bluuebunny/crossref_metadata_2025 huggingface dataset:
Direct numerical simulation of stratified flow past a sphere at a subcritical Reynolds number of 3700 and moderate Froude number
Authors: Pal Anikesh , Sarkar Sutanu , Posa Antonio , Balaras Elias
Published: August 2017

Direct numerical simulation of flow past a sphere in a stratified fluid is carried out at a subcritical Reynolds number of 3700 and $Fr=U_{\infty }/ND=1,2$ and 3 to understand the dynamics of moderately stratified flows with $Fr=O(1)$. Here, $U_{\infty }$ is the free stream velocity, $N$ is the background buoyancy frequency and $D$ is the sphere diameter. The unstratified flow past the sphere consists of a separated shear layer that transitions to turbulence, a recirculation zone and a wake with a mean centreline deficit velocity, $U_{0}$, that decreases with downstream distance as a power law. With increasing stratification, the separated shear layer plunges inward vertically and its roll up is inhibited, the recirculation zone is shortened and the mean wake decays at a slower rate of $U_{0}\propto (x_{1}/D)^{-0.25}$ in the non-equilibrium (NEQ) region. The transition from the near wake where $U_{0}$ has a decay rate similar to the unstratified case to the NEQ regime occurs as an oscillatory modulation by a steady lee wave pattern with a period of $t=2\unicode[STIX]{x03C0}/N$ that leads to accelerated $U_{0}$ between $Nt=\unicode[STIX]{x03C0}$ and approximately $Nt=2\unicode[STIX]{x03C0}$. Far downstream, the wake is dominated by coherent horizontal motions. The acceleration of $U_{0}$ by the lee wave and the lower turbulence production in the NEQ regime, thereby less loss to turbulence, prolongs the lifetime of the wake relative to its unstratified counterpart. The intensity, temporal spectra and structure of turbulent fluctuations in the wake are assessed. Buoyancy induces significant anisotropy among the velocity components and between their vertical and horizontal profiles. Consequently, the near wake ($x_{1}/D<10$) exhibits significant differences in turbulence profiles relative to its unstratified counterpart. Spectra of vertical velocity show a discrete peak in the near wake that is maintained further downstream. The turbulent kinetic energy (TKE) balance is computed and contributions from pressure transport and buoyancy are found to become increasingly important as stratification increases. The findings of this investigation will be helpful in designing accurate initial conditions for the temporally evolving model of stratified wakes.
Non-wetting impact of a sphere onto a bath and its application to bouncing droplets
Authors: Galeano-Rios Carlos A. , Milewski Paul A. , Vanden-Broeck J.-M.
Published: August 2017

We present a fully predictive model for the impact of a smooth, convex and perfectly hydrophobic solid onto the free surface of an incompressible fluid bath of infinite depth in a regime where surface tension is important. During impact, we impose natural kinematic constraints along the portion of the fluid interface that is pressed by the solid. This provides a mechanism for the generation of linear surface waves and simultaneously yields the pressure applied on the impacting masses. The model compares remarkably well with data of the impact of spheres and bouncing droplet experiments, and is completely free of any of impact parametrisation.
The Landau–Squire plume
Authors: Secchi Eleonora , Marbach Sophie , Niguès Antoine , Siria Alessandro , Bocquet Lydéric
Published: August 2017

In this paper, we analyse the dispersion of a dye by a Landau–Squire plume, generated by a jet flow emerging from a nanocapillary into a reservoir. We demonstrate analytically that the dye concentration profile exhibits a long-range profile decaying as the inverse of the distance to the origin, whereas the plume shape is only a function of a Péclet number defined in terms of the flow characteristics inside the nanocapillary. These predictions are successfully compared with experiments on fluorescent dye dispersion from nanocapillaries under pressure-driven flow. The plume shape allows extraction of the nanojet force characterizing the Landau–Squire velocity profile for a given pressure drop, with results in full agreement with direct velocimetry measurements and finite-element calculations. The peculiarities of the Landau–Squire plume make it a sensitive probe of the flow properties inside the seeding nanocapillary.
The Distribution of Ratings Assigned to Blind Replicates
Authors: Bodington Jeffrey C.
Published: August 2017

The inability of many wine judges to achieve perfect consistency by assigning the same rating to the same wine in a blind tasting is well established. Results for four wine tastings that include blind replicates are examined in this article. Although perfection is rare, the probability distributions of those results show that wine judges do tend to assign closer ratings to replicates than is likely due to chance alone. Approximately one-third of judges assign ratings that are within one rank of perfect consistency, and two-thirds assign ratings within two ranks of perfect consistency. This finding is sensitive to judges’ capabilities, the mechanics of the tasting protocol, and the extent to which the replicate is different from other wines in the tasting. Much wine-related research to date takes judges’ individual ratings as deterministic, yet these results show that those ratings are stochastic. These results yield a probability distribution that may guide future research concerning the uses and economic implications of wine ratings. (JEL Classifications: A10, C10, C00, C12, D12)
Photometry of WD 1145+017 in Early 2017
Authors: Kjurkchieva Diana P. , Dimitrov Dinko P. , Petrov Nikola I.
Published: August 2017

