bluuebunny/crossref_metadata_2025 huggingface dataset:
Untangling direct species associations from mediator species effects with graphical models
Authors: Popovic Gordana C. , Warton David I. , Thomson Fiona J. , Hui Francis K. C. , Moles Angela T.
Published: November 2018

Ecologists often investigate co-occurrence patterns in multi-species data in order to gain insight into the ecological causes of observed co-occurrences. Apart from direct associations between two species, two species may co-occur because they both respond in similar ways to environmental variables, or due to the presence of other (mediator) species.

A wide variety of methods are now available for modelling how environmental filtering drives species distributions. In contrast, methods for studying other causes of co-occurence are much more limited. “Graphical” methods, which can be used to study how mediator species impact co-occurrence patterns, have recently been proposed for use in ecology. However, available methods are limited to presence/absence data and methods assuming multivariate normality, which is problematic when analysing abundances.

We propose Gaussian copula graphical models (GCGMs) for studying the effect of mediator species on co-occurence patterns. GCGMs are a flexible type of graphical model which naturally accommodates all data types – binary (presence/absence), counts, as well as ordinal data and biomass, in a unified framework. Simulations for count data demonstrate that GCGMs are better able to distinguish effects of mediator species from direct associations than using existing methods designed for multivariate normal data.

We apply GCGMs to counts of hunting spiders, in order to visualise associations between species. We then analyze abundance data of New Zealand native forest cover (on an ordinal scale) to show how GCGMs can be used analyze large and complex datasets. In these data, we were able to reproduce known species relationships as well as generate new ecological hypotheses about species associations.
Recurrent losses and rapid evolution of the condensin II complex in insectsg
Authors: King T. , Leonard C.J. , Cooper J.C. , Nguyen S. , Joyce E. , Phadnis N.
Published: November 2018

Condensins play a crucial role in the organization of genetic material by compacting and disentangling chromosomes. The condensin I and condensin II complexes are widely considered to have distinct functions based on studies in a few model organisms, although the specific functions of each complex are yet to be fully understood. The condensin II complex is critical for genome organization in Drosophila, and is a key anti-pairing factor that separates homologous chromosomes in somatic cells. Intriguingly, the Cap-G2 subunit of condensin II is absent in Drosophila melanogaster, and this loss may be related to the high levels of homologous chromosome pairing in somatic cells seen in flies. Here, we find that this Cap-G2 loss predates the origin of Dipterans, and other CapG2 losses have occurred independently in multiple insect lineages. Furthermore, the Cap-H2 and Cap-D3 subunits have also been repeatedly and independently lost in several insect orders, and some taxa lack condensin II-specific subunits entirely. We used Oligopaint DNA-FISH to quantify pairing levels in ten species across seven orders, representing several different configurations of the condensin II complex. We find that all non-Dipteran insects display near-uniform low pairing levels, suggesting that some key aspects of genome organization are robust to condensin II subunit losses. Finally, we observe consistent signatures of positive selection in condensin II subunits across flies and mammals. These findings suggest that these ancient complexes are far more evolutionarily labile than previously suspected, and are at the crossroads of several forms of genomic conflicts. Our results raise fundamental questions about the specific functions of the two condensin complexes and the interplay between them in taxa that have experienced subunit losses, and open the door to further investigations to elucidate the diversity of molecular mechanisms that underlie genome organization across various life forms.
The Antibiotic Neomycin Enhances Coxsackievirus Plaque Formation
Authors: Woods Acevedo Mikal A. , Pfeiffer Julie K.
Published: November 2018

Coxsackievirus typically infects humans via the gastrointestinal tract, which has a large number of microorganisms collectively referred to as the microbiota. To study how the intestinal microbiota influence enteric virus infection, several groups have used an antibiotic regimen in mice to deplete bacteria. These studies have shown that bacteria promote infection with several enteric viruses. However, very little is known about whether antibiotics influence viruses in a microbiota-independent manner. Here, we sought to determine the effects of antibiotics on coxsackievirus B3 (CVB3) using anin vitrocell culture model in the absence of bacteria. We determined that an aminoglycoside antibiotic, neomycin, enhanced plaque size of CVB3-Nancy strain. Neomycin treatment did not alter viral attachment, translation, or replication. However, we found that the positive charge of neomycin and other positively charged compounds enhanced viral diffusion by overcoming the negative inhibitory effect of sulfated polysaccharides present in agar overlays. Overall, these data lend further evidence that antibiotics can play non-canonical roles in viral infections and that this should be considered when studying enteric virus-microbiota interactions.

