bluuebunny/crossref_metadata_2025 huggingface dataset:
Environmental oestrogens cause predation-induced population decline in a freshwater fish
Authors: Rearick Daniel C. , Ward Jessica , Venturelli Paul , Schoenfuss Heiko
Published: October 2018

Understanding population-level effects of environmental stressors on aquatic biota requires knowledge of the direct adverse effects of pollutants on individualsandspecies interactions that relate to survival and reproduction. Here, we connect behavioural assays with survival trials and a modelling approach to quantify changes in antipredator escape performance of a larval freshwater fish following exposure to an environmental oestrogen, and predict changes in population abundance. We quantified the effects of short-term (21 days) exposure to 17β-oestradiol (E2) on the antipredator escape performance of larval fathead minnows (Pimephales promelas) and the probability of predation by a natural predator, the bluegill sunfish (Lepomis macrochirus). Compared with unexposed minnows, minnows exposed to environmentally relevant concentrations of E2 that approach total oestrogenic activity of wastewater-dominated environments (38 and 103 ng l−1) had delayed response times and slower escape speeds, and were more susceptible to predation. Incorporating these data into a stage-structured population model demonstrated that enhanced predation mortality at the larval stage can result in population declines. These results indicate that subtle, sub-lethal shifts in the behaviour of individuals due to human-mediated environmental change can impact species interactions with measurable population-level effects. Such changes have the potential to alter higher-order trophic interactions and disrupt aquatic communities.
On the development of instabilities in an annulus and a shell composed of a poro-hyperelastic material
Authors: Selvadurai A. P. S. , Suvorov A. P.
Published: October 2018

The paper investigates the development of instability in an internally pressurized annulus of a poro-hyperelastic material. The theory of poro-hyperelasticity is proposed as an approach for modelling the mechanical behaviour of highly deformable elastic materials, the pore space of which is saturated with a fluid. The consideration of coupling between the mechanical response of the hyperelastic porous skeleton and the pore fluid is important when applying the developments to soft tissues encountered in biomechanical applications. The paper examines the development of an instability in a poro-hyperelastic annulus subjected to internal pressure. Using a computational approach, numerical solutions are obtained for the internal pressures that promote either short-term or long-term instability in a poro-hyperelastic annulus and a poro-hyperelastic shell. In addition, time-dependent effects of stability loss are examined. The analytical solutions are used to benchmark the accuracy of the computational approach.
Stability analysis of Beck's column over a fractional-order hereditary foundation
Authors: Bologna E. , Zingales M.
Published: October 2018

This paper considers the case of Beck's column resting on a hereditary bed of independent springpots. The springpot possesses an intermediate rheological behaviour among linear spring and linear dashpot. It is defined by means of couple (
C

β

, 
β
) that characterize the material of the element and is ruled by a Caputo's fractional derivative. In this paper, we investigate the critical load of the column under the action of a follower load by means of a novel complex transform that allows to use the Routh–Hurwitz theorem in the complex half-plane for the stability analysis.
Physics of unsteady thrust and flow generation by a flexible surface flapping in the absence of a free stream
Authors: Shinde Sachin Y. , Arakeri Jaywant H.
Published: October 2018

Inspired by the flexible wings and fins of flying and swimming animals, we investigate the flow induced by the interaction between a flapping flexible surface and the surrounding fluid for the limiting case of Strouhal numberSt→∞(zero free-stream speed). The model selected for this purpose is a two-dimensional sinusoidally pitching rigid symmetric foil to which is attached at the trailing edge a thin chordwise flexible surface (along the chord line). The flow so generated is a coherent jet aligned along the foil centreline, containing a reverse Bénard–Kármán vortex street and delivering a corresponding unidirectional thrust. We analyse the flow and thrust generation process. The measured velocity field suggests that the flow and thrust generation mainly occurs during the phases when the trailing edge is near the centreline. Flexibility of the surface is important in accelerating the near-wake flow and in transferring momentum and energy to the fluid. We present a detailed account of when and where the momentum and energy are added to the fluid. This study shows that the deformations of the flexible surface are responsible for generating a favourable pressure gradient along the jet direction, and for the observed unsteady actuator disc-type action.
A simple derivation of the quantum state from two assumptions
Authors: Sun Bo-Yu
Published: October 2018

In this paper, based on the discussion on what the real state of a coin at each point should be, we propose two basic assumptions. Then we point out the mathematical foundations that these two assumptions rely on and the familiar physical principles which these two assumptions, respectively, correspond to. These two assumptions, as required, do not seek help from the well-known formulation of quantum mechanics. They are self-consistent in a new presentation. Based on two basic assumptions, we derive the real state in a simple way and claim that the real state equals the quantum state totally after comparison from different aspects. We thus prove that the quantum state is the ontological object which obeys the redefinition of the reality rather than just a vague concept in quantum theory. We also consider the way in which Born's rule arises naturally.
DNA methylation links prenatal smoking exposure to later life health outcomes in offspring
Authors: Wiklund Petri , Karhunen Ville , Richmond Rebecca C , Rodriguez Alina , De Silva Maneka , Wielscher Matthias , Rezwan Faisal I , Richardson Tom G , Veijola Juha , Heinz-Herzig Karl , Holloway John W , Relton Caroline L , Sebert Sylvain , Järvelin Marjo-Riitta
Published: October 2018