We present photometric observations of WD 1145+017 during six nights in early 2017. They exhibited asymmetric transits with durations of 10–50 mins and depths up to 50% in flux. We managed to track two deep features that drift in phase during 2.5-month season. This effect may be explained by period decreasing of the transiting formations due to their slow spiralling to the white dwarf. One of them seems to fragment in several smaller parts within a month. The structures causing the two deep transits have elongated shape whose sizes perpendicular and along the orbit are of the order of 1 R⊕ and 100 R⊕. They are parts of geometrically thin inhomogeneous disk (ring) around the white dwarf that is well within its Roche radius. This explains the observed dip activity of WD 1145+017 during the year 2017.
A mawsoniid coelacanth (Sarcopterygii: Actinistia) from the Rhaetian (Upper Triassic) of the Peygros quarry, Le Thoronet (Var, southeastern France)
Authors: DEESRI UTHUMPORN , CAVIN LIONEL , AMIOT ROMAIN , BARDET NATHALIE , BUFFETAUT ERIC , CUNY GILLES , GINER STEPHEN , MARTIN JEREMY E. , SUAN GUILLAUME
Published: August 2017

Remains of a coelacanth specimen are described from Rhaetian deposits of the Var Department, southeastern France. They comprise the lower part of a branchial apparatus associated with a left lower jaw and a basisphenoid. Osteological features of the angular and basisphenoid and the teeth ornamentation allow the inclusion of the specimen in the mawsoniid family, genus and species indeterminate. Mawsoniids are known in freshwater environments from the Triassic of North America and from the Cretaceous of Western Gondwana and Europe, as well as from Late Jurassic marine environments from Europe. The new discovery here reported represents the first coelacanth from the marine Triassic of France and improves the understanding of the palaeobiogeography of the Mawsoniidae.
Workers of the World? A British Liberal-Pluralist Critique of Marcel van der Linden’s Global Labour History
Authors: Ackers Peter
Published: August 2017

Marcel van der Linden has championed Global Labour History (GLH) as a solution to the decline of Labour History as an academic field. His 2008Workers of the World(and other writing) strives to transcend methodological nationalism and provides a new global framework to study labour through the ages. This British liberal-pluralist critique argues that Van der Linden’s version of GLH is essentially a re-packaging of Marxism that narrows the conceptual foundations of the field and overlooks both the full political crisis of state-socialism and its limited historical appeal to working people. The article concludes by defending a national approach centred on civil society institutions, as represented in the 2016 collection edited by P. Ackers and A.J. Reid,Alternatives to State-Socialism in Britain: Other Worlds of Labour in the Twentieth Century.
SEX COMPOSITION OF TWINS AND ASSOCIATIONS WITH MORBIDITY, MORTALITY AND MATERNAL TREATMENT-SEEKING OUTCOMES IN RESOURCE-POOR SETTINGS
Authors: Stephenson Rob , Tharp Mondie Blalock , Wiginton John Mark , Metheny Nicholas
Published: August 2017

Societal gender inequality and a preference for male children has been shown to be detrimental to girls’ health. This is despite females’ innate biological advantage early in life. The negative effects of gender inequity on female health are most pronounced in resource-poor countries, where cultural norms supporting a preference for male children are strongest. However, most of what is known about gender inequality and child health comes from studies of singleton births. There is little evidence for how, or if, the disadvantages associated with gender bias and son preference extend to multiple births, a population inherently at risk for a number of health challenges. This analysis examines whether gender bias in health outcomes exists for twins. Data on live twin births from 38 Demographic and Health Surveys were compiled (n=11,528 individuals) and twins were categorized as girl/girl, girl/boy, boy/girl or girl/girl. Gender inequality was measured via the Gender Inequality Index. Multilevel logistic regression models examined associations between twin sex composition, gender inequality and eight outcomes of infant and child morbidity, mortality and mother’s treatment-seeking behaviours. Twin pairs containing girls had significantly lower odds of first-year mortality. Higher country-level gender inequality was associated with higher odds of reporting diarrhoea and fever/cough, as well as an increased odds of post-neonatal mortality. Results suggest that the biological advantage for females may be stronger than son preference and gender inequality in the first year of life. Understanding these relationships has the potential to inform efforts to curb the influence of gender preference on the health of female children in resource-poor settings.
Variety of shapes of solar wind ion flux spectra: Spektr-R measurements
Authors: Riazantseva Maria , Budaev V. , Rakhmanova L. , Zastenker G. , Yermolaev Yu. , Lodkina I. , Šafránková J. , Němeček Z. , Přech L.
Published: August 2017

The paper is devoted to the shapes of the solar wind ion flux fluctuation spectrum at the transition between the inertial and the kinetic range usingin situhigh-resolution measurements of the Russian mission Spektr-R. We analyse the variability of the transition region and select five typical types of spectral shapes: (i) spectra with two slopes and one break, (ii) spectra characterized by a nonlinear steepening in the kinetic range, (iii) spectra with flattening in the vicinity of the break, (iv) spectra with a bump in the vicinity of the break and (v) spectra without any steepening in the kinetic range. The most popular is the well-known type (i) observed in approximately half of the cases. The second most popular type of spectra is type (iii) occurring in approximately one third of the cases. The other three types are observed less often: type (ii) – in approximately 6 %; type (iv) in 3 % and type (v) in 6 % of cases. An analysis of typical plasma conditions for different types of spectra revealed that the last two type of spectra (iv) and (v) are generally observed in a very slow solar wind with a low proton density, (i) and (iii) are observed in the solar wind with rather typical conditions and (ii) is usually observed in high-speed streams. The effect of nonlinear steepening of the spectra in the kinetic range increases with the solar wind speed. We present also the analysis of statistical properties of the observed events and compare them with the predictions of several statistical turbulence models. We show that intermittency is always observed in the solar wind flow despite the presence of one or another shape of spectra. The log-Poisson model with a dominant contribution of filament-like structures shows the best parameterization of the experimentally observed scaling.
Genotyping ofBartonellabacteria and their animal hosts: current status and perspectives
Authors: KOSOY M. , MCKEE C. , ALBAYRAK L. , FOFANOV Y.
Published: August 2017

