bluuebunny/crossref_metadata_2025 huggingface dataset:
Revisiting the functional significance of binocular cues for perceiving motion-in-depth
Authors: Kohler Peter J. , Meredith Wesley J. , Norcia Anthony M.
Published: August 2018

Binocular differencing of spatial cues required for perceiving depth relationships is associated with decreased sensitivity to the corresponding retinal image displacements. However, binocular summation of contrast signals increases sensitivity. Here, we investigated this divergence in sensitivity by making direct neural measurements of responses to suprathreshold motion in human adults and 5-month-old infants using steady-state visually evoked potentials. Interocular differences in retinal image motion generated suppressed response functions and correspondingly elevated perceptual thresholds compared to motion matched between the two eyes. This suppression was of equal strength for horizontal and vertical motion and therefore not specific to the perception of motion-in-depth. Suppression is strongly dependent on the presence of spatial references in the image and highly immature in infants. Suppression appears to be the manifestation of a succession of spatial and interocular opponency operations that occur at an intermediate processing stage either before or in parallel with the extraction of motion-in-depth.
P38α/JNK signaling restrains erythropoiesis by suppressing Ezh2-mediated epigenetic silencing of Bim
Authors: Hu Ping , Nebreda Angel R. , Hanenberg Helmut , Kinnebrew Garrett H. , Ivan Mircea , Yoder Mervin C. , Filippi Marie-Dominique , Broxmeyer Hal E. , Kapur Reuben
Published: August 2018

While erythropoietin (EPO) constitutes the major treatment for anemia, a range of anemic disorders remain resistant to EPO treatment. The need for alternative therapeutic strategies requires the identification of mechanisms that physiologically restrain erythropoiesis. Here we show that P38α restrains erythropoiesis in mouse and human erythroblasts independently of EPO by integrating apoptotic signals during recovery from anemia. P38α deficiency promotes JNK activation through increased expression of Map3k4 via a negative feedback mechanism. JNK prevents Cdk1-mediated phosphorylation and subsequent degradation by Smurf2 of the epigenetic silencer Ezh2. Stabilized Ezh2 silences Bim expression and protects erythroblasts from apoptosis. Thus, we identify P38α/JNK signaling as a molecular brake modulating erythropoiesis through epigenetic silencing of Bim. We propose that inhibition of P38α, by enhancing erythropoiesis in an EPO-independent fashion, may provide an alternative strategy for the treatment of anemia.
A molecular switch orchestrates enzyme specificity and secretory granule morphology
Authors: Ji Suena , Samara Nadine L. , Revoredo Leslie , Zhang Liping , Tran Duy T. , Muirhead Kayla , Tabak Lawrence A. , Ten Hagen Kelly G.
Published: August 2018

Regulated secretion is an essential process where molecules destined for export are directed to membranous secretory granules, where they undergo packaging and maturation. Here, we identify a gene (pgant9) that influences the structure and shape of secretory granules within the Drosophila salivary gland. Loss of pgant9, which encodes an O-glycosyltransferase, results in secretory granules with an irregular, shard-like morphology, and altered glycosylation of cargo. Interestingly, pgant9 undergoes a splicing event that acts as a molecular switch to alter the charge of a loop controlling access to the active site of the enzyme. The splice variant with the negatively charged loop glycosylates the positively charged secretory cargo and rescues secretory granule morphology. Our study highlights a mechanism for dictating substrate specificity within the O-glycosyltransferase enzyme family. Moreover, our in vitro and in vivo studies suggest that the glycosylation status of secretory cargo influences the morphology of maturing secretory granules.
The photoregulation of a mechanochemical polymer scission
Authors: Kida Jumpei , Imato Keiichi , Goseki Raita , Aoki Daisuke , Morimoto Masakazu , Otsuka Hideyuki
Published: August 2018

Control over mechanochemical polymer scission by another external stimulus may offer an avenue to further advance the fields of polymer chemistry, mechanochemistry, and materials science. Herein, we demonstrate that light can regulate the mechanochemical behavior of a diarylethene-conjugated Diels–Alder adduct (DAE/DA) that reversibly isomerizes from a weaker open form to a stronger closed form under photoirradiation. Pulsed ultrasonication experiments, spectroscopic analyses, and density functional theory calculations support the successful photoregulation of the reactivity of this DAE/DA mechanophore, which is incorporated at the mid-chain of a polymer, and indicate that higher force and energy are required to cleave the closed form of the DAE/DA mechanophore relative to the open form. The present photoregulation concept provides an attractive approach toward the generation of new mechanofunctional polymers.
The dominant role of critical valence fluctuations on high Tc superconductivity in heavy fermions
Authors: Scheerer Gernot W. , Ren Zhi , Watanabe Shinji , Lapertot Gérard , Aoki Dai , Jaccard Didier , Miyake Kazumasa
Published: August 2018

