bluuebunny/crossref_metadata_2025 huggingface dataset:
Spatial variation of the native colon microbiota in healthy adults
Authors: Flynn Kaitlin J. , Ruffin Mack T. , Turgeon D. Kim , Schloss Patrick D.
Published: November 2017

The microbiome has been implicated in the development of colorectal cancer (CRC) and inflammatory bowel diseases (IBD). The specific traits of these diseases vary along the axis of the digestive tract. Further, variation in the structure of the gut microbiota has been associated with both diseases. Here we profiled the microbiota of the healthy proximal and distal mucosa and lumen to better understand how bacterial populations vary along the colon. We used a two-colonoscope approach to sample proximal and distal mucosal and luminal contents from the colons of 20 healthy subjects that had not undergone any bowel preparation procedure. The biopsies and home-collected stool were subjected to 16S rRNA gene sequencing and Random Forest classification models were built using taxa abundance and location to identify microbiota specific to each site. The right mucosa and lumen had the most similar community structures of the five sites we considered from each subject. The distal mucosa had higher relative abundance ofFinegoldia, Murdochiella, Peptoniphilus, PorphyromonasandAnaerococcus. The proximal mucosa had more of the generaEnterobacteriaceae, BacteroidesandPseudomonas. The classification model performed well when classifying mucosal samples into proximal or distal sides (AUC = 0.808). Separating proximal and distal luminal samples proved more challenging (AUC = 0.599) and specific microbiota that differentiated the two were hard to identify. By sampling the unprepped colon, we identified distinct bacterial populations native to the proximal and distal sides. Further investigation of these bacteria may elucidate if and how these groups contribute to different disease processes on their respective sides of the colon.
A GenoChemetic strategy for derivatization of the violacein natural product scaffold
Authors: Lai Hung-En , Obled Alan M. C. , Chee Soo Mei , Morgan Rhodri M. , Lynch Rosemary , Sharma Sunil V. , Moore Simon J. , Polizzi Karen M. , Goss Rebecca J. M. , Freemont Paul S.
Published: November 2017

Natural products and their analogues are often challenging to synthesise due to their complex scaffolds and embedded functional groups. Solely relying on engineering the biosynthesis of natural products may lead to limited compound diversity. Integrating synthetic biology with synthetic chemistry allows rapid access to much more diverse portfolios of xenobiotic compounds which may accelerate the discovery of new therapeutics. As a proof-of-concept, by supplementing an Escherichia coli strain expressing the violacein biosynthesis pathway with 5-bromo-tryptophan in vitro or tryptophan 7-halogenase RebH in vivo, 6 halogenated analogues of violacein or deoxyviolacein were generated, demonstrating promiscuity of the violacein biosynthesis pathway. Furthermore, 20 new derivatives were generated from 5-brominated violacein analogues via Suzuki-Miyaura cross-coupling reaction directly using the crude extract without prior purification. Herein, we demonstrate a flexible and rapid approach to access diverse chemical space that can be applied to a wide range of natural product scaffolds.
Ribosome profiling uncovers selective mRNA translation associated with eIF2 phosphorylation in erythroid progenitors
Authors: Paolini Nahuel A. , Moore Kat S. , di Summa Franca M. , Fokkema Ivo F.A.C. , ‘t Hoen Peter A.C. , von LIndern Marieke
Published: November 2017

The regulation of translation initiation factor 2 (eIF2) is important for erythroid survival and differentiation. Lack of iron, a critical component of heme and hemoglobin, activates Heme Regulated Inhibitor (HRI). This results in phosphorylation of eIF2 and reduced eIF2 availability, which inhibits protein synthesis. Translation of specific transcripts such as Atf4, however, is enhanced. Upstream open reading frames (uORFs) are key to this regulation. The aim of this study is to investigate how eIF2 phosphorylation affects mRNA translation in erythroblasts. Ribosome profiling combined with RNA sequencing was used to determine translation initiation sites and ribosome density on individual transcripts. Treatment of erythroblasts with Tunicamycin (Tm) increased phosphorylation of eIF2 2-fold. At a false discovery rate of 1%, ribosome density was increased for 147 transcripts, among which transcriptional regulators such as Atf4, Tis7/Ifrd1, Pnrc2, Gtf2h, Mbd3, JunB and Kmt2e. Translation of 337 transcripts decreased more than average, among which Dym and Csde1. Ribosome profiling following Harringtonine treatment uncovered novel translation initiation sites and uORFs. Surprisingly, translated uORFs did not predict eIF2-dependent translation efficiency, but uORF identity differs. The regulation of transcription and translation factors in reponse to eIF2 phosphorylation may explain the large overall response to iron deficiency in erythroblasts.