Importance

Coxsackieviruses primarily infect the gastrointestinal tract of humans, but they can disseminate systemically and cause severe disease. Using antibiotic treatment regimens to deplete intestinal microbes in mice, several groups have shown the bacteria promote infection with a variety of enteric viruses. However, it is possible that antibiotics have microbiota-independent effects on viruses. Here, we show that an aminoglycoside antibiotic, neomycin, can influence quantification of coxsackievirus in cultured cells in absence of bacteria.
Natural strain variation reveals diverse biofilm regulation in squid-colonizingVibrio fischeri
Authors: Rotman Ella R. , Bultman Katherine M. , Brooks John F. , Gyllborg Mattias C. , Burgos Hector L. , Wollenberg Michael S. , Mandel Mark J.
Published: November 2018

The mutualistic symbiontVibrio fischeribuilds a symbiotic biofilm during colonization of squid hosts. Regulation of the exopolysaccharide component, termed Syp, has been examined in strain ES114, where production is controlled by a phosphorelay that includes the inner membrane hybrid histidine kinase RscS. Most strains that lack RscS or encode divergent RscS proteins cannot colonize a squid host unless RscS from a squid symbiont is heterologously expressed. In this study, we examineV. fischeriisolates worldwide to understand the landscape of biofilm regulation during beneficial colonization. We provide a detailed study of three distinct evolutionary groups ofV. fischeriand find that while the RscS-Syp biofilm pathway is required in one of the groups, two other groups of squid symbionts require Syp independent of RscS. Mediterranean squid symbionts, includingV. fischeriSR5, colonize without an RscS homolog encoded in their genome. Additionally, Group AV. fischeristrains, which form a tightly-related clade of Hawaii isolates, have a frameshift inrscSand do not require the gene for squid colonization or competitive fitness. These same strains have a frameshift insypE, and we provide evidence that this Group AsypEallele leads to an upregulation in biofilm activity. This work thus describes the central importance of Syp biofilm in colonization of diverse isolates, and demonstrates that significant evolutionary transitions correspond to regulatory changes in thesyppathway.

IMPORTANCE

Biofilms are surface-associated, matrix-encased bacterial aggregates that exhibit enhanced protection to antimicrobial agents. Previous work has established the importance of biofilm formation by a strain of luminousVibrio fischeribacteria as the bacteria colonize their host, the Hawaiian bobtail squid. In this study, expansion of this work to many natural isolates revealed that biofilm genes are universally required, yet there has been a shuffling of the regulators of those genes. This work provides evidence that even when bacterial behaviors are conserved, dynamic regulation of those behaviors can underlie evolution of the host colonization phenotype. Furthermore, this work emphasizes the importance of investigating natural diversity as we seek to understand molecular mechanisms in bacteria.
TNF-α differentially regulates cell cycle genes in promyelocytic and granulocytic HL-60/S4 cells
Authors: Jacobson Elsie C. , Jain Lekha , Perry Jo K. , Vickers Mark H. , Olins Ada L. , Olins Donald E. , O’Sullivan Justin M.
Published: November 2018

Tumor necrosis factor alpha (TNF-α) is a potent cytokine involved in systemic inflammation and immune modulation. Signaling responses that involve TNF-α are context dependent and capable of stimulating pathways promoting both cell death and survival. TNF-α treatment has been investigated as part of a combined therapy for acute myeloid leukemia due to its modifying effects on all-trans retinoic acid (ATRA) mediated differentiation into granulocytes.

To investigate the interaction between cellular differentiation and TNF-α, we performed RNA-sequencing on two forms of the human HL-60/S4 promyelocytic leukemia cell line treated with TNF-α. The ATRA-differentiated granulocytic form of HL-60/S4 cells had an enhanced transcriptional response to TNF-α treatment compared to the undifferentiated promyelocytes. The observed TNF-α responses included differential expression of cell cycle gene sets, which were generally upregulated in TNF-α treated promyelocytes, and downregulated in TNF-α treated granulocytes. This is consistent with TNF-α induced cell cycle repression in granulocytes and cell cycle progression in promyelocytes. Moreover, comparisons with gene expression changes associated with differentiation indicated that TNF-α treatment of granulocytes shifts the transcriptome towards that of a macrophage.

We conclude that TNF-α treatment promotes a divergent transcriptional program in promyelocytes and granulocytes. TNF-α promotes cell cycle associated gene expression in promyelocytes. In contrast, TNF-α stimulated granulocytes have reduced cell cycle gene expression, and a macrophage-like transcriptional program.
Immuno-proteomic interrogation of dengue infection reveals novel HLA haplotype-specific MHC-I antigens
Authors: Swaminathan Kavya , Olsson Niclas , Lund Peder J. , Marceau Caleb D. , Wagar Lisa E. , Tian Yuan , Sidney John , Weiskopf Daniela , Majzoub Karim , de Silva Aruna D. , Harris Eva , Davis Mark M. , Sette Alessandro , Carette Jan E. , Elias Joshua E.
Published: November 2018

Broadly effective vaccines against dengue virus (DENV) infection have remained elusive, despite rising infection rates in the developing world. Infection-specific peptide ligands presented on Major Histocompatibility Complexes (MHC) open new avenues for developing T-cell-based interventions. Past efforts towards mapping viral MHC epitopes were based on computational predictions that only partially reflected actual antigen presentation. To empirically identify DENV-specific MHC ligands, we developed an immuno-proteomics approach for interrogating DENV- and self-derived MHC ligands from infected B-lymphocytes. Here, we report four fundamental findings: First, over 700 infection-specific MHC-ligands reflected host cellular responses to DENV that were not apparent from the proteome. Second, we report 121 viral MHC-I ligands (108 novel) which clustered into discrete hotspots across the DENV polyprotein, some of which spanned DENV polyprotein components, described here as MHC ligands for the first time. Third, we found DENV ligands which were distinctly presented by MHC alleles previously associated with either high or low anti-DENV response. Fourth, we demonstrate that while ourin vitroassay only overlapped with a small fraction of previously described DENV T-cell epitopes, several novel MHC ligands identified here were recognized by T-cells from DENV-infected patients despite having low binding affinities. Together, these discoveries suggest that virus and host-derived MHC ligands have under-exploited potential for describing the cell biology of DENV infection, and as candidates for designing effective DENV vaccines.
Selection, linkage, and population structure interact to shape genetic variation among threespine stickleback genomes
Authors: Nelson Thomas C. , Crandall Johnathan G. , Ituarte Catherine M. , Catchen Julian M , Cresko William A.
Published: November 2018