Despite almost 40 years of research, the origin of heavy-fermion superconductivity is still strongly debated. Especially, the pressure-induced enhancement of superconductivity in CeCu2Si2 away from the magnetic breakdown is not sufficiently taken into consideration. As recently reported in CeCu2Si2 and several related compounds, optimal superconductivity occurs at the pressure of a valence crossover, which arises from a virtual critical end point at negative temperature Tcr. In this context, we did a meticulous analysis of a vast set of top-quality high-pressure electrical resistivity data of several Ce-based heavy fermion compounds. The key novelty is the salient correlation between the superconducting transition temperature Tc and the valence instability parameter Tcr, which is in line with theory of enhanced valence fluctuations. Moreover, it is found that, in the pressure region of superconductivity, electrical resistivity is governed by the valence crossover, which most often manifests in scaling behavior. We develop the new idea that the optimum superconducting Tc of a given sample is mainly controlled by the compound’s Tcr and limited by non-magnetic disorder. In this regard, the present study provides compelling evidence for the crucial role of critical valence fluctuations in the formation of Cooper pairs in Ce-based heavy fermion superconductors besides the contribution of spin fluctuations near magnetic quantum critical points, and corroborates a plausible superconducting mechanism in strongly correlated electron systems in general.
Adaptation reveals sensory and decision components in the visual estimation of locomotion speed
Authors: Mather George , Parsons Todd
Published: August 2018

Locomotion speed provides important social information about an individual’s fitness, mood and intent. Visual estimation of locomotion speed is a complex task for the visual system because viewing distance must be taken into account, and the estimate has to be calibrated by recent experience of typical speeds. Little is known about how locomotion speed judgements are made. Previous research indicates that the human visual system possesses neurons that respond specifically to moving human forms. This research used point-light walker (PLW) displays that are known to activate these cells, in order to investigate the process mediating locomotion speed judgements. The results of three adaptation experiments show that these judgements involve both a low-level sensory component and a high-level decision component. A simple theoretical scheme is proposed, in which neurons sensitive to image flicker rate (temporal frequency) provide a sensory speed code, and a benchmark ‘norm’ value of the speed code, based on prevailing locomotion speeds, is used to make decisions about objective speed. The output of a simple computational model of the scheme successfully captured variations in locomotion speed in the stimuli used in the experiments. The theory offers a biologically-motivated account of how locomotion speed can be visually estimated.
Gas exchange mechanisms in preterm infants on HFOV – a computational approach
Authors: Roth Christian J. , Förster Kai M. , Hilgendorff Anne , Ertl-Wagner Birgit , Wall Wolfgang A. , Flemmer Andreas W.
Published: August 2018

High-frequency oscillatory ventilation (HFOV) is a commonly used therapy applied to neonates requiring ventilatory support during their first weeks of life. Despite its wide application, the underlying gas exchange mechanisms promoting the success of HVOF in neonatal care are not fully understood until today. In this work, a highly resolved computational lung model, derived from Magnetic Resonance Imaging (MRI) and Infant Lung Function Testing (ILFT), is used to reveal the reason for highly efficient gas exchange during HFOV, in the preterm infant. In total we detected six mechanisms that facilitate gas exchange during HFOV: (i) turbulent vortices in large airways; (ii) asymmetric in- and expiratory flow profiles; (iii) radial mixing in main bronchi; (iv) laminar flow in higher generations of the respiratory tract; (v) pendelluft; (vi) direct ventilation of central alveoli. The illustration of six specific gas transport phenomena during HFOV in preterm infants advances general knowledge on protective ventilation in neonatal care and can support decisions on various modes of ventilatory therapy at high frequencies.
Local probe for connectivity and coupling strength in quantum complex networks
Authors: Nokkala Johannes , Maniscalco Sabrina , Piilo Jyrki
Published: August 2018

We develop a local probe to estimate the connectivity of complex quantum networks. Our results show how global properties of different classes of complex networks can be estimated – in quantitative manner with high accuracy – by coupling a probe to a single node of the network. Here, our interest is focused on probing the connectivity, i.e. the degree sequence, and the value of the coupling constant within the complex network. The scheme combines results on classical graph theory with the ability to develop quantum probes for networks of quantum harmonic oscillators. Whilst our results are proof-of-principle type, within the emerging field of quantum complex networks they may have potential applications for example to the efficient transfer of quantum information or energy or possibly to shed light on the connection between network structure and dynamics.
Precipitous change of the irreversible strain limit with heat-treatment temperature in Nb3Sn wires made by the restacked-rod process
Authors: Cheggour Najib , Stauffer Theodore C. , Starch William , Lee Peter J. , Splett Jolene D. , Goodrich Loren F. , Ghosh Arup K.
Published: August 2018

The intrinsic irreversible strain limit εirr,0 of Nb3Sn superconducting wires, made by the restacked-rod process and doped with either Ti or Ta, undergoes a precipitous change as a function of temperature θ of the final heat-treatment for forming the A15 phase. Nb3Sn transitions from a highly brittle state where it cracks as soon as it is subjected to an axial tensile strain of any measurable amount, to a state more resilient to tensile strain as high as 0.4%. The remarkable abruptness of this transition (as most of it occurs over a range of only 10 °C) could pose real challenges for the heat-treatment of large magnets, such as those fabricated for the high-luminosity upgrade of the Large Hadron Collider (LHC). We named this behavior the strain irreversibility cliff (SIC) to caution magnet developers. The approach to fulfilling application requirements just in terms of the conductor’s residual resistivity ratio RRR and critical-current density Jc is incomplete. Along with RRR and Jc wire specifications, and sub-element size requirements that reduce wire magnetization and instabilities effects, SIC imposes additional constraints on the choice of heat-treatment conditions to ensure mechanical integrity of the conductor.
A Sensitive Thresholding Method for Confocal Laser Scanning Microscope Image Stacks of Microbial Biofilms
Authors: Luo Ting L. , Eisenberg Marisa C. , Hayashi Michael A. L. , Gonzalez-Cabezas Carlos , Foxman Betsy , Marrs Carl F. , Rickard Alexander H.
Published: August 2018