- eif2 dependent translation in erythroblasts during proteotoxic stress determined by ribosome footprinting

- identification of transcription factors upregulated in response to eIF2 phosphorylation

- Advantages and disadvantages of translation initiation site determination using harringtonine

- distinct uORF pattern in transcripts with enhanced, or more than average reduced translation upon proteotoxic stress
A robust and tunable mitotic oscillator in artificial cells
Authors: Guan Ye , Li Zhengda , Wang Shiyuan , Barnes Patrick M. , Liu Xuwen , Xu Haotian , Jin Minjun , Liu Allen P. , Yang Qiong
Published: November 2017

Single-cell analysis is pivotal to deciphering complex phenomena like cellular heterogeneity, bistable switch, and oscillations, where a population ensemble cannot represent the individual behaviors. Bulk cell-free systems, despite having unique advantages of manipulation and characterization of biochemical networks, lack the essential single-cell information to understand a class of out-of-steady-state dynamics including cell cycles. Here we develop a novel artificial single-cell system by encapsulatingXenopusegg extracts in water-in-oil microemulsions to study mitotic dynamics. These “cells”, adjustable in sizes and periods, sustain oscillations for over 30 cycles, and function in forms from the simplest cytoplasmic-only to the more complicated ones involving nuclei dynamics, mimicking real mitotic cells. Such innate flexibility and robustness make it key to studying clock properties of tunability and stochasticity. Our result also highlights energy supply as an important regulator of cell cycles. We demonstrate a simple, powerful, and likely generalizable strategy of integrating strengths of single-cell approaches into conventionalin vitrosystems to study complex clock functions.
Reactive and pre-emptive vaccination strategies to control hepatitis E infection in emergency and refugee settings: a modelling study
Authors: Cooper Ben S , White Lisa J , Siddiqui Mahveen R
Published: November 2017

Background

Hepatitis E Virus (HEV) is an important cause of morbidity and mortality in emergency and refugee camp settings. Symptomatic infection is associated with case fatality rates of ~20% in pregnant women. However, its epidemiology is poorly understood and the potential impact of immunisation in outbreak settings uncertain. We aimed to estimate key epidemiological parameters for HEV and to evaluate the potential impact of both reactive vaccination (initiated in response to an epidemic) and pre-emptive vaccination.

Methods

We analysed data from one of the world’s largest recorded HEV epidemics, which occurred in refugee camps in Uganda (2007-2009), using transmission dynamic models to estimate epidemiological parameters and assess the potential impact of reactive and pre-emptive vaccination strategies.

Results

Under baseline assumptions we estimated the basic reproduction number of HEV to range from 3.9 (95% CrI 2.8, 5.4) to 8.9 (5.4, 14.2). Mean latent and infectious periods were estimated to be 34 (28, 39) and 40 (23, 71) days respectively.

Reactive two-dose vaccination of those aged 16-65 years excluding pregnant women (for whom vaccine is not licensed), if initiated after 50 reported cases, led to mean camp-specific reductions in mortality of 10 to 29%. Pre-emptive vaccination with two doses reduced mortality by 35 to 65%. Both strategies were more effective if coverage was extended to groups for whom the vaccine is not currently licensed. For example, two dose pre-emptive vaccination, if extended to include pregnant women, led to mean reductions in mortality of 66 to 82%.

Conclusions

HEV has a high transmission potential in refugee camp settings. Substantial reductions in mortality through vaccination are expected, even if used reactively. There is potential for greater impact if vaccine safety and effectiveness can be established in pregnant women.

Funding

Wellcome Trust (106491/Z/14/Z and 089275/Z/09/Z). BC: MRC/DfID (MR/K006924/1).
Extracting biological age from biomedical data via deep learning: too much of a good thing?
Authors: Pyrkov Tim , Slipensky Konstantin , Barg Mikhail , Kondrashin Alexey , Zhurov Boris , Zenin Alexander , Pyatnitskiy Mikhail , Menshikov Leonid , Markov Sergei , Fedichev Peter O.
Published: November 2017

Aging-related physiological changes are systemic and, at least in humans, are linearly associated with age. Therefore, linear combinations of physiological measures trained to estimate chronological age have recently emerged as a practical way to quantify aging in the form of biological age. Aging acceleration, defined as the difference between the predicted and chronological age was found to be elevated in patients with major diseases and is predictive of mortality. In this work, we compare three increasingly accurate biological age models: metrics derived from unsupervised Principal Components Analysis (PCA), alongside two supervised biological age models; a multivariate linear regression and a state-of-the-art deep convolution neural network (CNN). All predictions were made using one-week long locomotor activity records from a 2003-2006 National Health and Nutrition Examination Survey (NHANES) dataset. We found that application of the supervised approaches improves the accuracy of the chronological age estimation at the expense of a loss of the association between the aging acceleration predicted by the model and all-cause mortality. Instead, we turned to the NHANES death register and introduced a novel way to train parametric proportional hazards models in a form suitable for out-of-the-box implementation with any modern machine learning software. Finally, we characterized a proof-of-concept example, a separate deep CNN trained to predict mortality risks that outperformed any of the biological age or simple linear proportional hazards models. Our findings demonstrate the emerging potential of combined wearable sensors and deep learning technologies for applications involving continuous health risk monitoring and real-time feedback to patients and care providers.
On the Calculation of Betweenness Centrality in Marine Connectivity Studies Using Transfer Probabilities
Authors: Costa Andrea , Petrenko Anne A. , Guizien Katell , Doglioli Andrea M.
Published: November 2017