Growing evidence demonstrates that bacterial species diversity is substantial, and many of these species are pathogenic in some contexts or hosts. At the same time, laboratories and museums have collected valuable animal tissue and ectoparasite samples that may contain substantial novel information on bacterial prevalence and diversity. However, the identification of bacterial species is challenging, partly due to the difficulty in culturing many microbes and the reliance on molecular data. Although the genomics revolution will surely add to our knowledge of bacterial systematics, these approaches are not accessible to all researchers and rely predominantly on cultured isolates. Thus, there is a need for comprehensive molecular analyses capable of accurately genotyping bacteria from animal tissues or ectoparasites using common methods that will facilitate large-scale comparisons of species diversity and prevalence. To illustrate the challenges of genotyping bacteria, we focus on the genusBartonella, vector-borne bacteria common in mammals. We highlight the value and limitations of commonly used techniques for genotyping bartonellae and make recommendations for researchers interested in studying the diversity of these bacteria in various samples. Our recommendations could be applicable to many bacterial taxa (with some modifications) and could lead to a more complete understanding of bacterial species diversity.
Regional organisations and enduring defective democratic members
Authors: Davies Mathew
Published: August 2017

Instead of asking whether regional organisations can promote democracy, a well-established conclusion, this article asks what type of democracy regional organisations can promote. Where their commitments to democracy are weak, regional organisations can promote the transition away from authoritarianism but cannot drive that process to completion with the creation of embedded liberal democracies. Under such circumstances regional organisations serve as regimes of bounded toleration, and can provide regional linkages that sustain defective democracies. Through examining the relationship between the Association of Southeast Asian Nations and Myanmar, three supporting roles are identified; regional legitimacy, defence from external pressure, and future-oriented accommodation. The presence of these linkages between defective democracies and regional organisations provides a caveat to the positive assessments of regional organisations as socialisers of democracy.
Why is terrorism a man’s business?
Authors: Möller-Leimkühler Anne Maria
Published: August 2017

Terrorism, whether it is group-related or performed as lone actor terrorism, is a predominantly male phenomenon. Generally and throughout history, young males have been the main protagonists of criminal and political violence.

This article aims to contribute, from different perspecives, to the question of what makes young men violent. These include neurobiological aspects, such as sex differences in the brain that predispose males to physical aggression and violence; gender role aspects, with regard to aggression and violence being basic components for demonstrating and reconstructing masculinity; demographic aspects of male youth bulges as potential breeding grounds for terrorism; aspects of group dynamics and identity fusion in the process of radicalization; and psychosocial characteristics of lone actor terrorists, which differ from group-related terrorists.

It is concluded that in addition to ideological, political, economic, regional, demographic, or psychosocial causes, experiences of threatened masculinity may be an underlying factor and driving force for terrorism.
The forsaking of the clinical EEG by psychiatry: how justified?
Authors: Boutros Nash N.
Published: August 2017

Despite decades of publications attesting to the role of the clinical EEG in diagnosing and managing psychiatric disorders, the procedure remains highly underutilized in the practice of psychiatry. The visually inspected EEG (vEEG) can detect various forms of abnormalities, each with its own clinical significance. Abnormalities can be paroxysmal (i.e., suggestive of an epileptic-like process) or stationary. The most important unanswered question remains the value of detecting epileptiform activity in a nonepileptic psychiatric patient in predicting favorable responses to anticonvulsant treatment. Despite the many shortcomings of vEEG, the available evidence suggests that in the presence of paroxysmal activity in a nonepileptic psychiatric patient a trial of a psychotropic anticonvulsant may be warranted if standard treatment has failed. More research on the contribution of paroxysmal EEG abnormalities to the problem of episodic psychiatric symptoms (e.g., panic attacks, dissociative episodes, repeated violence) is sorely needed. It is postulated that at least some of these conditions may represent an epilepsy spectrum disorder. Similarly, the significance of the presence of a slow-wave activity (whether focal or generalized) also deserves further well-designed research to ascertain the exact clinical significance. Nonetheless, the available data suggest that further medical workup is necessary to ascertain the nature and degree of the pathology when present.
CM RELATIONS IN FIBERED POWERS OF ELLIPTIC FAMILIES
Authors: Barroero Fabrizio
Published: August 2017

Let$E_{\unicode[STIX]{x1D706}}$be the Legendre family of elliptic curves. Given$n$points$P_{1},\ldots ,P_{n}\in E_{\unicode[STIX]{x1D706}}(\overline{\mathbb{Q}(\unicode[STIX]{x1D706})})$, linearly independent over$\mathbb{Z}$, we prove that there are at most finitely many complex numbers$\unicode[STIX]{x1D706}_{0}$such that$E_{\unicode[STIX]{x1D706}_{0}}$has complex multiplication and$P_{1}(\unicode[STIX]{x1D706}_{0}),\ldots ,P_{n}(\unicode[STIX]{x1D706}_{0})$are linearly dependent over End$(E_{\unicode[STIX]{x1D706}_{0}})$. This implies a positive answer to a question of Bertrand and, combined with a previous work in collaboration with Capuano, proves the Zilber–Pink conjecture for a curve in a fibered power of an elliptic scheme when everything is defined over$\overline{\mathbb{Q}}$.
Evolution of new regulatory functions on biophysically realistic fitness landscapes
Authors: Friedlander Tamar , Prizak Roshan , Barton Nicholas H. , Tkačik Gašper
Published: August 2017