Biofilms are surface-attached microbial communities whose architecture can be captured with confocal microscopy. Manual or automatic thresholding of acquired images is often needed to help distinguish biofilm biomass from background noise. However, manual thresholding is subjective and current automatic thresholding methods can lead to loss of meaningful data. Here, we describe an automatic thresholding method designed for confocal fluorescent signal, termed the biovolume elasticity method (BEM). We evaluated BEM using confocal image stacks of oral biofilms grown in pooled human saliva. Image stacks were thresholded manually and automatically with three different methods; Otsu, iterative selection (IS), and BEM. Effects on biovolume, surface area, and number of objects detected indicated that the BEM was the least aggressive at removing signal, and provided the greatest visual and quantitative acuity of single cells. Thus, thresholding with BEM offers a sensitive, automatic, and tunable method to maintain biofilm architectural properties for subsequent analysis.
Effects of Compositional Tailoring on Drug Delivery Behaviours of Silica Xerogel/Polymer Core-shell Composite Nanoparticles
Authors: Huang Wenfei , Tsui Chi Pong , Tang Chak Yin , Gu Linxia
Published: August 2018

Conventional core-shell polymer nanoparticles usually exhibit a rapid release rate with their release kinetics mainly adjusted through changing composition of the polymer shells, limiting their applications for prolonged drug delivery. As a solution to these problems, silica xerogel/polymer core-shell-structured composite nanoparticles have been proposed. Different with our previous work centring on studying process variables, we here focused on investigating the effects of key compositional variables on essential properties of the composite nanoparticles. The drug release profiles (in vitro) were well interpreted by the Baker and Lonsdale model on a predicted two-stage basis. The first stage (<1 day) was well controlled from 18.6% to 45.9%; the second stage (1–14 days) was tailored in a range from 28.7 to 58.2% by changing the composition of the silica xerogel cores and polymeric shells. A substantial achievement was reducing the release rate by more than 40 times compared with that of conventional polymer nanoparticles by virtue of the silica xerogel cores. A semi-empirical model was also established in the first attempt to describe the effects of polymer concentration and drug loading capacity on the size of the composite nanoparticles. All these results indicated that the composite nanoparticles are promising candidates for prolonged drug delivery applications.
Rab GTPase regulation of bacteria and protozoa phagocytosis occurs through the modulation of phagocytic receptor surface expression
Authors: Seixas Elsa , Escrevente Cristina , Seabra Miguel C. , Barral Duarte C.
Published: August 2018

Phagocytosis of invading microorganisms by professional phagocytic cells has a central role in innate immunity. However, several microorganisms developed strategies to subvert this process. Previously, we reported that bacteria and protozoa modulate differently the expression of Rab GTPases. Moreover, our results suggested that this modulation can contribute to avoid phagocytosis. Here, we investigated the mechanism by which the malaria parasite Plasmodium berghei and the bacterium Escherichia coli subvert phagocytosis through the modulation of Rab14 or Rab9a expression, respectively. We first confirmed that the scavenger receptor CD36 and the Toll-like receptor (TLR) 4 are required for the phagocytosis of P. berghei and E. coli, respectively. Interestingly, we observed that Rab14 silencing leads to an increase in the surface expression of CD36 in macrophages, which can explain the increase in the phagocytosis of P. berghei we reported previously. Similar results were obtained for Rab9a and TLR4, i.e. Rab9a silencing causes an upregulation of TLR4 surface expression in macrophages. Furthermore, we found that the decrease in the internalization of CD36 and TLR4, upon Rab14 or Rab9a silencing, respectively, can explain the increase in the surface levels of these receptors. Thus, our studies provide evidence that the modulation of phagocytosis caused by changes in Rab expression is operated, at least partly through changes in the surface levels of phagocytic receptors.
Weighted Stochastic Block Models of the Human Connectome across the Life Span
Authors: Faskowitz Joshua , Yan Xiaoran , Zuo Xi-Nian , Sporns Olaf
Published: August 2018

The human brain can be described as a complex network of anatomical connections between distinct areas, referred to as the human connectome. Fundamental characteristics of connectome organization can be revealed using the tools of network science and graph theory. Of particular interest is the network’s community structure, commonly identified by modularity maximization, where communities are conceptualized as densely intra-connected and sparsely inter-connected. Here we adopt a generative modeling approach called weighted stochastic block models (WSBM) that can describe a wider range of community structure topologies by explicitly considering patterned interactions between communities. We apply this method to the study of changes in the human connectome that occur across the life span (between 6–85 years old). We find that WSBM communities exhibit greater hemispheric symmetry and are spatially less compact than those derived from modularity maximization. We identify several network blocks that exhibit significant linear and non-linear changes across age, with the most significant changes involving subregions of prefrontal cortex. Overall, we show that the WSBM generative modeling approach can be an effective tool for describing types of community structure in brain networks that go beyond modularity.
Regional disparities in warm season rainfall changes over arid eastern–central Asia
Authors: Dong Wenhao , Lin Yanluan , Wright Jonathon S. , Xie Yuanyu , Ming Yi , Zhang Han , Chen Rensheng , Chen Yaning , Xu Fanghua , Lin Namei , Yu Chaoqing , Zhang Bin , Jin Shuang , Yang Kun , Li Zhongqin , Guo Jianping , Wang Lei , Lin Guanghui
Published: August 2018