Maternal smoking during pregnancy is associated with adverse offspring health outcomes across their life course. We hypothesize that DNA methylation is a potential mediator of this relationship. To test this, we examined the association of prenatal maternal smoking with DNA methylation in 2,821 individuals (age 16 to 48 years) from five prospective birth cohort studies and perform Mendelian randomization and mediation analyses to assess, whether methylation markers have causal effects on disease outcomes in the offspring. We identify 69 differentially methylated CpGs in 36 genomic regions (P < 1×10−7), and show that DNA methylation may represent a biological mechanism through which maternal smoking is associated with increased risk of psychiatric morbidity in the exposed offspring.
Clean lighting leads to decreased indoor air pollution and improved respiratory health in rural Uganda
Authors: Nyakato Viola N. , Mwine Nicholas , Aiden Erez Lieberman , Aiden Aviva P.
Published: October 2018

Abstract

Exposure to smoke is a major cause of respiratory illness in the developing world. To date, cookstoves have been the most widely studied source of smoke exposure in developing countries. We hypothesized that exposure to kerosene lighting, utilized by 86% of rural off-the-grid communities in sub-Saharan Africa may also be a significant source of smoke exposure and may be responsible for respiratory pathology. We performed an interventional field trial including 230 people in rural Uganda to assess the impact of clean lighting on indoor air pollution and respiratory health. Each member of the study households were asked about their exposure to smoke, the types of lighting they used, and their recent history of respiratory symptoms. Next, we provided solar-powered lamps to households in the intervention group, and compared to households in the control group who continued to use kerosene lamps. We monitored indoor air quality in a subset of intervention and control households over a three-month period, and performed an exit survey to assess symptoms of respiratory illness in both groups. All of the households we surveyed were found to use kerosene lamps as their primary lighting source. We found that the average person was exposed to 3.3 hours of smoke from kerosene lamps, as compared to 44 minutes of exposure from cookstoves. Next, we found that average soot levels (elemental carbon) in intervention homes were 19-fold lower than soot levels in control homes. After three months, we observed reduced rates of all symptoms assessed, and significantly reduced risk of cough, sore throat, and overall illness in the intervention homes. Our findings demonstrate that kerosene lighting is a significant source of smoke exposure in the developing world, and that the introduction of clean lighting in homes reliant on kerosene lighting can have a rapid and significant impact on overall health.
A curated list of genes that control elemental accumulation in plants
Authors: Whitt Lauren , Ricachenevsky Felipe Klein , Ziegler Greg , Clemens Stephan , Walker Elsbeth , Maathuis Frans JM , Kear Philip , Baxter Ivan
Published: October 2018

Understanding the mechanisms underlying plants’ adaptation to their environment will require knowledge of the genes and alleles underlying elemental composition. Modern genetics is capable of quickly, and cheaply indicating which regions of DNA are associated with particular phenotypes in question, but most genes remain poorly annotated, hindering the identification of candidate genes. To help identify candidate genes underlying elemental accumulations, we have created the known ionome gene (KIG) list: a curated collection of genes experimentally shown to change uptake, accumulation, and distribution of elements. We have also created an automated computational pipeline to generate lists of KIG orthologs in other plant species using the PhytoMine database. The current version of KIG consists of 176 known genes covering 5 species, 23 elements and their 1588 orthologs in 10 species. Analysis of the known genes demonstrated that most were identified in the model plant Arabidopsis thaliana, and that transporter coding genes and genes altering the accumulation of iron and zinc are overrepresented in the current list.
Learning mechanism of chromatin domain formation with big data
Authors: Xie Wen Jun , Zhang Bin
Published: October 2018

Chromatin modifications play critical roles in gene regulation and encoding cell phenotypic diversity. The molecular mechanism for their establishment and maintenance is not fully understood due to the complexity of chromatin regulatory pathways. Here we took a data-driven approach and parameterized an information-theoretic model to infer mechanism of chromatin domain formation from genome-wide epigenetic modification profiles. The energy landscape of this model reveals many important chromatin domains that span multiple nucleosomes and exhibit distinct combinatorial patterns of histone modifications, including super (stretch) enhancers, broad H3K4me3 promoter domains, heterochromatin, etc. Transition path analysis further demonstrates that enhancer and promoter domains undergo a sequential maturation process along which the regulatory elements grow from short but stable nucleosome segments to long and potent ones that are modified with many activation marks. On the other hand, the formation of heterochromatin domains is a highly cooperative process, and no intermediate states were found along the transition path. Interaction energies of the information-theoretic model further suggest that heterochromatin domains adopt collapsed, globular three-dimensional conformations that can be stabilized by phase-separated liquid droplets.Our results demonstrate the usefulness of statistical mechanical models and molecular biophysical approaches in interpreting the rich information encoded in epigenomics data.
Infectious Entry of Merkel Cell Polyomavirus
Authors: Becker Miriam , Dominguez Melissa , Greune Lilo , Soria-Martinez Laura , Pfleiderer Moritz M. , Schowalter Rachel , Buck Christopher B. , Blaum Bärbel S. , Alexander Schmidt M. , Schelhaas Mario
Published: October 2018