Gene expression is controlled by networks of regulatory proteins that interact specifically with external signals and DNA regulatory sequences. These interactions force the network components to co-evolve so as to continually maintain function. Yet, existing models of evolution mostly focus on isolated genetic elements. In contrast, we study the essential process by which regulatory networks grow: the duplication and subsequent specialization of network components. We synthesize a biophysical model of molecular interactions with the evolutionary framework to find the conditions and pathways by which new regulatory functions emerge. We show that specialization of new network components is usually slow, but can be drastically accelerated in the presence of regulatory crosstalk and mutations that promote promiscuous interactions between network components.
Agonist-induced dimer dissociation as a macromolecular step in G protein-coupled receptor signaling
Authors: Petersen Julian , Wright Shane C. , Rodríguez David , Matricon Pierre , Lahav Noa , Vromen Aviv , Friedler Assaf , Strömqvist Johan , Wennmalm Stefan , Carlsson Jens , Schulte Gunnar
Published: August 2017

G protein-coupled receptors (GPCRs) constitute the largest family of cell surface receptors. They can exist and act as dimers, but the requirement of dimers for agonist-induced signal initiation and structural dynamics remains largely unknown. Frizzled 6 (FZD6) is a member of Class F GPCRs, which bind WNT proteins to initiate signaling. Here, we show that FZD6 dimerizes and that the dimer interface of FZD6 is formed by the transmembrane α-helices four and five. Most importantly, we present the agonist-induced dissociation/re-association of a GPCR dimer through the use of live cell imaging techniques. Further analysis of a dimerization-impaired FZD6 mutant indicates that dimer dissociation is an integral part of FZD6 signaling to extracellular signal-regulated kinases1/2. The discovery of agonist-dependent dynamics of dimers as an intrinsic process of receptor activation extends our understanding of Class F and other dimerizing GPCRs, offering novel targets for dimer-interfering small molecules.
RETRACTED ARTICLE:Endocrine disruptors induce perturbations in endoplasmic reticulum and mitochondria of human pluripotent stem cell derivatives
Authors: Rajamani Uthra , Gross Andrew R. , Ocampo Camille , Andres Allen M. , Gottlieb Roberta A. , Sareen Dhruv
Published: August 2017

Persistent exposure to man-made endocrine disrupting chemicals during fetal endocrine development may lead to disruption of metabolic homeostasis contributing to childhood obesity. Limited cellular platforms exist to test endocrine disrupting chemical-induced developmental abnormalities in human endocrine tissues. Here we use an human-induced pluripotent stem cell-based platform to demonstrate adverse impacts of obesogenic endocrine disrupting chemicals in the developing endocrine system. We delineate the effects upon physiological low-dose exposure to ubiquitous endocrine disrupting chemicals including, perfluoro-octanoic acid, tributyltin, and butylhydroxytoluene, in endocrine-active human-induced pluripotent stem cell-derived foregut epithelial cells and hypothalamic neurons. Endocrine disrupting chemicals induce endoplasmic reticulum stress, perturb NF-κB, and p53 signaling, and diminish mitochondrial respiratory gene expression, spare respiratory capacity, and ATP levels. As a result, normal production and secretion of appetite control hormones, PYY, α-MSH, and CART, are hampered. Blocking NF-κB rescues endocrine disrupting chemical-induced aberrant mitochondrial phenotypes and endocrine dysregulation, but not ER-stress and p53-phosphorylation changes.
Evolutionary conservation of a core root microbiome across plant phyla along a tropical soil chronosequence
Authors: Yeoh Yun Kit , Dennis Paul G. , Paungfoo-Lonhienne Chanyarat , Weber Lui , Brackin Richard , Ragan Mark A. , Schmidt Susanne , Hugenholtz Philip
Published: August 2017

Culture-independent molecular surveys of plant root microbiomes indicate that soil type generally has a stronger influence on microbial communities than host phylogeny. However, these studies have mostly focussed on model plants and crops. Here, we examine the root microbiomes of multiple plant phyla including lycopods, ferns, gymnosperms, and angiosperms across a soil chronosequence using 16S rRNA gene amplicon profiling. We confirm that soil type is the primary determinant of root-associated bacterial community composition, but also observe a significant correlation with plant phylogeny. A total of 47 bacterial genera are associated with roots relative to bulk soil microbial communities, including well-recognized plant-associated genera such as Bradyrhizobium, Rhizobium, and Burkholderia, and major uncharacterized lineages such as WPS-2, Ellin329, and FW68. We suggest that these taxa collectively constitute an evolutionarily conserved core root microbiome at this site. This lends support to the inference that a core root microbiome has evolved with terrestrial plants over their 400 million year history.
A Plasmodium yoelii HECT-like E3 ubiquitin ligase regulates parasite growth and virulence
Authors: Nair Sethu C. , Xu Ruixue , Pattaradilokrat Sittiporn , Wu Jian , Qi Yanwei , Zilversmit Martine , Ganesan Sundar , Nagarajan Vijayaraj , Eastman Richard T. , Orandle Marlene S. , Tan John C. , Myers Timothy G. , Liu Shengfa , Long Carole A. , Li Jian , Su Xin-zhuan
Published: August 2017