Multiple studies have reported a shift in the trend of warm season rainfall over arid eastern–central Asia (AECA) around the turn of the new century, from increasing over the second half of the twentieth century to decreasing during the early years of the twenty-first. Here, a closer look based on multiple precipitation datasets reveals important regional disparities in these changes. Warm-season rainfall increased over both basin areas and mountain ranges during 1961–1998 due to enhanced moisture flux convergence associated with changes in the large-scale circulation and increases in atmospheric moisture content. Despite a significant decrease in warm-season precipitation over the high mountain ranges after the year 1998, warm season rainfall has remained large over low-lying basin areas. This discrepancy, which is also reflected in changes in river flow, soil moisture, and vegetation, primarily results from disparate responses to enhanced warming in the mountain and basin areas of AECA. In addition to changes in the prevailing circulation and moisture transport patterns, the decrease in precipitation over the mountains has occurred mainly because increases in local water vapor saturation capacity (which scales with temperature) have outpaced the available moisture supply, reducing relative humidity and suppressing precipitation. By contrast, rainfall over basin areas has been maintained by accelerated moisture recycling driven by rapid glacier retreat, snow melt, and irrigation expansion. This trend is unsustainable and is likely to reverse as these cryospheric buffers disappear, with potentially catastrophic implications for local agriculture and ecology.
Stress response of Escherichia coli to essential oil components – insights on low-molecular-weight proteins from MALDI-TOF
Authors: Božik Matěj , Cejnar Pavel , Šašková Martina , Nový Pavel , Maršík Petr , Klouček Pavel
Published: August 2018

The antibacterial effects of essential oils and their components (EOCs) are usually attributed to effects on membranes and metabolism. Studies of the effects of EOCs on protein expression have primarily analysed proteins larger than 10 kDa using gel electrophoresis. In the present study, we used MALDI-TOF-MS to investigate the effects of EOCs on low-molecular-weight proteins. From 297 m/z features, we identified 94 proteins with important differences in expression among untreated samples, samples treated with EOCs, and samples treated with antibiotics, peroxide, or chlorine. The targets of these treatments obviously differ, even among EOCs. In addition to ribosomal proteins, stress-, membrane- and biofilm-related proteins were affected. These findings may provide a basis for identifying new targets of essential oils and synergies with other antibiotics.
Differentiation and comparison of Wolfiporia cocos raw materials based on multi-spectral information fusion and chemometric methods
Authors: Li Yan , Wang Yuanzhong
Published: August 2018

In order to achieve the target of deeper insight into the differentiation and comparison of Wolfiporia cocos, a total of 350 samples including distinct growth patterns, various collection regions and different medicinal parts were investigated using multi-spectral information fusion based on ultraviolet (UV) and Fourier transform infrared (FT-IR) spectroscopies coupled with chemometrics. From the results, the discrimination of samples was obtained successfully and good classification performances were shown according to partial least squares discriminant analysis (PLS-DA) models. Comparatively, the distinctness of chemical information in the two medicinal parts of W. cocos were much more than that in the same part with different growth patterns and collection areas. Meanwhile, an interesting finding suggested that growth patterns rather than geographical origins could be the dominant factor to effect the chemical properties of the same part samples, especially for the epidermis. Compared with the epidermis samples, there were better quality consistency for the inner part of W. cocos. Totally, this study demonstrated that the developed method proved to be reliable to perform comparative analysis of W. cocos. Moreover, it could provide more comprehensive chemical evidence for the critical supplement of quality assessment on the raw materials of W. cocos.
Seroprevalence of Maternal and Cord Antibodies Specific for Diphtheria, Tetanus, Pertussis, Measles, Mumps and Rubella in Shunyi, Beijing
Authors: Meng Qing-hong , Liu Ying , Yu Jin-qian , Li Li-jun , Shi Wei , Shen Ying-jie , Li Li , Zhan Shi-na , Yang Fan , Wang Ya-juan , Yao Kai-hu
Published: August 2018

Maternal antibodies contribute to the protection of young infants from infectious diseases during the early life. However, vaccinations for women of child-bearing age are not routine in China. Therefore, we investigated the level of protective immunity against vaccine preventable diseases in pregnant women and newborns in China. A total of 194 paired maternal and cord blood samples were collected in Beijing from 2016 to 2017. Antibodies specific for the antigens covered by diphtheria-tetanus-pertussis (DTP) and measles-mumps-rubella (MMR) vaccine were determined by ELISA (Euroimmun, Lübeck, Germany). The cut off value of ≥0.1 IU/ml (anti-diphtheria), >0.1 IU/ml (anti-tetanus), >40 IU/ml (anti-pertussis toxin), ≥200 IU/l (anti-measles), ≥45 RU/ml (anti-mumps) and ≥10 IU/ml (anti-rubella) were used to assess the percentage of newborns with protective IgG concentrations, respectively. The results revealed that 61.3%, 73.2%, 97.4%, 30.4%, 65.5% and 17.0% of newborns had no protection against diphtheria, tetanus, pertussis, measles, mumps and rubella. Only 1.0% and 23.7% of newborns had protection against all three components of DTP or MMR, respectively. The finding suggested that most of newborns were susceptible to diphtheria, tetanus, pertussis and mumps, almost one-third of this population had no immune protection against measles, and about one-sixth of them were under threat of rubella infection. These data supported the immunization program for DTP and MMR vaccine in women at child-bearing age.
The Alboran volcanic-arc modulated the Messinian faunal exchange and salinity crisis
Authors: Booth-Rea Guillermo , R. Ranero César , Grevemeyer Ingo
Published: August 2018