The outcome of selection on genetic variation depends on the geographic organization of individuals and populations as well as the syntenic organization of loci within the genome. Spatially variable selection between marine and freshwater habitats has had a significant and heterogeneous impact on patterns of genetic variation across the genome of threespine stickleback fish. When marine stickleback invade freshwater habitats, more than a quarter of the genome can respond to divergent selection, even in as little as 50 years. This process largely uses standing genetic variation that can be found ubiquitously at low frequency in marine populations, can be millions of years old, and is likely maintained by significant bidirectional gene flow. Here, we combine population genomic data of marine and freshwater stickleback from Cook Inlet, Alaska, with genetic maps of stickleback fish derived from those same populations to examine how linkage to loci under selection affects genetic variation across the stickleback genome. Divergent selection has had opposing effects on linked genetic variation on chromosomes from marine and freshwater stickleback populations: near loci under selection, marine chromosomes are depauperate of variation while these same regions among freshwater genomes are the most genetically diverse. Forward genetic simulations recapitulate this pattern when different selective environments also differ in population structure. Lastly, dense genetic maps demonstrate that the interaction between selection and population structure may impact large stretches of the stickleback genome. These findings advance our understanding of how the structuring of populations across geography influences the outcomes of selection, and how the recombination landscape broadens the genomic reach of selection.
Inherited defects in natural killer cells shape tumor immune microenvironment, clinical outcome and immunotherapy response
Authors: Xu Xue , Li Jianqiang , Zou Jinfeng , Feng Xiaowen , Zhang Chao , Zheng Ruiqing , Duanmu Weixiang , Saha-Mandal Arnab , Ming Zhong , Wang Edwin
Published: November 2018

Tumor immune microenvironment (TIME) plays an important role in metastasis and immunotherapy. However, it has been not much known how to classify TIMEs and how TIMEs are genetically regulated. Here we showed that tumors were classified into TIME-rich, -intermediate and -poor subtypes which had significant differences in clinical outcomes, abundances of tumor-infiltrating lymphocytes (TILs), the degree of key immune programs’ activation, and immunotherapy response across 13 common cancer types (n= ∼6,000). Furthermore, TIME-intermediate/-poor patients had significantly more inherited genetic defects (i.e., functional germline variants) in natural killer (NK) cells, antigen processing and presentation (APP) and Wnt signaling pathways than TIME-rich patients, and so did cancer patients than non-cancer individuals (n=4,500). These results suggested that individuals who had more inherited defects in NK cells, APP and Wnt pathways had a higher risk of developing cancers. Moreover, in the 13 common cancers the number of inheritably defected genes of NK cells was significantly negative-correlated with patients’ survival, TILs’ abundance in TIMEs and immunotherapy response, suggesting that inherited defects in NK cells alone were sufficient to shape TILs’ recruitment, clinical outcome, and immunotherapy response, highlighting that NK cell activation was required in the 13 cancer types to drive the recruitment of immune troops into TIMEs. Thus, we proposed that cancer was a disease of NK cell inherited deficiencies. These results had implications in identifying of high-risk individuals based on germline genomes, implementing precision cancer prevention by adoptive transfer of healthy NK cells, and improving existing immunotherapies by combining of adoptive NK cell transfer (i.e., converting TIME-intermediate/-poor tumors into TIME-rich tumors) and anti-PD-1 or CAR-T therapy.

Contact

EW (edwin.wang@ucalgary.ca)
Chemo-mechanical Coupling in the Transport Cycle of a Type II ABC Transporter
Authors: Tamura Koichi , Sugimoto Hiroshi , Shiro Yoshitsugu , Sugita Yuji
Published: November 2018

AT P -binding cassette (ABC) transporters are integral membrane proteins that translocate a wide range of substrates across biological membranes, harnessing free energy from the binding and hydrolysis of ATP. To understand the mechanism of the inward- to outward-facing transition that could be achieved by tight regulation of ATPase activity through extensive conformational changes of the protein, we applied template-based iterative all-atom molecular dynamics (MD) simulation to the heme ABC transporter BhuUV-T. The simulations, together with biased MDs, predict two new conformations of the protein, namely, occluded (Occ) and outward-facing (OF) conformations. The comparison between the inward-facing crystal structure and the predicted two structures shows atomic details of the gating motions at the transmembrane helices and dimerization of the nucleotide-binding domains (NBDs). The MD simulations further reveal a novel role of the ABC signature motifs (LSGG[Q/E]) at the NBDs in decelerating ATPase activity in the Occ form through sporadic flipping of the side chains of the LSGG[Q/E] catalytic serine residues. The orientational changes are coupled to loose NBD dimerization in the Occ state, whereas they are blocked in the OF form where the NBDs are tightly dimerized. The chemo-mechanical coupling mechanism may apply to other types of ABC transporters having the conserved LSGG[Q/E] signature motifs.
Insights into the microbiota of Asian seabass (Lates calcarifer) with tenacibaculosis symptoms and description ofsp. nov. Tenacibaculum singaporense
Authors: Miyake Sou , Soh Melissa , Azman Muhamad Nursyafiq , Ngoh Si Yan , Orbán László , Seedorf Henning
Published: November 2018