Infection of mice with strains of Plasmodium yoelii parasites can result in different pathology, but molecular mechanisms to explain this variation are unclear. Here we show that a P. yoelii gene encoding a HECT-like E3 ubiquitin ligase (Pyheul) influences parasitemia and host mortality. We genetically cross two lethal parasites with distinct disease phenotypes, and identify 43 genetically diverse progeny by typing with microsatellites and 9230 single-nucleotide polymorphisms. A genome-wide quantitative trait loci scan links parasite growth and host mortality to two major loci on chromosomes 1 and 7 with LOD (logarithm of ﻿the odds) scores = 6.1 and 8.1, respectively. Allelic exchange of partial sequences of Pyheul in the chromosome 7 locus and modification of the gene expression alter parasite growth and host mortality. This study identifies a gene that may have a function in parasite growth, virulence, and host–parasite interaction, and therefore could be a target for drug or vaccine development.
An early mechanical coupling of planktonic bacteria in dilute suspensions
Authors: Sretenovic Simon , Stojković Biljana , Dogsa Iztok , Kostanjšek Rok , Poberaj Igor , Stopar David
Published: August 2017

It is generally accepted that planktonic bacteria in dilute suspensions are not mechanically coupled and do not show correlated motion. The mechanical coupling of cells is a trait that develops upon transition into a biofilm, a microbial community of self-aggregated bacterial cells. Here we employ optical tweezers to show that bacteria in dilute suspensions are mechanically coupled and show long-range correlated motion. The strength of the coupling increases with the growth of liquid bacterial culture. The matrix responsible for the mechanical coupling is composed of cell debris and extracellular polymer material. The fragile network connecting cells behaves as viscoelastic liquid of entangled extracellular polymers. Our findings point to physical connections between bacteria in dilute bacterial suspensions that may provide a mechanistic framework for understanding of biofilm formation, osmotic flow of nutrients, diffusion of signal molecules in quorum sensing, or different efficacy of antibiotic treatments at low and high bacterial densities.
Single cardiomyocyte nuclear transcriptomes reveal a lincRNA-regulated de-differentiation and cell cycle stress-response in vivo
Authors: See Kelvin , Tan Wilson L. W. , Lim Eng How , Tiang Zenia , Lee Li Ting , Li Peter Y. Q. , Luu Tuan D. A. , Ackers-Johnson Matthew , Foo Roger S.
Published: August 2017

Cardiac regeneration may revolutionize treatment for heart failure but endogenous progenitor-derived cardiomyocytes in the adult mammalian heart are few and pre-existing adult cardiomyocytes divide only at very low rates. Although candidate genes that control cardiomyocyte cell cycle re-entry have been implicated, expression heterogeneity in the cardiomyocyte stress-response has never been explored. Here, we show by single nuclear RNA-sequencing of cardiomyocytes from both mouse and human failing, and non-failing adult hearts that sub-populations of cardiomyocytes upregulate cell cycle activators and inhibitors consequent to the stress-response in vivo. We characterize these subgroups by weighted gene co-expression network analysis and discover long intergenic non-coding RNAs (lincRNA) as key nodal regulators. KD of nodal lincRNAs affects expression levels of genes related to dedifferentiation and cell cycle, within the same gene regulatory network. Our study reveals that sub-populations of adult cardiomyocytes may have a unique endogenous potential for cardiac regeneration in vivo.
Duplication events downstream of IRX1 cause North Carolina macular dystrophy at the MCDR3 locus
Authors: Cipriani Valentina , Silva Raquel S. , Arno Gavin , Pontikos Nikolas , Kalhoro Ambreen , Valeina Sandra , Inashkina Inna , Audere Mareta , Rutka Katrina , Puech Bernard , Michaelides Michel , van Heyningen Veronica , Lace Baiba , Webster Andrew R. , Moore Anthony T.
Published: August 2017

Autosomal dominant North Carolina macular dystrophy (NCMD) is believed to represent a failure of macular development. The disorder has been linked to two loci, MCDR1 (chromosome 6q16) and MCDR3 (chromosome 5p15-p13). Recently, non-coding variants upstream of PRDM13 (MCDR1) and a duplication including IRX1 (MCDR3) have been identified. However, the underlying disease-causing mechanism remains uncertain. Through a combination of sequencing studies on eighteen NCMD families, we report two novel overlapping duplications at the MCDR3 locus, in a gene desert downstream of IRX1 and upstream of ADAMTS16. One duplication of 43 kb was identified in nine families (with evidence for a shared ancestral haplotype), and another one of 45 kb was found in a single family. Three families carry the previously reported V2 variant (MCDR1), while five remain unsolved. The MCDR3 locus is thus refined to a shared region of 39 kb that contains DNAse hypersensitive sites active at a restricted time window during retinal development. Publicly available data confirmed expression of IRX1 and ADAMTS16 in human fetal retina, with IRX1 preferentially expressed in fetal macula. These findings represent a major advance in our understanding of the molecular genetics of NCMD and provide insights into the genetic pathways involved in human macular development.
Quantitative diagnostic imaging of cancer tissues by using phosphor-integrated dots with ultra-high brightness
Authors: Gonda Kohsuke , Watanabe Mika , Tada Hiroshi , Miyashita Minoru , Takahashi-Aoyama Yayoi , Kamei Takashi , Ishida Takanori , Usami Shin , Hirakawa Hisashi , Kakugawa Yoichiro , Hamanaka Yohei , Yoshida Ryuichi , Furuta Akihiko , Okada Hisatake , Goda Hideki , Negishi Hiroshi , Takanashi Kensaku , Takahashi Masaru , Ozaki Yuichi , Yoshihara Yuka , Nakano Yasushi , Ohuchi Noriaki
Published: August 2017