Merkel Cell Polyomavirus (MCPyV) is a small, non-enveloped tumor virus associated with an aggressive form of skin cancer, the Merkel cell carcinoma (MCC). MCPyV infections are highly prevalent in the human population with MCPyV virions being continuously shed from human skin. However, the precise host cell tropism(s) of MCPyV remains unclear: MCPyV is able to replicate within a subset of dermal fibroblasts, but MCPyV DNA has also been detected in a variety of other tissues. However, MCPyV appears different from other polyomaviruses as it requires sulfated polysaccharides such as heparan sulfates and/or chondroitin sulfates for initial attachment. Like other polyomaviruses, MCPyV engages sialic acid as a (co-receptor). To explore the infectious entry process of MCPyV, we analyzed the cell biological determinants of MCPyV entry into A549 cells, a highly transducible lung carcinoma cell line, in comparison to well-studied simian virus 40 and a number of other viruses. Our results indicate that MCPyV enters cells via caveolar/lipid raft-mediated endocytosis but not macropinocytosis, clathrin-mediated endocytosis or glycosphingolipid-enriched carriers. The viruses internalized in small endocytic pits that led the virus to endosomes and from there to the endoplasmic reticulum (ER). Similar to other polyomaviruses, trafficking required microtubular transport, acidification of endosomes, and a functional redox environment. To our surprise, the virus was found to acquire a membrane envelope within endosomes, a phenomenon not reported for other viruses. Only minor amounts of viruses reached the ER, while the majority was retained in endosomal compartments suggesting that endosome-to-ER trafficking is a bottleneck during infectious entry.

Importance

MCPyV is the first polyomavirus directly implicated in the development of an aggressive human cancer, the Merkel Cell Carcinoma (MCC). Although MCPyV is constantly shed from healthy skin, MCC incidence increases among aging and immunocompromised individuals. To date, the events connecting initial MCPyV infection and subsequent transformation still remain elusive. MCPyV differs from other known polyomaviruses concerning its cell tropism, entry receptor requirements, and infection kinetics. In this study, we examined the cellular requirements for endocytic entry as well as the subcellular localization of incoming virus particles. A thorough understanding of the determinants of the infectious entry pathway and the specific biological niche will benefit prevention of virus-derived cancers such as MCC.
PRODIGY: personalized prioritization of driver genes
Authors: Dinstag Gal , Shamir Ron
Published: October 2018

Background

Evolution of cancer is driven by few somatic mutations that disrupt cellular processes, causing abnormal proliferation and tumor development, while most somatic mutations have no impact on progression. Distinguishing those mutated genes that drive tumorigenesis in a patient is a primary goal in cancer therapy: Knowledge of these genes and the pathways on which they operate can illuminate disease mechanisms and indicate potential therapies and drug targets. Current research focuses mainly on cohort-level driver gene identification, but patient-specific driver gene identification remains a challenge.

Methods

We developed a new algorithm for patient-specific ranking of driver genes. The algorithm, called PRODIGY, analyzes the expression and mutation profiles of the patient along with data on known pathways and protein-protein interactions. Prodigy quantifies the impact of each mutated gene on every deregulated pathway using the prize collecting Steiner tree model. Mutated genes are ranked by their aggregated impact on all deregulated pathways.

Results

In testing on five TCGA cancer cohorts spanning >2500 patients and comparison to validated driver genes, Prodigy outperformed extant methods and ranking based on network centrality measures. Our results pinpoint the pleiotropic effect of driver genes and show that Prodigy is capable of identifying even very rare drivers. Hence, Prodigy takes a step further towards personalized medicine and treatment.

Availability

The Prodigy R package is available at: https://github.com/Shamir-Lab/PRODIGY.
Is physiological stress state reflected in acoustic structure of vocalizations? An experimental test in wild North American red squirrels
Authors: Sehrsweeney Matt , Wilson David R. , Bain Maggie , Boutin Stan , Lane Jeffrey E. , McAdam Andrew G. , Dantzer Ben
Published: October 2018

Acoustic signaling is an important means by which animals communicate both stable and labile characteristics. Although it is widely appreciated that vocalizations can convey information on labile state, such as fear and aggression, very few studies have experimentally examined the acoustic expression of short-term stress state. The transmission of such information about physiological state could have broad implications, potentially allowing other individuals to modify their behavior or life history traits in response to this public information. North American red squirrels (Tamiasciurus hudsonicus) produce vocalizations known as rattles that advertise territorial ownership. We examined the influence of changes in physiological stress state on rattle acoustic structure through the application of a stressor (trapping and handling the squirrels) and by provisioning squirrels with exogenous glucocorticoids (GCs). We characterized the acoustic structure of rattles emitted by these squirrels by measuring rattle duration, mean frequency, and entropy. Our results provide mixed evidence that rattles show a “stress signature”. When squirrels were trapped and handled, they produced rattles that were longer in duration with a higher frequency and increased entropy. However, squirrels that were administered exogenous GCs had similar rattle duration, frequency, and entropy as squirrels that received control treatments and unmanipulated (unfed) squirrels. Our results indicate that short-term stress does affect the acoustic structure of vocalizations, but elevated circulating GC levels are not solely responsible for such changes.
Personalized and graph genomes reveal missing signal in epigenomic data
Authors: Groza Cristian , Kwan Tony , Soranzo Nicole , Pastinen Tomi , Bourque Guillaume
Published: October 2018

Background

Epigenomic studies that use next generation sequencing experiments typically rely on the alignment of reads to a reference sequence. However, because of genetic diversity and the diploid nature of the human genome, we hypothesized that using a generic reference could lead to incorrectly mapped reads and bias downstream results.

