-EBUS-guided bronchial brushing specimens for NSCLC diagnosis and EGFR genotyping. We enrolled 941 consecutive patients with peripheral pulmonary lesions who underwent R-EBUS. Cytology-positive brushing specimens from non-squamous NSCLC patients were tested for EGFR mutations. Non-squamous NSCLC was diagnosed in 624 patients (66.3%). Positive cytology was documented in the brushing samples of 376 patients (60.3%). Higher diagnostic yields were obtained in patients exhibiting bronchus signs on chest tomography, and those with R-EBUS probe located within the lesion. EGFR genotyping was successfully performed in 363 samples (96.5% of cytology-positive brushing samples). EGFR genotyping concordance between brushing specimens and matched tissue samples was 88.7% (kappa = 0.745, P < 0.001). Furthermore, 144 non-squamous NSCLC patients (23.1%) with failed pathological diagnosis or EGER sequencing by R-EBUS-guided transbronchial biopsy required repeat biopsies. However, it was achieved successfully from the brushing specimens of 57 patients (39.6%). In conclusion, for patients with peripheral lung cancer, R-EBUS-guided bronchial brushing could provide an additional sampling method for diagnosis and EGFR genotyping.
Genome wide analysis of the transition to pathogenic lifestyles in Magnaporthales fungi
Authors: Zhang Ning , Cai Guohong , Price Dana C. , Crouch Jo Anne , Gladieux Pierre , Hillman Bradley , Khang Chang Hyun , LeBrun Marc-Henri , Lee Yong-Hwan , Luo Jing , Qiu Huan , Veltri Daniel , Wisecaver Jennifer H. , Zhu Jie , Bhattacharya Debashish
Published: April 2018

The rice blast fungus Pyricularia oryzae (syn. Magnaporthe oryzae, Magnaporthe grisea), a member of the order Magnaporthales in the class Sordariomycetes, is an important plant pathogen and a model species for studying pathogen infection and plant-fungal interaction. In this study, we generated genome sequence data from five additional Magnaporthales fungi including non-pathogenic species, and performed comparative genome analysis of a total of 13 fungal species in the class Sordariomycetes to understand the evolutionary history of the Magnaporthales and of fungal pathogenesis. Our results suggest that the Magnaporthales diverged ca. 31 millon years ago from other Sordariomycetes, with the phytopathogenic blast clade diverging ca. 21 million years ago. Little evidence of inter-phylum horizontal gene transfer (HGT) was detected in Magnaporthales. In contrast, many genes underwent positive selection in this order and the majority of these sequences are clade-specific. The blast clade genomes contain more secretome and avirulence effector genes, which likely play key roles in the interaction between Pyricularia species and their plant hosts. Finally, analysis of transposable elements (TE) showed differing proportions of TE classes among Magnaporthales genomes, suggesting that species-specific patterns may hold clues to the history of host/environmental adaptation in these fungi.
Pretreatment rate of decay in forced vital capacity predicts long-term response to pirfenidone in patients with idiopathic pulmonary fibrosis
Authors: Biondini Davide , Balestro Elisabetta , Lacedonia Donato , Cerri Stefania , Milaneschi Rosanna , Luppi Fabrizio , Cocconcelli Elisabetta , Bazzan Erica , Clini Enrico , Foschino Barbaro Maria Pia , Gregori Dario , Cosio Manuel G , Saetta Marina , Spagnolo Paolo
Published: April 2018

Pirfenidone reduces functional decline in patients with Idiopathic Pulmonary Fibrosis (IPF). However, response to treatment is highly heterogeneous. We sought to evaluate whether response to pirfenidone is influenced by the pretreatment rate of forced vital capacity (FVC) decline. Fifty-six IPF patients were categorized as rapid (RP) or slow progressors (SP) based on whether their FVC decline in the year preceding pirfenidone treatment was > or ≤ 10% predicted. Following pirfenidone treatment patients were followed-up every 6 months and up to 24 months. In the entire population, pirfenidone reduced significantly FVC decline from 231 to 49 ml/year at 6 months (T6) (p = 0.003) and this effect was maintained at the 12-, 18- and 24-month time points (p value for trend n.s.). In RP, the reduction of FVC decline was evident at 6 months (36 vs 706 ml/year pretreatment; p = 0.002) and maintained, though to a lesser degree, at 12 (106 ml/year), 18 (176 ml/year) and 24 months (162 ml/year; p value for trend n.s). Among SP, the reduction in FVC decline was not significant at any of the time points analyzed. In conclusion, pirfenidone reduces FVC decline in IPF patients. However, its beneficial effect is more pronounced in patients with rapidly progressive disease.