Outbreaks of diseases in farmed fish remain a recurring problem despite the development of vaccines and improved hygiene standards on aquaculture farms. One commonly observed bacterial disease in tropical aquaculture of the South-East Asian region is tenacibaculosis, which is attributed to members of the Bacteroidetes genusTenacibaculum, most notablyT. maritimum. The impact of tenacibaculosis on fish microbiota remains poorly understood. In this study, we analysed the microbiota of different tissue types of commercially reared Asian seabass (Lates calcarifer) that showed symptoms of tenacibaculosis and compared the microbial communities to those of healthy and experimentally infected fish that were exposed to diseased farm fish. The microbiota of diseased farm fish was dominated by Proteobacteria (relative abundance±standard deviation, 74.5%±22.8%) and Bacteroidetes (18.07%±21.7%), the latter mainly comprised by a high abundance ofTenacibaculumspecies (17.6%±20.7%). In healthy seabass Proteobacteria had also highest relative abundance (48.04%±0.02%), but Firmicutes (34.2%±0.02%) and Fusobacteria (12.0%±0.03%) were the next two major constituents. Experimentally infected fish developed lesions characteristic for tenacibaculosis, but the microbiota was primarily dominated by Proteobacteria (90.4%±0.2%) and Firmicutes (6.2%±0.1%). The relative abundance ofTenacibaculumspecies in experimentally infected fish was significantly lower than in the commercially reared diseased fish and revealed a higher prevalence of differentTenacibaculumspecies. One strain was isolated and is described here assp. nov. Tenacibaculum singaporenseTLL-A1T(=DSM 106434T, KCTC 62393T). The genome ofT. singaporensewas sequenced and compared to those ofT. maritimumDSM 17995Tand the newly sequencedT. mesophilumDSM 13764T.

Importance

Fish production from aquaculture facility has become a major source of protein for human consumption and is expected to further grow to meet the growing demands. Devastating fish diseases, such as tenacibaculosis, can eradicate entire stocks of aquaculture fish in a short time and pose a serious threat to individual fish farmers and overall fish production. Understanding the disease processes and the individual microbial players involved has the potential to develop methods to prevent or mitigate infections on aquaculture farms. This study provides important insights into the microbial ecology of tenacibaculosis from an aquaculture facility in Singapore and highlights the complexity of this fish disease at two different disease stages. Furthermore, the isolation of a novelTenacibaculumspecies and comparative genome analysis of three differentTenacibaculumspecies enhance our view of this economically and environmentally important bacterial genus.
Light remote control of alternative splicing in roots through TOR kinase
Authors: Riegler Stefan , Servi Lucas , Fuchs Armin , Herz Micaela A. Godoy , Kubaczka María G. , Venhuizen Peter , Schweighofer Alois , Simpson Craig , Brown John W.S. , Meyer Christian , Kalyna Maria , Barta Andrea , Petrillo Ezequiel
Published: November 2018

For plants, light is the source of energy and the most relevant regulator of growth and adaptations to the environment by inducing changes in gene expression at various levels, including alternative splicing. Chloroplasts trigger retrograde signals that control alternative splicing in leaves and roots in response to light. Here we provide evidence suggesting that sugars, derived from photosynthesis, act as mobile signals controlling alternative splicing in roots. The inhibition of TOR kinase activity diminishes the alternative splicing response to light and/or sugars in roots, showing the relevance of the TOR pathway in this signaling mechanism. Furthermore, disrupting the function of the mitochondria abolishes alternative splicing changes supporting a key role for these organelles in this signaling axis. We conclude that sugars can act as mobile signals coordinating alternative splicing responses to light throughout the whole plant, exerting this function in roots by activating the TOR pathway.

Graphical Abstract

Art by Dr. Luciana Giono.
Tryptophan fluorescence quenching in β-lactam-interacting proteins is modulated by the structure of intermediates and final products of the acylation reaction
Authors: Triboulet Sébastien , Edoo Zainab , Compain Fabrice , Ourghanlian Clément , Dupuis Adrian , Dubée Vincent , Sutterlin Laetitia , Atze Heiner , Ethève-Quelquejeu Mélanie , Hugonnet Jean-Emmanuel , Arthur Michel
Published: November 2018