Results

We show that accounting for genetic variation using a modified reference genome (MPG) or a denovo assembled genome (DPG) can alter histone H3K4me1 and H3K27ac ChIP-seq peak calls by either creating new personal peaks or by the loss of reference peaks. MPGs are found to alter approximately 1% of peak calls while DPGs alter up to 5% of peaks. We also show statistically significant differences in the amount of reads observed in regions associated with the new, altered and unchanged peaks. We report that short insertions and deletions (indels), followed by single nucleotide variants (SNVs), have the highest probability of modifying peak calls. A counter-balancing factor is peak width, with wider calls being less likely to be altered. Next, because high-quality DPGs remain hard to obtain, we show that using a graph personalized genome (GPG), represents a reasonable compromise between MPGs and DPGs and alters about 2.5% of peak calls. Finally, we demonstrate that altered peaks have a genomic distribution typical of other peaks. For instance, for H3K4me1, 518 personal-only peaks were replicated using at least two of three approaches, 394 of which were inside or within 10Kb of a gene.

Conclusions

Analysing epigenomic datasets with personalized and graph genomes allows the recovery of new peaks enriched for indels and SNVs. These altered peaks are more likely to differ between individuals and, as such, could be relevant in the study of various human phenotypes.
Novel Mechanism for Surface Layer Shedding and Regenerating in Bacteria Exposed to Metal-Contaminated Conditions
Authors: Chandramohan Archjana , Duprat Elodie , Remusat Laurent , Zirah Severine , Lombard Carine , Adrienne Kish
Published: October 2018

Surface layers (S-layers) are self-assembling, ordered structures composed of repeating protein subunits found as components of the cell walls throughout the Bacteria and the Archaea. S-layers act as an interface between prokaryotic cells and their surrounding environment, and provide protection for microorganisms against diverse environmental stresses including heavy metal stress. We have previously characterized the process by which S-layers serve as a nucleation site for metal mineralization in the presence of high concentration of metals. Here, we test the hypothesis originally proposed in cyanobacteria that a “shedding” mechanism exists in prokaryotes for replacing S-layers that have become mineral-encrusted. We used a metallotolerant gram-positive bacterium bearing an S-layer,Lysinibacillussp. TchIII 20n38, as a model organism. We characterize for the first time a mechanism for resistance to metals through S-layer shedding and regeneration. S-layers nucleate the formation of Fe-mineral on the cell surface, leading to the encrustation of the S-layer. Using a combination of scanning electron microscopy (SEM) and nanoSIMS, we show that mineral-encrusted S-layers are shed by the bacterial cells, and the emerging cells regenerate new S-layers as part of their cell wall structure. This novel mechanism for the survival of prokaryotes in metal-contaminated environments may also provide elements necessary for the development of renewable systems for metal bioremediation.
N6-methyladenosine mRNA marking promotes selective translation of regulons required for human erythropoiesis
Authors: Kuppers Daniel A. , Arora Sonali , Lim Yiting , Lim Andrea , Carter Lucas , Corrin Philip , Plaisier Christopher L. , Basom Ryan , Delrow Jeffrey J. , Wang Shiyan , He Housheng Hansen , Torok-Storb Beverly , Hsieh Andrew C. , Paddison Patrick J.
Published: October 2018

Many of the regulatory features governing erythrocyte specification, maturation, and associated disorders remain enigmatic. To identify new regulators of erythropoiesis, we performed a functional genomic screen for genes affecting expression of the erythroid marker CD235a/GYPA. Among validating hits were genes coding for the N6-methyladenosine (m6A) mRNA methyltransferase (MTase) complex, including,METTL14,METTL3, andWTAP. We found that m6A MTase activity promotes erythroid gene expression programs and lineage specification through selective translation of >200 m6A marked mRNAs, including those coding for SETD methyltransferase, ribosome, and polyA RNA binding proteins. Remarkably, loss of m6A marks resulted in dramatic loss of H3K4me3 across key erythroid-specific KLF1 transcriptional targets (e.g., Heme biosynthesis genes). Further, each m6A MTase subunit and a subset of their mRNAs targets, includingBRD7,CXXC1,PABPC1,PABPC4,STK40, andTADA2B, were required for erythroid specification. Thus, m6A mRNA marks promote the translation of a network of genes required for human erythropoiesis.
High-throughput identification of FLT3 wild-type and mutant kinase substrate preferences and application to design of sensitive in vitro kinase assay substrates
Authors: Perez Minervo , Blankenhorn John , Murray Kevin J. , Parker Laurie L.
Published: October 2018