What process triggered the Mediterranean Sea restriction remains debated since the discovery of the Messinian Salinity Crisis (MSC). Recent hypotheses infer that the MSC initiated after the closure of the Atlantic-Mediterranean Betic and Rifean corridors, being modulated through restriction at the Gibraltar Strait. These hypotheses however, do not integrate contemporaneous speciation patterns of the faunal exchange between Iberia and Africa and several geological features like the evaporite distribution. Exchange of terrestrial biota occurred before, during and after the MSC, and speciation models support an exchange path across the East Alborán basin (EAB) located a few hundreds of km east of the Gibraltar Strait. Yet, a structure explaining jointly geological and biological observations has remained undiscovered. We present new seismic data showing the velocity structure of a well-differentiated 14–17-km thick volcanic arc in the EAB. Isostatic considerations support that the arc-crust buoyancy created an archipelago leading to a filter bridge across the EAB. Sub-aerial erosional unconformities and onlap relationships support that the arc was active between ~10–6 Ma. Progressive arc build-up leading to an archipelago and its later subsidence can explain the extended exchange of terrestrial biota between Iberia and Africa (~7–3 Ma), and agrees with patterns of biota speciation and terrestrial fossil distribution before the MSC (10–6.2 Ma). In this scenario, the West Alboran Basin (WAB) could then be the long-postulated open-marine refuge for the Mediterranean taxa that repopulated the Mediterranean after the MSC, connected to the deep restricted Mediterranean basin through a sill at the Alboran volcanic arc archipelago.
Rapid and simple detection of Tamiflu-resistant influenza virus: Development of oseltamivir derivative-based lateral flow biosensor for point-of-care (POC) diagnostics
Authors: Hwang Seul Gee , Ha Kab , Guk Kyeonghye , Lee Do Kyung , Eom Gayoung , Song Sinae , Kang Taejoon , Park Hwangseo , Jung Juyeon , Lim Eun-Kyung
Published: August 2018

We have developed a novel oseltamivir derivative (oseltamivir hexylthiol; OHT) that exhibits a higher binding affinity for Tamiflu-resistant virus (Tamiflu resistance) than for the wild-type virus (Tamiflu-susceptible virus; WT) as an antibody. First, OHT-modified gold nanoparticles (OHT-GNPs) are used in a simple colorimetric assay as nanoprobes for the Tamiflu-resistant virus. In the presence of Tamiflu-resistant virus, they show a colorimetric change from deep red to purple because of the OHT-GNP aggregation driven by strong interactions between OHT and neuraminidase (NA) on the surface of the Tamiflu-resistance. Moreover, the color gradually turns purple as the concentration of the Tamiflu-resistant virus increases, allowing the determination of the presence of the virus with the naked eye. Furthermore, an OHT-based lateral flow assay (LFA) has been developed as a rapid and easy detection device for Tamiflu resistance. It shows detection specificity for various virus concentrations of Tamiflu-resistant virus even for the mixture of WT and Tamiflu-resistant viruses, where the limit of detection (LOD) is 5 × 102 ~ 103 PFU per test (=1 × 104 PFU/mL). It has been confirmed that this platform can provide accurate information on whether a virus exhibits Tamiflu resistance, thus supporting the selection of appropriate treatments using point-of-care (POC) diagnostics.
The Ras-related gene ERAS is involved in human and murine breast cancer
Authors: Suárez-Cabrera Cristian , de la Peña Bárbara , González Laura L. , Page Angustias , Martínez-Fernández Mónica , Casanova M. Llanos , Paramio Jesús M. , Rojo-Sebastián Alejandro , Moreno-Bueno Gema , Maroto Alicia , Ramírez Ángel , Navarro Manuel
Published: August 2018

Although Ras genes are frequently mutated in human tumors, these mutations are uncommon in breast cancer. However, many breast tumors show evidences of Ras pathway activation. In this manuscript, we have analyzed and characterized mouse mammary tumors generated by random Sleeping Beauty transposon mutagenesis and identify ERAS -a member of the RAS family silenced in adult tissues- as a new gene involved in progression and malignancy of breast cancer. Forced expression of ERAS in human non-transformed mammary gland cells induces a process of epithelial-to-mesenchymal transition and an increase in stem cells markers; these changes are mediated by miR-200c downregulation. ERAS expression in human tumorigenic mammary cells leads to the generation of larger and less differentiated tumors in xenotransplant experiments. Immunohistochemical, RT-qPCR and bioinformatics analysis of human samples show that ERAS is aberrantly expressed in 8–10% of breast tumors and this expression is associated with distant metastasis and reduced metastasis-free survival. In summary, our results reveal that inappropriate activation of ERAS may be important in the development of a subset of breast tumors. These findings open the possibility of new specific treatments for this subset of ERAS-expressing tumors.
Nexilin/NEXN controls actin polymerization in smooth muscle and is regulated by myocardin family coactivators and YAP
Authors: Zhu Baoyi , Rippe Catarina , Holmberg Johan , Zeng Shaohua , Perisic Ljubica , Albinsson Sebastian , Hedin Ulf , Uvelius Bengt , Swärd Karl
Published: August 2018