In most bacteria, β-lactam antibiotics inhibit the last cross-linking step of peptidoglycan synthesis by acylation of the active-site Ser of D,D-transpeptidases belonging to the penicillin-binding protein (PBP) family. In mycobacteria, cross-linking is mainly ensured by L,D-transpeptidases (LDTs), which are promising targets for the development of β-lactam-based therapies for multidrug-resistant tuberculosis. For this purpose, fluorescence spectroscopy is used to investigate the efficacy of LDT inactivation by β-lactams but the basis for fluorescence quenching during enzyme acylation remains unknown. In contrast to what has been reported for PBPs, we show here using a model L,D-transpeptidase (Ldtfm) that fluorescence quenching of Trp residues does not depend upon direct hydrophobic interaction between Trp residues and β-lactams. Rather, Trp fluorescence was quenched by the drug covalently bound to the active-site Cys residue of Ldtfm. Fluorescence quenching was not quantitatively determined by the size of the drug and was not specific of the thioester link connecting the β-lactam carbonyl to the catalytic Cys as quenching was also observed for acylation of the active-site Ser of β-lactamase BlaC from M. tuberculosis. Fluorescence quenching was extensive for reaction intermediates containing an amine anion and for acylenzymes containing an imine stabilized by mesomeric effect, but not for acylenzymes containing a protonated β-lactam nitrogen. Together, these results indicate that the extent of fluorescence quenching is determined by the status of the β-lactam nitrogen. Thus, fluorescence kinetics can provide information not only on the efficacy of enzyme inactivation but also on the structure of the covalent adducts responsible for enzyme inactivation.
Revealing dynamic protein acetylation across subcellular compartments
Authors: Baeza Josue , Lawton Alexis J. , Fan Jing , Smallegan Michael J. , Lienert Ian , Gandhi Tejas , Bernhardt Oliver M. , Reiter Lukas , Denu John M.
Published: November 2018

Protein acetylation is a widespread post-translational modification implicated in many cellular processes. Recent advances in mass spectrometry have enabled the cataloging of thousands of sites throughout the cell, however identifying regulatory acetylation marks have proven to be a daunting task. Knowledge of the kinetics and stoichiometry of site-specific acetylation are important factors to uncover function. Here, an improved method of quantifying acetylation stoichiometry was developed and validated, providing a detailed landscape of dynamic acetylation stoichiometry within cellular compartments. The dynamic nature of site-specific acetylation in response to serum stimulation was revealed. In two distinct human cell lines, growth factor stimulation led to site-specific, temporal acetylation changes, revealing diverse kinetic profiles that clustered into several groups. Overlap of dynamic acetylation sites among two different human cell lines suggested similar regulatory control points across major cellular pathways that include splicing, translation, and protein homeostasis. Rapid increases in acetylation on protein translational machinery suggest a positive regulatory role under pro-growth conditions. Lastly, higher median stoichiometry was observed in cellular compartments where active acetyltransferases are well-described.
Functional interrogation of a depression-related serotonergic SNP, rs6295, using a humanized mouse model
Authors: Cunningham Ashley M. , Santos Tabia L. , Gutzeit Vanessa A. , Hamilton Heather , Hen René , Donaldson Zoe R.
Published: November 2018

The serotonin 1A receptor (5-HT1A) system has been extensively implicated in modulating mood and behavior. Notably, 5-HT1A levels in humans display remarkable variation and differences in receptor levels have been linked with a variety of psychiatric disorders. Further, manipulation of receptor levels in mice suggests that changes in receptor levels that model existing human variation are sufficient to drive behavioral alterations. As a result, genetic mechanisms that modulate human 5-HT1A levels may be important for explaining individual differences in mood and behavior, representing a potential source of psychiatric disease risk. One common genetic variant implicated in differential 5-HT1A levels is the G/C single nucleotide polymorphism (SNP), rs6295, located upstream of the human 5-HT1A gene. This SNP differentially binds the transcription factor, NUDR/Deaf1, leading to cell-type specific effects on transcription in vitro. To investigate the direct effects of this SNP in the heterogeneous cellular context of the brain, we generated humanized transgenic mice using a design that maximized the local transcriptional landscape of the human HTR1A gene while also controlling for effects of genomic insertion location. Expression of the human transgene in a 5-HT1A null mouse resulted in line-dependent expression of human 5-HT1A. The effect of rs6295 on protein levels and behavior similarly differed across lines, suggesting that the penetrance of rs6295 may depend upon background genetic factors. Together, this work confirms that relatively subtle differences in 5-HT1A levels can contribute to differences in behavior and highlights the challenges of modeling human non-coding genetic variation in mice.
Continuous chromatin state feature annotation of the human epigenome
Authors: Chen Bowen , Kenari Neda Shokraneh , Libbrecht Maxwell W
Published: November 2018

Semi-automated genome annotation (SAGA) methods are widely used to understand genome activity and gene regulation. These methods take as input a set of sequencing-based assays of epigenomic activity (such as ChIP-seq measurements of histone modification and transcription factor binding), and output an annotation of the genome that assigns a chromatin state label to each genomic position. Existing SAGA methods have several limitations caused by the discrete annotation framework: such annotations cannot easily represent varying strengths of genomic elements, and they cannot easily represent combinatorial elements that simultaneously exhibit multiple types of activity. To remedy these limitations, we propose an annotation strategy that instead outputs a vector of chromatin state features at each position rather than a single discrete label. Continuous modeling is common in other fields, such as in topic modeling of text documents. We propose a method, epigenome-ssm, that uses a Kalman filter state space model to efficiently annotate the genome with chromatin state features. We show that chromatin state features from epigenome-ssm are more useful for several downstream applications than both continuous and discrete alternatives, including their ability to identify expressed genes and enhancers. Therefore, we expect that these continuous chromatin state features will be valuable reference annotations to be used in visualization and downstream analysis.
Transcriptome dynamics in developing leaves from C3and C4Flaveriaspecies reveal determinants of Kranz anatomy
Authors: Billakurthi Kumari , Wrobel Thomas J. , Bräutigam Andrea , Weber Andreas P.M. , Westhoff Peter , Gowik Udo
Published: November 2018