The quantitative sensitivity and dynamic range of conventional immunohistochemistry (IHC) with 3,3′-diaminobenzidine (IHC-DAB) used in pathological diagnosis in hospitals are poor, because enzyme activity can affect the IHC-DAB chromogenic reaction. Although fluorescent IHC can effectively increase the quantitative sensitivity of conventional IHC, tissue autofluorescence interferes with the sensitivity. Here, we created new fluorescent nanoparticles called phosphor-integrated dots (PIDs). PIDs have 100-fold greater brightness and a more than 300-fold greater dynamic range than those of commercially available fluorescent nanoparticles, quantum dots, whose fluorescence intensity is comparable to tissue autofluorescence. Additionally, a newly developed image-processing method enabled the calculation of the PID particle number in the obtained image. To quantify the sensitivity of IHC using PIDs (IHC-PIDs), the IHC-PIDs method was compared with fluorescence-activated cell sorting (FACS), a method well suited for evaluating total protein amount, and the two values exhibited strong correlation (R = 0.94). We next applied IHC-PIDs to categorize the response to molecular target-based drug therapy in breast cancer patients. The results suggested that the PID particle number estimated by IHC-PIDs of breast cancer tissues obtained from biopsy before chemotherapy can provide a score for predicting the therapeutic effect of the human epidermal growth factor receptor 2-targeted drug trastuzumab.
KDM4B-mediated reduction of H3K9me3 and H3K36me3 levels improves somatic cell reprogramming into pluripotency
Authors: Wei Jingwei , Antony Jisha , Meng Fanli , MacLean Paul , Rhind Rebekah , Laible Götz , Oback Björn
Published: August 2017

Correct reprogramming of epigenetic marks is essential for somatic cells to regain pluripotency. Repressive histone (H) lysine (K) methylation marks are known to be stable and difficult to reprogram. In this study, we generated transgenic mice and mouse embryonic fibroblasts (MEFs) for the inducible expression of KDM4B, a demethylase that removes H3 K9 and H3K36 trimethylation (me3) marks (H3K9/36me3). Upon inducing Kdm4b, H3K9/36me3 levels significantly decreased compared to non-induced controls. Concurrently, H3K9me1 levels significantly increased, while H3K9me2 and H3K27me3 remained unchanged. The global transcriptional impact of Kdm4b-mediated reduction in H3K9/36me3 levels was examined by comparative microarray analysis and mRNA-sequencing of three independent transgenic MEF lines. We identified several commonly up-regulated targets, including the heterochromatin-associated zinc finger protein 37 and full-length endogenous retrovirus repeat elements. Following optimized zona-free somatic nuclear transfer, reduced H3K9/36me3 levels were restored within hours. Nevertheless, hypo-methylated Kdm4b MEF donors reprogrammed six-fold better into cloned blastocysts than non-induced donors. They also reprogrammed nine-fold better into induced pluripotent stem cells that gave rise to teratomas and chimeras. In summary, we firmly established H3K9/36me3 as a major roadblock to somatic cell reprogramming and identified transcriptional targets of derestricted chromatin that could contribute towards improving this process in mouse.
Unraveling heme detoxification in the malaria parasite by in situ correlative X-ray fluorescence microscopy and soft X-ray tomography
Authors: Kapishnikov Sergey , Grolimund Daniel , Schneider Gerd , Pereiro Eva , McNally James G. , Als-Nielsen Jens , Leiserowitz Leslie
Published: August 2017

A key drug target for malaria has been the detoxification pathway of the iron-containing molecule heme, which is the toxic byproduct of hemoglobin digestion. The cornerstone of heme detoxification is its sequestration into hemozoin crystals, but how this occurs remains uncertain. We report new results of in vivo rate of heme crystallization in the malaria parasite, based on a new technique to measure element-specific concentrations at defined locations in cell ultrastructure. Specifically, a high resolution correlative combination of cryo soft X-ray tomography has been developed to obtain 3D parasite ultrastructure with cryo X-ray fluorescence microscopy to measure heme concentrations. Our results are consistent with a model for crystallization via the heme detoxification protein. Our measurements also demonstrate the presence of considerable amounts of non-crystalline heme in the digestive vacuole, which we show is most likely contained in hemoglobin. These results suggest a tight coupling between hemoglobin digestion and heme crystallization, highlighting a new link in the crystallization pathway for drug development.
RETRACTED ARTICLE: P16INK4a Deletion Ameliorated Renal Tubulointerstitial Injury in a Stress-induced Premature Senescence Model of Bmi-1 Deficiency
Authors: Jin Jianliang , Tao Jianguo , Gu Xin , Yu Zhenzhen , Wang Rong , Zuo Guoping , Li Qing , Lv Xianhui , Miao Dengshun
Published: August 2017