Nexilin, encoded by the NEXN gene, is expressed in striated muscle and localizes to Z-discs, influencing mechanical stability. We examined Nexilin/NEXN in smooth muscle cells (SMCs), and addressed if Nexilin localizes to dense bodies and dense bands and whether it is regulated by actin-controlled coactivators from the MRTF (MYOCD, MKL1, MKL2) and YAP/TAZ (YAP1 and WWTR1) families. NEXN expression in SMCs was comparable to that in striated muscles. Immunofluorescence and immunoelectron microscopy suggested that Nexilin localizes to dense bodies and dense bands. Correlations at the mRNA level suggested that NEXN expression might be controlled by actin polymerization. Depolymerization of actin using Latrunculin B repressed the NEXN mRNA and protein in bladder and coronary artery SMCs. Overexpression and knockdown supported involvement of both YAP/TAZ and MRTFs in the transcriptional control of NEXN. YAP/TAZ and MRTFs appeared equally important in bladder SMCs, whereas MRTFs dominated in vascular SMCs. Expression of NEXN was moreover reduced in situations of SMC phenotypic modulation in vivo. The proximal promoter of NEXN conferred control by MRTF-A/MKL1 and MYOCD. NEXN silencing reduced actin polymerization and cell migration, as well as SMC marker expression. NEXN targeting by actin-controlled coactivators thus amplifies SMC differentiation through the actin cytoskeleton, probably via dense bodies and dense bands.
A gene-rich fraction analysis of the Passiflora edulis genome reveals highly conserved microsyntenic regions with two related Malpighiales species
Authors: Munhoz Carla Freitas , Costa Zirlane Portugal , Cauz-Santos Luiz Augusto , Reátegui Alina Carmen Egoávil , Rodde Nathalie , Cauet Stéphane , Dornelas Marcelo Carnier , Leroy Philippe , Varani Alessandro de Mello , Bergès Hélène , Vieira Maria Lucia Carneiro
Published: August 2018

Passiflora edulis is the most widely cultivated species of passionflowers, cropped mainly for industrialized juice production and fresh fruit consumption. Despite its commercial importance, little is known about the genome structure of P. edulis. To fill in this gap in our knowledge, a genomic library was built, and now completely sequenced over 100 large-inserts. Sequencing data were assembled from long sequence reads, and structural sequence annotation resulted in the prediction of about 1,900 genes, providing data for subsequent functional analysis. The richness of repetitive elements was also evaluated. Microsyntenic regions of P. edulis common to Populus trichocarpa and Manihot esculenta, two related Malpighiales species with available fully sequenced genomes were examined. Overall, gene order was well conserved, with some disruptions of collinearity identified as rearrangements, such as inversion and translocation events. The microsynteny level observed between the P. edulis sequences and the compared genomes is surprising, given the long divergence time that separates them from the common ancestor. P. edulis gene-rich segments are more compact than those of the other two species, even though its genome is much larger. This study provides a first accurate gene set for P. edulis, opening the way for new studies on the evolutionary issues in Malpighiales genomes.
Unsupervised Medical Image Segmentation Based on the Local Center of Mass
Authors: Aganj Iman , Harisinghani Mukesh G. , Weissleder Ralph , Fischl Bruce
Published: August 2018

Image segmentation is a critical step in numerous medical imaging studies, which can be facilitated by automatic computational techniques. Supervised methods, although highly effective, require large training datasets of manually labeled images that are labor-intensive to produce. Unsupervised methods, on the contrary, can be used in the absence of training data to segment new images. We introduce a new approach to unsupervised image segmentation that is based on the computation of the local center of mass. We propose an efficient method to group the pixels of a one-dimensional signal, which we then use in an iterative algorithm for two- and three-dimensional image segmentation. We validate our method on a 2D X-ray image, a 3D abdominal magnetic resonance (MR) image and a dataset of 3D cardiovascular MR images.
Author Correction: Variabilities in retinal function and structure in a canine model of cone-rod dystrophy associated with RPGRIP1 support multigenic etiology
Authors: Das Rueben G. , Marinho Felipe Pompeo , Iwabe Simone , Santana Evelyn , McDaid Kendra Sierra , Aguirre Gustavo D. , Miyadera Keiko
Published: August 2018

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
Time-Series Analysis of Tumorigenesis in a Murine Skin Carcinogenesis Model
Authors: Aoto Yoshimasa , Okumura Kazuhiro , Hachiya Tsuyoshi , Hase Sumitaka , Wakabayashi Yuichi , Ishikawa Fuyuki , Sakakibara Yasubumi
Published: August 2018

Recent years have witnessed substantial progress in understanding tumor heterogeneity and the process of tumor progression; however, the entire process of the transition of tumors from a benign to metastatic state remains poorly understood. In the present study, we performed a prospective cancer genome-sequencing analysis by employing an experimental carcinogenesis mouse model of squamous cell carcinoma to systematically understand the evolutionary process of tumors. We surgically collected a part of a lesion of each tumor and followed the progression of these tumors in vivo over time. Comparative time-series analysis of the genomes of tumors with different fates, i.e., those that eventually metastasized and regressed, suggested that these tumors acquired and inherited different mutations. These findings suggest that despite the occurrence of an intra-tumor selection event for malignant alteration during the transformation from early- to late-stage papilloma, the fate determination of tumors might be determined at an even earlier stage.
Redox state affects fecundity and insecticide susceptibility in Anopheles gambiae
Authors: Champion Cody J. , Xu Jiannong
Published: August 2018