Acute myeloid leukemia (AML) is an aggressive disease that is characterized by abnormal increase of immature myeloblasts in blood and bone marrow. The FLT3 receptor tyrosine kinase plays an integral role in haematopoiesis, and one third of AML diagnoses exhibit gain-of-function mutations in FLT3, with the juxtamembrane domain internal tandem duplication (ITD) and the kinase domain D835Y variants observed most frequently. Few FLT3 substrates or phosphorylation sites are known, which limits insight into FLT3’s substrate preferences and makes assay design particularly challenging. We applied in vitro phosphorylation of a cell lysate digest (adaptation of the Kinase Assay Linked with Phosphoproteomics (KALIP) technique and similar methods) for high-throughput identification of substrates for three FLT3 variants (wild-type, ITD mutant, and D835Y mutant). Incorporation of identified substrate sequences as input into the KINATEST-ID substrate preference analysis and assay development pipeline facilitated the design of several peptide substrates that are phosphorylated efficiently by all three FLT3 kinase variants. These substrates could be used in assays to identify new FLT3 inhibitors that overcome resistant mutations to improve FLT3-positive AML treatment.
Mutations in Rv2983 as a novel determinant of resistance to nitroimidazole drugs in Mycobacterium tuberculosis
Authors: Rifat Dalin , Li Si-Yang , Ioerger Thomas , Lanoix Jean-Philippe , Lee Jin , Bashiri Ghader , Sacchettini James , Nuermberger Eric
Published: October 2018

Delamanid represents one of two novel antimicrobial classes approved to treat tuberculosis in over 40 years. Pretomanid is another promising nitroimidazole pro-drug in clinical development. Characterization of the full spectrum of mutations conferring resistance to nitroimidazoles and their related phenotypes in Mycobacterium tuberculosis will inform development of suitable genotypic and phenotypic drug susceptibility tests. Here, we used a range of pretomanid doses to select pretomanid-resistant mutants in two pathologically distinct murine TB models. The frequency of spontaneous pretomanid resistance mutations was approximately 10−5 CFU. Pretomanid demonstrated dose-dependent bactericidal activity and selective amplification of resistant mutants. Whole genome sequencing of 161 resistant isolates from 47 mice revealed 99 unique mutations, 90% of which were found in 1 of 5 genes previously associated with nitroimidazole activation and resistance. The remaining 10% harbored isolated mutations in Rv2983. Complementing an Rv2983 mutant with a wild-type copy of Rv2983 restored wild-type susceptibility to pretomanid and delamanid, confirming that loss of Rv2983 function causes nitroimidazole resistance. By quantifying F420 and its precursor Fo in Mycobacterium smegmatis overexpressing Rv2983 and an M. tuberculosis Rv2983 mutant, we provide evidence that Rv2983 is necessary for F420 biosynthesis and nitroimidazole activation, perhaps as the guanylyltransferase CofC. F420H2-deficient mutants displayed hypersusceptibility to malachite green (MG), a selective decontaminant present in solid media used to isolate and propagate mycobacteria from clinical samples. The wide diversity of mutations causing high-level pretomanid resistance and MG hypersusceptibility of most mutants poses significant challenges to clinical detection of nitroimidazole resistance using either genotypic or phenotypic methods.

Significance

Nitroimidazole pro-drugs represent a promising new class of anti-tuberculosis drugs. Reliable methods to assure nitroimidazole susceptibility are critical to assure their optimal use. Yet, the spectrum of nitroimidazole resistance mutations remains incompletely characterized. Using 161 pretomanid-resistant Mycobacterium tuberculosis isolates selected in pretomanid-treated mice, we discovered a novel resistance determinant, Rv2983, required for cofactor F420 biosynthesis and characterized the remarkable diversity of mutations in this and 5 other genes involved in nitroimidazole activation. We show that F420H2–deficient nitroimidazole-resistant mutants are hypersusceptible to the selective decontaminant malachite green used in solid media to isolate mycobacteria and may evade detection on such media. These results have important implications for development and clinical use of genotypic and phenotypic methods for nitroimidazole susceptibility testing.
Remodelling of pSK1 Family Plasmids and Enhanced Chlorhexidine Tolerance in Methicillin-ResistantStaphylococcus aureus
Authors: Baines Sarah L , Jensen Slade O , Firth Neville , da Silva Anders Gonçalves , Seemann Torsten , Carter Glen , Williamson Deborah A. , Howden Benjamin P , Stinear Timothy P
Published: October 2018