To determine whether p16

INK4a
deletion ameliorated renal tubulointerstitial injury by inhibiting a senescence-associated secretory phenotype (SASP) in Bmi-1-deficient (Bmi-1
−/−) mice, renal phenotypes were compared among 5-week-old Bmi-1 and p16

INK4a
double-knockout, and Bmi-1
−/− and wild-type mice. Fifth-passage renal interstitial fibroblasts (RIFs) from the three groups were analyzed for senescence and proliferation. The effect of Bmi-1 deficiency on epithelial-to-mesenchymal transition (EMT) was examined in Bmi-1-knockdown human renal proximal tubular epithelial (HK2) cells, which were treated with concentrated conditioned medium (CM) from the fifth-passage renal interstitial fibroblasts (RIFs) of above three group mice or with exogenous TGF-β1. Our results demonstrated that p16

INK4a
deletion largely rescued renal aging phenotypes caused by Bmi-1 deficiency, including impaired renal structure and function, decreased proliferation, increased apoptosis, senescence and SASP, DNA damage, NF-κB and TGF-β1/Smad signal activation, inflammatory cell infiltration, and tubulointerstitial fibrosis and tubular atrophy. P16

INK4a
deletion also promoted proliferation, reduced senescence and SASP of RIFs and subsequently inhibited EMT of Bmi-1-knockdown HK2 cells. TGF-β1 further induced the EMT of Bmi-1-knockdown HK2 cells. Thus, p16

INK4a
positive senescent cells would be a therapeutic target for preventing renal tubulointerstitial injury.
Respiratory oscillations in alveolar oxygen tension measured in arterial blood
Authors: Formenti Federico , Bommakanti Nikhil , Chen Rongsheng , Cronin John N. , McPeak Hanne , Holopherne-Doran Delphine , Hedenstierna Goran , Hahn Clive E. W. , Larsson Anders , Farmery Andrew D.
Published: August 2017

Arterial oxygen partial pressure can increase during inspiration and decrease during expiration in the presence of a variable shunt fraction, such as with cyclical atelectasis, but it is generally presumed to remain constant within a respiratory cycle in the healthy lung. We measured arterial oxygen partial pressure continuously with a fast intra-vascular sensor in the carotid artery of anaesthetized, mechanically ventilated pigs, without lung injury. Here we demonstrate that arterial oxygen partial pressure shows respiratory oscillations in the uninjured pig lung, in the absence of cyclical atelectasis (as determined with dynamic computed tomography), with oscillation amplitudes that exceeded 50 mmHg, depending on the conditions of mechanical ventilation. These arterial oxygen partial pressure respiratory oscillations can be modelled from a single alveolar compartment and a constant oxygen uptake, without the requirement for an increased shunt fraction during expiration. Our results are likely to contribute to the interpretation of arterial oxygen respiratory oscillations observed during mechanical ventilation in the acute respiratory distress syndrome.
Intestinal toxicity of the type B trichothecene mycotoxin fusarenon-X: whole transcriptome profiling reveals new signaling pathways
Authors: Alassane-Kpembi Imourana , Gerez Juliana Rubira , Cossalter Anne-Marie , Neves Manon , Laffitte Joëlle , Naylies Claire , Lippi Yannick , Kolf-Clauw Martine , Bracarense Ana Paula L. , Pinton Philippe , Oswald Isabelle P.
Published: August 2017

The few data available on fusarenon-X (FX) do not support the derivation of health-based guidance values, although preliminary results suggest higher toxicity than other regulated trichothecenes. Using histo-morphological analysis and whole transcriptome profiling, this study was designed to obtain a global view of the intestinal alterations induced by FX. Deoxynivalenol (DON) served as a benchmark. FX induced more severe histological alterations than DON. Inflammation was the hallmark of the molecular toxicity of both mycotoxins. The benchmark doses for the up-regulation of key inflammatory genes by FX were 4- to 45-fold higher than the previously reported values for DON. The transcriptome analysis revealed that both mycotoxins down-regulated the peroxisome proliferator-activated receptor (PPAR) and liver X receptor - retinoid X receptor (LXR-RXR) signaling pathways that control lipid metabolism. Interestingly, several pathways, including VDR/RXR activation, ephrin receptor signaling, and GNRH signaling, were specific to FX and thus discriminated the transcriptomic fingerprints of the two mycotoxins. These results demonstrate that FX induces more potent intestinal inflammation than DON. Moreover, although the mechanisms of toxicity of both mycotoxins are similar in many ways, this study emphasize specific pathways targeted by each mycotoxin, highlighting the need for specific mechanism-based risk assessments of Fusarium mycotoxins.
Polyphyllin I suppresses human osteosarcoma growth by inactivation of Wnt/β-catenin pathway in vitro and in vivo
Authors: Chang Junli , Li Yimian , Wang Xianyang , Hu Shaopu , Wang Hongshen , Shi Qi , Wang Yongjun , Yang Yanping
Published: August 2017