Redox reactions play a central role in the metabolism of an organism. It is vital to maintain redox homeostasis in response to the fluctuation of redox shift in various biological contexts. NADPH-dependent reducing capacity is one of the key factors contributing to the redox homeostasis. To understand the redox capacity and its impact on mosquito fecundity and susceptibility to insecticides in Anopheles gambiae, we examined the dynamics of elevated oxidative state via induction by paraquat (PQ) and the inhibition of NADPH regeneration by 6-aminonicotinamide (6AN). In naïve conditions, inherent oxidative capacity varies between individuals, as measured by GSSG/GSH ratio. The high GSSG/GSH ratio was negatively correlated with fecundity. Both PQ and 6AN feeding increased GSSG/GSH ratio and elevated protein carbonylation, a marker of oxidative damage. Both pro-oxidants lowered egg production. Co-feeding the pro-oxidants with antioxidant lycopene attenuated the adverse effects on fecundity, implying that oxidative stress was the cause of this phenotype. Pre-feeding with 6AN increased insecticide susceptibility in DDT resistant mosquitoes. These results indicate that oxidative state is delicate in mosquitoes, manipulation of NADPH pool may adversely affect fecundity and insecticide detoxification capacity. This knowledge can be exploited to develop novel vector control strategies targeting fecundity and insecticide resistance.
The invasiveness of human cervical cancer associated to the function of NaV1.6 channels is mediated by MMP-2 activity
Authors: Lopez-Charcas Osbaldo , Espinosa Ana Maria , Alfaro Ana , Herrera-Carrillo Zazil , Ramirez-Cordero Belen Ernestina , Cortes-Reynosa Pedro , Perez Salazar Eduardo , Berumen Jaime , Gomora Juan Carlos
Published: August 2018

Voltage-gated sodium (NaV) channels have been related with cell migration and invasiveness in human cancers. We previously reported the contribution of NaV1.6 channels activity with the invasion capacity of cervical cancer (CeCa) positive to Human Papilloma Virus type 16 (HPV16), which accounts for 50% of all CeCa cases. Here, we show that NaV1.6 gene (SCN8A) overexpression is a general characteristic of CeCa, regardless of the HPV type. In contrast, no differences were observed in NaV1.6 channel expression between samples of non-cancerous and cervical intraepithelial neoplasia. Additionally, we found that CeCa cell lines, C33A, SiHa, CaSki and HeLa, express mainly the splice variant of SCN8A that lacks exon 18, shown to encode for an intracellularly localized NaV1.6 channel, whereas the full-length adult form was present in CeCa biopsies. Correlatively, patch-clamp experiments showed no evidence of whole-cell sodium currents (INa) in CeCa cell lines. Heterologous expression of full-length NaV1.6 isoform in C33A cells produced INa, which were sufficient to significantly increase invasion capacity and matrix metalloproteinase type 2 (MMP-2) activity. These data suggest that upregulation of NaV1.6 channel expression occurs when cervical epithelium have been transformed into cancer cells, and that NaV1.6-mediated invasiveness of CeCa cells involves MMP-2 activity. Thus, our findings support the notion about using NaV channels as therapeutic targets against cancer metastasis.
Identification of Magnesium Oxychloride Cement Biomaterial Heterogeneity using Raman Chemical Mapping and NIR Hyperspectral Chemical Imaging
Authors: Dorrepaal Ronan M. , Gowen Aoife A.
Published: August 2018

The present study investigated spatial heterogeneity in magnesium oxychloride cements within a model of a mould using hyperspectral chemical imaging (HCI). The ability to inspect cements within a mould allows for the assessment of material formation in real time in addition to factors affecting ultimate material formation. Both macro scale NIR HCI and micro scale pixel-wise Raman chemical mapping were employed to characterise the same specimens. NIR imaging is rapid, however spectra are often convoluted through the overlapping of overtone peaks, which can make interpretation difficult. Raman spectra are more easily interpretable, however Raman imaging can suffer from slower acquisition times, particularly when the signal to noise ratio is relatively poor and the spatial resolution is high. To overcome the limitations of both, Raman/NIR data fusion techniques were explored and implemented. Spectra collected using both modalities were co-registered and intra and inter-modality peak correlations were investigated while k-means cluster patterns were compared. In addition, partial least squares regression models, built using NIR spectra, predicted chemical-identifying Raman peaks with an R2 of up to >0.98. As macro scale imaging presented greater data collection speeds, chemical prediction maps were built using NIR HCIs.
3D cephalometric analysis using Magnetic Resonance Imaging: validation of accuracy and reproducibility
Authors: Juerchott Alexander , Saleem Muhammad Abdullah , Hilgenfeld Tim , Freudlsperger Christian , Zingler Sebastian , Lux Christopher J. , Bendszus Martin , Heiland Sabine
Published: August 2018

The aim of this study was to validate geometric accuracy and in vivo reproducibility of landmark-based cephalometric measurements using high-resolution 3D Magnetic Resonance Imaging (MRI) at 3 Tesla. For accuracy validation, 96 angular and 96 linear measurements were taken on a phantom in 3 different positions. In vivo MRI scans were performed on 3 volunteers in five head positions. For each in vivo scan, 27 landmarks were determined from which 19 angles and 26 distances were calculated. Statistical analysis was performed using Bland-Altman analysis, the two one-sided tests procedure and repeated measures one-way analysis of variance. In comparison to ground truth, all MRI-based phantom measurements showed statistical equivalence (p < 0.001) and an excellent agreement in Bland-Altman analysis (bias ranges: −0.090–0.044°, −0.220–0.241 mm). In vivo cephalometric analysis was highly reproducible among the five different head positions in all study participants, without statistical differences for all angles and distances (p > 0.05). Ranges between maximum and minimum in vivo values were consistently smaller than 2° and 2 mm, respectively (average ranges: 0.88°/0.87 mm). In conclusion, this study demonstrates that accurate and reproducible 3D cephalometric analysis can be performed without exposure to ionizing radiation using MRI.
Microparticles from β-thalassaemia/HbE patients induce endothelial cell dysfunction
Authors: Kheansaard Wasinee , Phongpao Kunwadee , Paiboonsukwong Kittiphong , Pattanapanyasat Kovit , Chaichompoo Pornthip , Svasti Saovaros
Published: August 2018