C4species have evolved more than 60 times independently from C3ancestors. This multiple and parallel evolution of the complex C4trait indicates common underlying evolutionary mechanisms that might be identified by comparative analysis of closely related C3and C4species. Efficient C4function depends on a distinctive leaf anatomy that is characterized by enlarged, chloroplast rich bundle sheath cells and a narrow vein spacing. To elucidate molecular mechanisms generating this so called Kranz anatomy, we analyzed a developmental series of leaves from the C4plantFlaveria bidentisand the closely related C3speciesFlaveria robustausing leaf clearing and whole transcriptome sequencing. Applying non-negative matrix factorization on the data identified four different zones with distinct transcriptome patterns in growing leaves of both species. Comparing these transcriptome patterns revealed an important role of auxin metabolism and especially auxin homeostasis for establishing the high vein density typical for C4leaves.
Complete genome of a Measles virus from Roraima state, Brazil
Authors: Ribeiro Meneses Cátia Alexandra , Nascimento Valdinete Alves do , de Souza Victor Costa , Maito Rodrigo Melo , Aragão Gomes Marconi , Brígida Cunha Claudeth Rocha Santa , Antony Ilma de Aguiar , Silva Maria Eliane Oliveira e , Campos Daniela Palha de Souza , de Lima Guerra Corado André , Pessoa Karina Pinheiro , Monteiro Dana Cristina da Silva , Okumoto Osnei , Coelho Cunha Marília , Caselli Pacheco Flávia , Naveca Felipe Gomes
Published: November 2018

Measles is a human infectious disease of global concern caused by the measles virus. In this study, we report the complete genome sequencing of one measles isolate, genotype D8, obtained in Boa Vista city, the capital of the Roraima State, Brazil, directly from the urine sample. Phylogenetics reconstruction grouped the genome described in this study with samples from Australia, Italy, United Kingdom, and the USA. To our knowledge, this is the first complete genome of a wild-type measles virus from Latin America. Therefore, the present data strengthens the current knowledge about the molecular epidemiology of measles worldwide.

Sponsorships

CNPq / CAPES / MS-DECIT / Fiocruz
Early-onset infant epileptic encephalopathy associated with a de novoPPP3CAgene mutation
Authors: Qian Yanyan , Wu Bingbing , Lu Yulan , Dong Xinran , Qin Qian , Zhou Wenhao , Wang Huijun
Published: November 2018

Epileptic encephalopathies are severe seizure disorders accompanied by intellectual disability. Whole-exome sequencing technology has enabled the discovery of genetic mutations responsible for a wide range of diseases, and severe epilepsy and neurodevelopmental diseases are often associated with rare de novo mutations. We identified a novel de novo frameshift mutation in thePPP3CAgene encoding calcium-dependent protein phosphatase (calcineurin) catalytic subunit A (c.1255_1256del, p.Ser419Cysfs*31) in an 11.5-mo-old female with early-onset refractory epilepsy and developmental delay. This finding expands the list ofPPP3CAmutations associated with early-onset severe neurodevelopmental disease with seizures and provides further details on clinical features.
Lifecycle-oriented design of ceramic tiles in sustainable supply chains (SSCs)
Authors: Settembre Blundo Davide , García Muiña Fernando Enrique , Pini Martina , Volpi Lucrezia , Siligardi Cristina , Ferrari Anna Maria
Published: November 2018

Purpose

The purpose of this paper is to analyse the production cycle of glazed porcelain stoneware, from the extraction of raw materials to the packaging of the finished product, with the aim of verifying the effects of integrating an environmental impact assessment into the decision-making process for managing the life cycle, to make it economically and ecologically sustainable, in a holistic approach along the supply-chain.

Design/methodology/approach

The research is performed using the life cycle assessment and life cycle costing methodologies, to identify environmental impacts and costs, that occur during extraction of raw materials, transportation, ceramic tiles production, material handling, distribution and end-of-life stages within a cradle to grave perspective.

Findings

Through the use of a comprehensive analysis of the environmental impact assessment and related externalities, three possible strategic options to improve the environmental performance and costs of ceramic tile production were formulated, leveraging sustainability as a competitive advantage.

Research limitations/implications

This exploratory research opens future lines of investigation, the first of which is to confirm the technological feasibility and market responsiveness to the three strategic solutions hypothesised thanks to the use of an innovative eco-design technique.

Originality/value

The research has allowed testing and validating the tools of environmental impact assessment (life cycle assessment) and economic impact assessment (life cycle costing as structured methodologies in a life cycle management framework, to help companies implement competitive strategies based on sustainability.
Developing a European Standard for International Data Transfers after Snowden: Opinion 1/15 on the EU‐Canada PNR Agreement
Authors: Zalnieriute Monika
Published: November 2018