Osteosarcoma is the most common primary bone cancer in children and adolescents. In spite of aggressive treatment, osteosarcoma has a high mortality rate with minimal improvements in survival over past few decades. Polyphyllin I (PPI), a component in the traditional Chinese medicinal herb Paris polyphylla Smith, has been shown to have anti-tumor properties. However, its mechanism as an anti-osteosarcoma agent has not been well elucidated. In this study, we found that PPI suppressed osteosarcoma cell viability, arrested cell cycle in G2/M phase, induced apoptosis and inhibited invasion and migration of osteosarcoma cells. Moreover, PPI significantly suppressed intratibial primary tumor growth in xenograft orthotopic mouse model without any obvious side effects. These therapeutic efficacies were associated with inactivation of Wnt/β-catenin pathway, as PPI treatment decreased the amount of p-GSK-3β, leading to down-regulated levels of active β-catenin. PPI induced inhibition of osteosarcoma cell viability was abolished upon addition of GSK-3β specific inhibitor, CHIR99021, while PPI induced inhibition of osteosarcoma cell viability and migration were potentiated by β-catenin silencing. These findings suggested that, in vitro and in vivo, PPI treatment inhibited osteosarcoma, at least in part, via the inactivation of Wnt/β-catenin pathway. Thus, PPI could serve a novel therapeutic option for osteosarcoma patients.
Different effects of accelerated development and enhanced growth on oxidative stress and telomere shortening in amphibian larvae
Authors: Burraco Pablo , Díaz-Paniagua Carmen , Gomez-Mestre Ivan
Published: August 2017

Organisms react to environmental changes through plastic responses that often involve physiological alterations with the potential to modify life-history traits and fitness. Environmentally induced shifts in growth and development in species with complex life cycles determine the timing of transitions between subsequent life stages, as well as body condition at transformation, which greatly determine survival at later stages. Here we show that spadefoot toad larvae surviving pond drying and predators experienced marked alterations in growth and development, and in their fat reserves, oxidative stress, and relative telomere length. Tadpoles accelerated development but reduced growth and consumed more fat reserves when facing pond drying. However, oxidative stress was buffered by increased antioxidant enzyme activity, and telomeres remained unchanged. Predators caused opposite effects: they reduced larval density, hence relaxing competition and allowing faster development and enhanced growth of survivors. Tadpoles surviving predators metamorphosed bigger and had larger fat bodies, increasing their short-term survival odds, but showed signs of oxidative stress and had shorter telomeres. Developmental acceleration and enhanced growth thus seemed to have different physiological consequences: reduced fat bodies and body size compromise short-term survival, but are reversible in the long run, whereas telomere shortening is non-reversible and could reduce long-term survival.
Activation-induced cytidine deaminase targets SUV4-20-mediated histone H4K20 trimethylation to class-switch recombination sites
Authors: Rodríguez-Cortez Virginia C. , Martínez-Redondo Paloma , Català-Moll Francesc , Rodríguez-Ubreva Javier , Garcia-Gomez Antonio , Poorani-Subramani Ganesh , Ciudad Laura , Hernando Henar , Pérez-García Arantxa , Company Carlos , Urquiza José M. , Ramiro Almudena R. , Di Noia Javier M. , Vaquero Alejandro , Ballestar Esteban
Published: August 2017

Activation-induced cytidine deaminase (AID) triggers antibody diversification in B cells by catalysing deamination and subsequently mutating immunoglobulin (Ig) genes. Association of AID with RNA Pol II and occurrence of epigenetic changes during Ig gene diversification suggest participation of AID in epigenetic regulation. AID is mutated in hyper-IgM type 2 (HIGM2) syndrome. Here, we investigated the potential role of AID in the acquisition of epigenetic changes. We discovered that AID binding to the IgH locus promotes an increase in H4K20me3. In 293F cells, we demonstrate interaction between co-transfected AID and the three SUV4-20 histone H4K20 methyltransferases, and that SUV4-20H1.2, bound to the IgH switch (S) mu site, is replaced by SUV4-20H2 upon AID binding. Analysis of HIGM2 mutants shows that the AID truncated form W68X is impaired to interact with SUV4-20H1.2 and SUV4-20H2 and is unable to bind and target H4K20me3 to the Smu site. We finally show in mouse primary B cells undergoing class-switch recombination (CSR) that AID deficiency associates with decreased H4K20me3 levels at the Smu site. Our results provide a novel link between SUV4-20 enzymes and CSR and offer a new aspect of the interplay between AID and histone modifications in setting the epigenetic status of CSR sites.
The transcription factor MafB promotes anti-inflammatory M2 polarization and cholesterol efflux in macrophages
Authors: Kim Hwijin
Published: August 2017

Macrophages play pivotal roles in the progression and regression of atherosclerosis. Accumulating evidence suggests that macrophage polarization into an anti-inflammatory M2 state is a key characteristic of atherosclerotic plaques undergoing regression. However, the molecular mechanisms underlying this potential association of the M2 polarization with atherosclerosis regression remain poorly understood. Further, human genetic factors that facilitate these anti-atherogenic processes remain largely unknown. We report that the transcription factor MafB plays pivotal roles in promoting macrophage M2 polarization. Further, MafB promotes cholesterol efflux from macrophage foam cells by directly up-regulating its key cellular mediators. Notably, MafB expression is significantly up-regulated in response to various metabolic and immunological stimuli that promote macrophage M2 polarization or cholesterol efflux, and thereby MafB mediates their beneficial effects, in both liver x receptor (LXR)-dependent and independent manners. In contrast, MafB is strongly down-regulated upon elevated pro-inflammatory signaling or by pro-inflammatory and pro-atherogenic microRNAs, miR-155 and miR-33. Using an integrative systems biology approach, we also revealed that M2 polarization and cholesterol efflux do not necessarily represent inter-dependent events, but MafB is broadly involved in both the processes. These findings highlight physiological protective roles that MafB may play against atherosclerosis progression.