Thromboembolic complication occurs frequently in β-thalassaemia/HbE patients, particularly in splenectomised patients. Endothelial cells play an important role in thrombosis. There is strong evidence of endothelial cell activation and dysfunction in β-thalassaemia. Microparticles (MPs) are associated with thrombosis and endothelial cell dysfunction in many diseases including β-thalassaemia. However, the effect of thalassaemic-MPs on endothelial cells mediating thrombus formation has not been elucidated. In this study, the effects of circulating MPs from β-thalassaemia/HbE patients on endothelial cell functions were investigated. The results showed that MPs directly induce tissue factor, interleukin (IL)-6, IL-8, intracellular adhesion molecule-1, vascular cell adhesion molecule-1 and E-selectin expression in human umbilical vein endothelial cells (HUVECs). Notably, the levels of these endothelial cell activation markers were significantly increased in HUVECs treated with MPs obtained from splenectomised β-thalassaemia/HbE patients when compared to MPs from non-splenectomised patients or normal subjects. The increased endothelial cell activation ultimately lead to increased monocyte-endothelial cell adhesion. THP-1 and HUVECs adhesion induced by MPs from normal subjects, non-splenectomised and splenectomised patients increased to 2.0 ± 0.4, 2.3 ± 0.4 and 3.8 ± 0.4 fold, respectively when compared to untreated cells. This finding suggests that MPs play an important role on thrombosis and vascular dysfunction in β-thalassaemia/HbE disease, especially in splenectomised cases.
Genetic and animal model analyses reveal the pathogenic role of a novel deletion of RELN in schizophrenia
Authors: Sobue Akira , Kushima Itaru , Nagai Taku , Shan Wei , Kohno Takao , Aleksic Branko , Aoyama Yuki , Mori Daisuke , Arioka Yuko , Kawano Naoko , Yamamoto Maeri , Hattori Mitsuharu , Nabeshima Toshitaka , Yamada Kiyofumi , Ozaki Norio
Published: August 2018

Reelin protein (RELN), an extracellular matrix protein, plays multiple roles that range from embryonic neuronal migration to spine formation in the adult brain. Results from genetic studies have suggested that RELN is associated with the risk of psychiatric disorders, including schizophrenia (SCZ). We previously identified a novel exonic deletion of RELN in a patient with SCZ. High-resolution copy number variation analysis revealed that this deletion included exons 52 to 58, which truncated the RELN in a similar manner to the Reln Orleans mutation (Relnrl-Orl). We examined the clinical features of this patient and confirmed a decreased serum level of RELN. To elucidate the pathophysiological role of the exonic deletion of RELN in SCZ, we conducted behavioral and neurochemical analyses using heterozygous Relnrl-Orl/+ mice. These mice exhibited abnormalities in anxiety, social behavior, and motor learning; the deficits in motor learning were ameliorated by antipsychotics. Methamphetamine-induced hyperactivity and dopamine release were significantly reduced in the Relnrl-Orl/+ mice. In addition, the levels of GABAergic markers were decreased in the brain of these mice. Taken together, our results suggest that the exonic deletion of RELN plays a pathological role, implicating functional changes in the dopaminergic and GABAergic systems, in the pathophysiology of SCZ.
A Novel Non-contact Heart Rate Monitor Using Impulse-Radio Ultra-Wideband (IR-UWB) Radar Technology
Authors: Lee Yonggu , Park Jun-Young , Choi Yeon-Woo , Park Hyun-Kyung , Cho Seok-Hyun , Cho Sung Ho , Lim Young-Hyo
Published: August 2018

We discovered that impulse-radio ultra-wideband (IR-UWB) radar could recognize cardiac motions in a non-contact fashion. Therefore, we measured the heart rate (HR) and rhythms using an IR-UWB radar sensor and evaluated the validity and reliability of the measurements in comparison to electrocardiography. The heart beats were measured in 6 healthy volunteers (18 samples) with normal sinus rhythm (NSR) and 16 patients (36 samples) with atrial fibrillation (AF) using both an IR-UWB radar sensor and electrocardiography simultaneously. The participants hold their breath for 20 seconds during the data acquisition. In subjects with NSR, there was excellent agreement of HR (intraclass correlation coefficient [ICC] 0.856), average R-R interval (ICC 0.997) and individual R-R intervals between the two methods (ICC 0.803). In subjects with AF, HR (ICC 0.871) and average R-R interval (ICC 0.925) from the radar sensor also agreed well with those from electrocardiography, though there was a small disagreement in the individual R-R intervals between the two methods (ICC 0.697). The rhythms computed by the signal-processing algorithm showed good agreement between the two methods (Cohen’s Kappa 0.922). The IR-UWB radar sensor is precise and accurate for assessing HR and rhythms in a non-contact fashion.