In Opinion 1/15 the Court of Justice of the European Union (CJEU) held that the proposed EU‐Canada Passenger Name Record (PNR) agreement must be revised because parts of it are incompatible with the EU fundamental rights framework. This note argues that the significance of Opinion 1/15 can only be understood in the broader historical context of increasing international securitisation between the 9/11 attacks in 2001 and the Snowden revelations in 2013. Opinion 1/15 emerges as a powerful addition to the existing data privacy trilogy established by the CJEU in the post‐Snowden era in an attempt to re‐balance the terms of international cooperation in data‐sharing between the EU and other countries. These terms were largely modelled around national security interests that have gained significant prominence in the aftermath of 9/11. While pro‐securitisation policies have been successful in gaining support among private and public actors, it is doubtful whether the CJEU pushback – without political support from EU Commission and Member States ‐ will achieve similar success.
Homicidal Paraquat Poisoning
Authors: Chen Fan , Ye Yi , Jin Bo , Yi Bo , Wei Qingtao , Liao Linchuan
Published: November 2018

Paraquat poisoning usually results from suicide, occupational, or accidental exposure. Herein, we report a rare fatal case of homicidal paraquat poisoning. A 58‐year‐old man was poisoned by taking paraquat‐mixed medicine and wearing paraquat‐soaked underwear. In the absence of a history of paraquat exposure, the patient was misdiagnosed with pulmonary infection and scrotal dermatitis and died of respiratory failure 24 days after the initial exposure to paraquat. Ultra‐performance liquid chromatography‐tandem mass spectrometry (UPLC‐MS/MS) was applied to detect and quantify paraquat in postmortem specimens. The concentration of paraquat in postmortem specimens from high to low is lung (0.49 μg/g), brain (0.32 μg/g), kidney (0.24 μg/g), liver (0.20 μg/g), cardiac blood (0.11 μg/mL), and stomach wall (<LOQ). Identification of homicidal paraquat poisoning is not easy for a clinician or a forensic pathologist, it is important to consider the possibility of paraquat poisoning when patients suffer from rapidly aggravating pneumonia of unknown origin.
HCN4 Gene Variations in Sudden Unexplained Nocturnal Death Syndrome in the Southern Han Chinese Population,
Authors: Wu Qiuping , Zhao Qianhao , Yin Kun , Hu Bing‐jie , Cheng Jianding
Published: November 2018

Sudden unexplained nocturnal death syndrome (SUNDS) is widely considered to be related to hereditary fatal arrhythmias. Hyperpolarization‐activated cyclic nucleotide‐gated channel 4 (HCN4) channels are widely distributed in sinus myocytes and play a profound role in generating pacemaker electro‐activity in cardiomyocytes. In the present study, the potential correlation between HCN4 gene variations and the occurrence of SUNDS was investigated. Genomic DNA was extracted from blood samples of both 119 unrelated SUNDS patients and 184 healthy individuals and screened for candidate HCN4 gene variants. One missense heterozygous variant c.1578C>T (Ala195Val) and four synonymous heterozygous variants c.1552C>T, c.2833C>T, c.3823C>T, and c.4189C>A were discovered in the SUNDS cases. The missense variant c.1578C>T (Ala195Val) was absent in 163 recruited controls and 105 persons of the Southern Han Chinese population, had in‐silico prediction indications as damaging, and was reported prevalent in sudden infant death, and is thus likely to be involved in SUNDS.
The CERN Community; A Mechanism for Effective Global Collaboration?
Authors: Robinson Mark
Published: November 2018

Gridlock is a term to describe the breakdown in cooperation of countries in international institutions to address policy problems that span borders; it refers both to deadlock in existing organisations and the difficulty of countries to come to new agreements as issues arise. Global science mega‐projects and their communities have seemingly been remarkably effective in evolving complex processes and mechanisms to enable collaboration. Previous research into CERN has focused on recounting the stories of CERN's scientific feats and technical innovations. This research has investigated the reasons behind these triumphs from a social sciences’ perspective to see why it is an exemplar of organisational success. The CERN communities’ governance and leadership regimes are examined. Extensive field work has added insights into two themes that emerge from the literature: the primacy of the state and the employment of combined routes through and beyond gridlock. Through exercising consensual governance with its Member States to manage multi‐polarity and using a light leadership approach with collaborative partners and international staff, CERN consistently achieves outstanding results. This research contributes to the global gridlock debate by being part of the examination of pathways and mechanisms in successful international collaborations.
PI3K activation within ventromedial prefrontal cortex regulates the expression of drug‐seeking in two rodent species
Authors: Szumlinski Karen K. , Ary Alexis W. , Shin Christina B. , Wroten Melissa G. , Courson Justin , Miller Bailey W. , Ruppert‐Majer Micaela , Hiller John W. , Shahin John R. , Ben‐Shahar Osnat , Kippin Tod E.
Published: November 2018