Staphylococcus aureusis a significant human pathogen whose evolution and adaptation has been shaped in part by mobile genetic elements (MGEs), facilitating global spread of extensive antimicrobial resistance. However, our understanding of the evolutionary dynamics surrounding MGEs is incomplete, in particular how changes in the structure of multidrug-resistant (MDR) plasmids may influence important staphylococcal phenotypes. Here, we undertook a population-and functional-genomics study of 212 methicillin-resistantS. aureus(MRSA) ST239 isolates collected over 32 years to explore the evolution of the pSK1 family of MDR plasmids, illustrating how these plasmids have co-evolved with and contributed to the successful adaptation of this persistent MRSA lineage. Using complete genomes and temporal phylogenomics we reconstructed the evolution of the pSK1 family lineage from its emergence in the late 1970s, with multiple structural variants arising. Plasmid maintenance and stability was linked to IS256- and IS257-mediated chromosomal integration and disruption of plasmid replication machinery. Overlaying genomic comparisons with phenotypic susceptibility data for gentamicin and chlorhexidine, it appeared that pSK1 has contributed to enhanced resistance in ST239 MRSA through two mechanisms: (i) acquisition of plasmid-borne resistance mechanisms increasing rates of gentamicin resistance and reduced chlorhexidine susceptibility, and (ii) changes in plasmid configuration linked with further enhancement of chlorhexidine tolerance. While the exact mechanism of enhanced tolerance remains elusive, this research has uncovered a clear evolutionary response of ST239 MRSA to chlorhexidine, one which may contribute to the ongoing persistence and adaptation of this lineage within healthcare institutions.
Data Denoising with transfer learning in single-cell transcriptomics
Authors: Wang Jingshu , Agarwal Divyansh , Huang Mo , Hu Gang , Zhou Zilu , Ye Chengzhong , Zhang Nancy R.
Published: October 2018

Single-cell RNA sequencing (scRNA-seq) data is noisy and sparse. Here, we show that transfer learning across datasets remarkably improves data quality. By coupling a deep autoencoder with a Bayesian model, SAVER-X extracts transferable gene-gene relationships across data from different labs, varying conditions, and divergent species to denoise target new datasets.
Integrating Molecular Simulation and Experimental Data: A Bayesian/Maximum Entropy reweighting approach
Authors: Bottaro Sandro , Bengtsen Tone , Lindorff-Larsen Kresten
Published: October 2018

We describe a Bayesian/Maximum entropy (BME) procedure and software to construct a conformational ensemble of a biomolecular system by integrating molecular simulations and experimental data. First, an initial conformational ensemble is constructed using for example Molecular Dynamics or Monte Carlo simulations. Due to potential inaccuracies in the model and finite sampling effects, properties predicted from simulations may not agree with experimental data. In BME we use the experimental data to refine the simulation so that the new conformational ensemble has the following properties: (i) the calculated averages are close to the experimental values taking uncertainty into account and (ii) it maximizes the relative Shannon entropy with respect to the original simulation ensemble. The output of this procedure is a set of optimized weights that can be used to calculate arbitrary properties and distributions. Here, we provide a practical guide on how to obtain and use such weights, how to choose adjustable parameters and discuss shortcomings of the method.
RNA is a critical element for the sizing and the composition of phase-separated RNA-protein condensates
Authors: Navarro Marina Garcia-Jove , Kashida Shunnichi , Chouaib Racha , Souquere Sylvie , Pierron Gerard , Weil Dominique , Gueroui Zoher
Published: October 2018

Liquid-liquid phase separation is thought to be a key organizing principle in eukaryotic cells to generate highly concentrated dynamic assemblies, such as the RNP granules. Numerous in vitro approaches have validated this model, yet a missing aspect is to take into consideration the complex molecular mixture and promiscuous interactions found in vivo. Here we report the versatile scaffold “ArtiG” to generate concentration-dependent RNA-protein condensates within living cells, as a bottom-up approach to study the impact of co-segregated endogenous components on phase separation. We demonstrate that intracellular RNA seeds the nucleation of the condensates, as it provides molecular cues to locally coordinate the formation of endogenous high order RNP assemblies. Interestingly, the co-segregation of intracellular components ultimately impacts the size of the phase-separated condensates. Thus, RNA arises as an architectural element that can influence the composition and the morphological outcome of the condensate phases in an intracellular context.
A completeCannabischromosome assembly and adaptive admixture for elevated cannabidiol (CBD) content
Authors: Grassa Christopher J. , Wenger Jonathan P. , Dabney Clemon , Poplawski Shane G. , Motley S. Timothy , Michael Todd P. , Schwartz C.J. , Weiblen George D.
Published: October 2018

Cannabishas been cultivated for millennia with distinct cultivars providing either fiber and grain or tetrahydrocannabinol. Recent demand for cannabidiol rather than tetrahydrocannabinol has favored the breeding of admixed cultivars with extremely high cannabidiol content. Despite several draftCannabisgenomes, the genomic structure ofcannabinoid synthaseloci has remained elusive. A genetic map derived from a tetrahydrocannabinol/cannabidiol segregating population and a complete chromosome assembly from a high-cannabidiol cultivar together resolve the linkage ofcannabidiolicandtetrahydrocannabinolic acid synthasegene clusters which are associated with transposable elements. High-cannabidiol cultivars appear to have been generated by integrating hemp-typecannabidiolic acid synthasegene clusters into a background of marijuana-type cannabis. Quantitative trait locus mapping suggests that overall drug potency, however, is associated with other genomic regions needing additional study.

Resources available online at:http://cannabisgenome.org

A complete chromosome assembly and an ultra-high-density linkage map together identify the genetic mechanism responsible for the ratio of tetrahydrocannabinol (THC) to cannabidiol (CBD) in Cannabis cultivars, allowing paradigms for the evolution and inheritance of drug potency to be evaluated.
Extracellular Electron Uptake by TwoMethanosarcinaSpecies
Authors: Yee Mon Oo , Snoeyenbos-West Oona , Thamdrup Bo , Ottosen Lars DM , Rotaru Amelia-Elena
Published: October 2018

Direct electron uptake by prokaryotes is a recently described mechanism with a potential application for energy and CO2storage into value added chemicals. Members of Methanosarcinales, an environmentally and biotechnologically relevant group of methanogens, were previously shown to retrieve electrons from an extracellular electrogenic partner performing Direct Interspecies Electron Transfer (DIET) and were therefore proposed to be electroactive. However, their intrinsic electroactivity has never been examined. In this study, we tested two methanogens belonging to the genusMethanosarcina, M. barkeriandM. horonobensis,regarding their ability to accept electrons directly from insoluble electron donors like other cells, conductive particles and electrodes. Both methanogens were able to retrieve electrons fromGeobacter metallireducensvia DIET. Furthermore, DIET was also stimulated upon addition of electrically conductive granular activated carbon (GAC) when each was co-cultured withG. metallireducens. However, when provided with a cathode poised at −400 mV (vs. SHE), onlyM. barkericould perform electromethanogenesis. In contrast, the strict hydrogenotrophic methanogen,Methanobacterium formicicum, did not produce methane regardless of the type of insoluble electron donor provided (Geobactercells, GAC or electrodes). A comparison of functional gene categories between the twoMethanosarcinashowed differences regarding energy metabolism, which could explain dissimilarities concerning electromethanogenesis at fixed potentials. We suggest that these dissimilarities are minimized in the presence of an electrogenic DIET partner (e.g.Geobacter), which can modulate its surface redox potentials by adjusting the expression of electroactive surface proteins.
The Cten signalling pathway stabilises Src protein to promote Epithelial-Mesenchymal Transition (EMT) in colorectal cancer
Authors: Asiri Abdulaziz , Toss Michael S , Pereira Raposo Teresa , Akhlaq Maham , Thorpe Hannah , Alfahed Abdulaziz , Asiri Abutaleb , Ilyas Mohammad
Published: October 2018

Cten is an oncogene which promotes epithelial-mesenchymal transition (EMT) in many signalling pathways. Having previously shown that Cten promotes EMT through Snail, we investigated whether Cten function could be mediated through Src (a known regulator of Snail).

Cten levels were modulated by forced expression in colorectal cancer (CRC) cell lines with low Cten expression (HCT116 and RKO) and gene knockdown in a cell line with high Cten expression (SW620). In all cell lines, Cten was a positive regulator of Src expression. The functional importance of Src was tested by forcibly expressing Cten and simultaneously knocking down Src. This resulted in abrogation of Cten motility-inducing activity (cell migration, cell invasion, wound healing – each p<0.001) and abrogation of the promotion of colony formation by Cten (p<0.001) together with failure to induce the Cten targets - Snail and ROCK1. To complement these experiments, Cten expression was restored by forced expression in a subclone of SW620 in which the Cten gene had been deleted (SW620ΔCten). SW620ΔCten showed reduced expression of Src which increased following restoration of Cten by forced expression. In SW620ΔCten, restoration of Cten increased cell motility (cell migration, cell invasion, wound healing) and colony formation (each p<0.001) which were all lost if Src was concomitantly knocked down. Quantitative Reverse-Transcription PCR (qRT-PCR) showed that modulation of Cten had no effect on Src mRNA levels. However, a cycloheximide (CHX) pulse chase assay demonstrated stabilisation of Src protein by Cten. Finally, the expression of Cten and Src was tested in a series of 84 primary CRCs and there was significant correlation between Cten and Src expression (p=0.001).

We conclude that Src is a novel and functionally important target of the Cten signalling pathway and that Cten protein causes post-transcriptional stabilisation of Src protein in order to promote EMT and possibly metastasis in CRC.
A new class of constitutively active super-enhancers is associated with fast recovery of 3D chromatin loops
Authors: Ryu Jayoung , Kim Hyunwoong , Yang Dongchan , Lee Andrew J. , Jung Inkyung
Published: October 2018

Super-enhancers or stretch enhancers are clusters of active enhancers that often coordinate cell-type specific gene regulation. However, little is known about the function of super-enhancers beyond gene regulation. In this study, through a comprehensive analysis of super-enhancers in 30 human cell/tissue types, we identified a new class of super-enhancers which are constitutively active across most cell/tissue types. These ‘common’ super-enhancers are associated with universally highly expressed genes in contrast to the canonical definition of super-enhancers that assert cell-type specific gene regulation. In addition, the genome sequence of these super-enhancers is highly conserved by evolution and among humans, advocating their universal function in genome regulation. Integrative analysis of 3D chromatin loops demonstrates that, in comparison to the cell-type specific super-enhancers, the cell-type common super-enhancers present a striking association with rapidly recovering loops. We propose that a new class of super-enhancers may play an important role in the early establishment of 3D chromatin structure.