Phosphatidylinositide 3‐kinases (PI3Ks) are intracellular signal transducer enzymes that recruit protein kinase B (aka Akt) to the cell membrane, the subsequent activation of which regulates many cellular functions. PI3K/Akt activity is up‐regulated within mesocorticolimbic structures in animal models of alcoholism, but less is known regarding PI3K/Akt activity in animal models of cocaine addiction. Given that prefrontal cortex (PFC) is grossly dysregulated in addiction, we studied how cocaine affects protein indices of PFC PI3K/Akt activity in rat and mouse models and examined the relevance of PI3K activity for cocaine‐related learning. Immunoblotting of mouse medial PFC at 3 weeks withdrawal from a cocaine‐sensitization regimen (seven injections of 30 mg/kg, intraperitoneal [IP]) revealed increased kinase activity, as did immunoblotting of tissue from the ventral PFC of rats with a history of long‐access intravenous cocaine self‐administration (0.25 mg/0.1 mL infusion; 10 days of 6 h/d cocaine access). Interestingly, increased Akt phosphorylation was observed in rat ventromedial PFC at both 3‐ and 30‐day withdrawal only in animals re‐exposed to cocaine‐associated cues. A conditioned place‐preference paradigm in mice and a cue‐elicited drug‐seeking test in rats were conducted to determine the functional relevance for elevated PI3K activity for addiction‐related behavior. In both cases, an intra‐PFC infusion of the PI3K inhibitor wortmannin (50μM) reduced drug‐seeking behavior. Taken together, this cross‐species, interdisciplinary, study provides convincing evidence that cocaine history produces an enduring increase in PI3K/Akt‐dependent signaling within the more ventral aspect of the PFC that is relevant to behavioral reactivity to drug‐associated cues/contexts. As such, PI3K inhibitors may well serve as an effective strategy for reducing drug cue reactivity and craving in cocaine addiction.
A comparison of embalming fluids on the structures and properties of tissue in human cadavers
Authors: Balta Joy Y. , Twomey Maria , Moloney Fiachra , Duggan Orla , Murphy Kevin P. , O’Connor Owen J. , Cronin Michael , Cryan John F. , Maher Michael M. , O’Mahony Siobhain M.
Published: November 2018

Cadaveric material has long been used to teach anatomy and more recently to train students in clinical skills. The aim of this study was to develop a systematic approach to compare the impact of four embalming solutions on the tissues of human cadavers. To this end, a formalin‐based solution, Thiel, Genelyn and Imperial College London soft‐preservation (ICL‐SP) solution were compared. The effect of these chemicals on the properties of the tissue was assessed by measuring the range of motion (ROM) of joints and measuring the dimensions of different structures on computed tomography (CT) images before and after embalming. The mean changes in the ratio (angle to ROM) differed statistically between embalming methods (Welch Statistic 3,1.672 = 67.213, p = 0.026). Thiel embalmed cadavers showed an increase in range of motion while ICL‐SP cadavers remained relatively the same. Genelyn and formalin embalmed cadavers registered a notable decrease in range of motion. Furthermore, investigation into the impact of the embalming chemicals on the dimensions of internal organs and vessels revealed that Thiel embalming technique leads to a decrease in the dimension of the cardiovascular system alone while formalin‐based solutions maintain the shape of the organs and vessels investigated. Our findings suggest that the joints of cadavers’ embalmed using ICL‐SP technique may faithfully mimic that of unembalmed cadavers and that formalin is necessary to retain shape and size of the organs and vessels investigated in this study. Despite this, a study with larger numbers of cadavers is required to confirm these findings.
Expression of glial cells molecules in the optic nerve of adult dromedary camel (Camelus dromedarius): A histological and immunohistochemical analysis
Authors: Metwally Elsayed , Farouk Sameh M. , Hossain Md Shafayat , Raihan Obayed
Published: November 2018

The optic nerve (ON) is an important organ in the visual system of animals, which transfers electrical impulses towards the brain from the retina. High enrichment of glial cells in ON is known to support neuron and regulate retinal homoeostasis. However, research on immunohistochemical of glial cells proteins in the camel is scanty in available literature. Hence, the current work is an attempt to investigate the histomorphology of camel ON with regard to the expression patterns of glial fibrillary acidic protein (GFAP), myelin basic protein (MBP) and Iba1 for the three glial subtypes, namely astrocytes, oligodendrocytes and microglia, respectively. Optic nerves from fourteen dromedary camels were dissected and preserved in 10% formalin. Then, the paraffin‐embedding sections were subjected for histochemical and immunohistochemical analysis. Our results demonstrated that ON axons aggregate into fascicles that surrounded by light and densely stained glial cells. Then, we examined the myelin sheath using Heidenhain's and Mallory's phosphotungstic acid staining. Immunoassay results revealed that GFAP is enriched in the ON and distributed evenly, whereas MBP and Iba1 were present at scanty levels. Further analysis of mRNA level of GFAP, MBP and Iba1 in the ON confirmed an elevation of GFAP expression compared to MBP and Iba1. We further found partial co‐localization of different types of glial cells that reflect their coordinated function in the ON. Although our data provide the first evidence for differential expression pattern of glial proteins, further molecular studies still required to reveal the specific function of these molecules in the camel ON.
The Ballerina and the Minister: Turf Wars and the Australian Government's Exceptional Granting of Political Asylum in 1980
Authors: Neumann Klaus , Taylor Savitri
Published: November 2018

On 22 April 1980, Australian Foreign Minister Andrew Peacock announced that East German ballet dancer Heidrun Giersch had been granted political asylum. His announcement came as a surprise, because it made Giersch become one of only a handful of people ever to be granted political asylum in Australia. This article explores the circumstances that led to Peacock's decision. We argue that it was not informed by considerations about any persecution faced by Giersch, nor was it the outcome of attempts to shore up support for an Australian boycott of the Moscow Olympic Games, as variously claimed at the time. Rather, it has to be seen in the context of different policies governing the granting of political asylum and the granting of protection following the determination of refugee status, and of conflicts between the Minister for Foreign Affairs and his department, on the one hand, and the Immigration Minister and the Department of Immigration and Ethnic Affairs, on the other, about their respective responsibilities for Australia's refugee and asylum seeker policies.