Background

Super-enhancers or stretch enhancers are defined by a strong enrichment of mediators and transcription-regulating proteins, appearing to play a deterministic role in cellular identity by controlling the expression of cell-type specific genes[1, 2]. Previous studies have revealed the critical function of super-enhancers during development and differentiation[3]. The enrichment of disease-associated single nucleotide polymorphism (SNP) in super-enhancers compared to that of typical enhancers proposed a substantial link between super-enhancers and many complex human diseases[2]. In addition, a set of recent studies have proposed potential functions of super-enhancers in the extremely long-range chromatin communications and the establishment of 3D chromatin loops[4]. These results suggest a more universal role of super-enhancers in genome regulation apart from cell-type specific gene regulation, but little is known about the mechanisms underlying these various functions. To extend the current knowledge of super-enhancers and their biological roles, we conducted a comprehensive analysis of super-enhancer activities across 30 human cell/tissue types. Our analysis suggests that a substantial number of super-enhancers exhibits prevalent activities across cell-types in terms of H3K27ac signals, and that these non-canonical super-enhancers are involved in the formation of fast recovering chromatin loops.

Note

A genome browser session has been set up for visualization of the super-enhancer domains described in the current study– https://genome.ucsc.edu/cgi-bin/hgTracks?hgS-doOtherUser=submit&hgS-otherUserName=abundantiavosliberabit&hgS-otherUserSessionName=SuperEnhancerDomain
Genome-wide data for effective conservation of manta and devil ray species
Authors: Hosegood Jane , Humble Emily , Ogden Rob , de Bruyn Mark , Creer Si , Stevens Guy , Abudaya Mohammed , Bassos-Hull Kim , Bonfil Ramon , Fernando Daniel , Foote Andrew D. , Hipperson Helen , Jabado Rima W. , Kaden Jennifer , Moazzam Muhammad , Peel Lauren , Pollett Stephen , Ponzo Alessandro , Poortvliet Marloes , Salah Jehad , Senn Helen , Stewart Joshua , Wintner Sabine , Carvalho Gary
Published: October 2018

Practical biodiversity conservation relies on delineation of biologically meaningful units, particularly with respect to global conventions and regulatory frameworks. Traditional approaches have typically relied on morphological observation, resulting in artificially broad delineations and non-optimal species units for conservation. More recently, species delimitation methods have been revolutionised with High-Throughput Sequencing approaches, allowing study of diversity within species radiations using genome-wide data. The highly mobile elasmobranchs, manta and devil rays (Mobulaspp.), are threatened globally by targeted and bycatch fishing pressures resulting in recent protection under several global conventions. However, a lack of global data, morphological similarities, a succession of recent taxonomic changes and ineffectual traceability measures combine to impede development and implementation of a coherent and enforceable conservation strategy. Here, we generate genome-wide Single Nucleotide Polymorphism (SNP) data from among the most globally and taxonomically representative set of mobulid tissues. The resulting phylogeny and delimitation of species units represents the most comprehensive assessment of mobulid diversity with molecular data to date. We find a mismatch between current species classifications, and optimal species units for effective conservation. Specifically, we find robust evidence for an undescribed species of manta ray in the Gulf of Mexico and show that species recently synonymised are reproductively isolated. Further resolution is achieved at the population level, where cryptic diversity is detected in geographically distinct populations, and indicates potential for future traceability work determining regional location of catch. We estimate the optimal species tree and uncover substantial incomplete lineage sorting, where standing variation in extinct ancestral populations is identified as a driver of phylogenetic uncertainty, with further conservation implications. Our study provides a framework for molecular genetic species delimitation that is relevant to wide-ranging taxa of conservation concern, and highlights the potential for genomic data to support effective management, conservation and law enforcement strategies.
BRK Phosphorylates SMAD4 for proteasomal degradation and inhibits tumor suppressor FRK to control SNAIL, SLUG and metastatic potential
Authors: Miah Sayem , Banks Charles A. S. , Ogunbolude Yetunde , Bagu Edward T. , MacAusland-Berg Josh , Saraf Anita , Hattem Gaye , Kempf Cassandra G. , Sardiu Mihaela , Napper Scott , Florens Laurence , Lukong Kiven E. , Washburn Michael P.
Published: October 2018

The tumor-suppressing function of SMAD4 is frequently subverted during mammary tumorigenesis, leading to cancer growth, invasion, and metastasis. A long-standing concept is that SMAD4 is not regulated by phosphorylation but ubiquitination. Interestingly, our search for signaling pathways regulated by BRK, a non-receptor protein tyrosine kinase that is up-regulated in ∼80% of invasive ductal breast tumors, led us to discover that BRK competitively binds and phosphorylates SMAD4, and regulates TGF-β/ SMAD4 signaling pathway. A constitutively active BRK (BRK-Y447F), phosphorylates SMAD4 resulting in its recognition by the ubiquitin-proteasome system, which accelerates SMAD4 degradation. In agreement, we also observed an inverse protein expression pattern of BRK and SMAD4 in a panel of breast cancer cell lines and breast tumors. Activated BRK mediated degradation of SMAD4 causes the repression of tumor suppressor genes FRK that was associated with increased expression of mesenchymal markers and decreased cell adhesion ability. Thus, our data suggest that combination therapies targeting activated BRK signaling may have synergized the benefits in the treatment of SMAD4 repressed cancers. Therefore, our data propose that combination therapies which includes targeting activated BRK signaling may synergize the benefits in the treatment of SMAD4 deficient cancers.