Betweenness has been used in a number of marine studies to identify portions of sea that sustain the connectivity of whole marine networks. Herein we highlight the need of methodological exactness in the calculation of betweenness when graph theory is applied to marine connectivity studies based on transfer probabilities. We show the inconsistency in calculating betweeness directly from transfer probabilities and propose a new metric for the node-to-node distance that solves it. Our argumentation is illustrated by both simple theoretical examples and the analysis of a literature data set.
The Basic Reproductive Number for Disease Systems with Multiple Coupled Heterogeneities
Authors: Lloyd Alun L. , Kitron Uriel , Perkins T. Alex , Vazquez-Prokopec Gonzalo M. , Waller Lance A.
Published: November 2017

In mathematical epidemiology, a well-known formula describes the impact of heterogeneity on the basic reproductive number,R0, for situations in which transmission is separable and for which there is one source of variation in susceptibility and one source of variation in infectiousness. This formula is written in terms of the magnitudes of the heterogeneities, as quantified by their coefficients of variation, and the correlation between them. A natural question to ask is whether analogous results apply when there are multiple sources of variation in susceptibility and/or infectiousness. In this paper we demonstrate that with three or more coupled heterogeneities,R0under separable transmission depends on details of the distribution of the heterogeneities in a way that is not seen in the well-known simpler situation. We provide explicit formulae for the cases of multivariate normal and multivariate log-normal distributions, showing thatR0can again be expressed in terms of the magnitudes of the heterogeneities and the pairwise correlations between them. The formulae, however, differ between the two multivariate distributions, demonstrating that no formula of this type applies generally when there are three or more coupled heterogeneities. We see that the results of the formulae are approximately equal when heterogeneities are relatively small and show that an earlier result in the literature (Koella, 1991) should be viewed in this light. We provide numerical illustrations of our results and discuss a setting in which coupled heterogeneities are likely to have a major impact on the value ofR0. We also describe a rather surprising result: in a system with three heterogeneities,R0can exhibit non-monotonic behavior with increasing levels of heterogeneity, in marked contrast to the familiar two heterogeneity setting in whichR0either increases or decreases with increasing heterogeneity.
Differential gene expression analysis tools exhibit substandard performance for long non-coding RNA–sequencing data
Authors: Assefa Alemu Takele , De Paepe Katrijn , Everaert Celine , Mestdagh Pieter , Thas Olivier , Vandesompele Jo
Published: November 2017

Background

Protein-coding RNAs (mRNA) have been the primary target of most transcriptome studies in the past, but in recent years, attention has expanded to include long non-coding RNAs (lncRNA). lncRNAs are typically expressed at low levels, and are inherently highly variable. This is a fundamental challenge for differential expression (DE) analysis. In this study, the performance of 14 popular tools for testing DE in RNA-seq data along with their normalization methods is comprehensively evaluated, with a particular focus on lncRNAs and low abundant mRNAs.

Results

Thirteen performance metrics were used to evaluate DE tools and normalization methods using simulations and analyses of six diverse RNA-seq datasets. Non-parametric procedures are used to simulate gene expression data in such a way that realistic levels of expression and variability are preserved in the simulated data. Throughout the assessment, we kept track of the results for mRNA and lncRNA separately. All statistical models exhibited inferior performance for lncRNAs compared to mRNAs across all simulated scenarios and analysis of benchmark RNA-seq datasets. No single tool uniformly outperformed the others.

Conclusion

Overall, the linear modeling with empirical Bayes moderation (limma) and the nonparametric approach (SAMSeq) showed best performance: good control of the false discovery rate (FDR) and reasonable sensitivity. However, for achieving a sensitivity of at least 50%, more than 80 samples are required when studying expression levels in a realistic clinical settings such as in cancer research. About half of the methods showed severe excess of false discoveries, making these methods unreliable for differential expression analysis and jeopardizing reproducible science. The detailed results of our study can be consulted through a user-friendly web application, http://statapps.ugent.be/tools/AppDGE/
RelTime relaxes the strict molecular clock throughout the phylogeny
Authors: Battistuzzi Fabia U. , Tao Qiqing , Jones Lance , Tamura Koichiro , Kumar Sudhir
Published: November 2017

The RelTime method estimates divergence times when evolutionary rates vary among lineages. Theoretical analyses show that RelTime relaxes the strict molecular clock throughout a molecular phylogeny, and it performs well in the analysis of empirical and computer simulated datasets in which evolutionary rates are variable. Lozano-Fernandez et al. (2017) found that the application of RelTime to one metazoan dataset (Erwin et al. 2011) produced equal rates for several ancient lineages, which led them to speculate that RelTime imposes a strict molecular clock for deep animal divergences. RelTime does not impose a strict molecular clock. The pattern observed by Lozano-Fernandez et al. (2017) was a result of the use of an option to assign the same rate to lineages in RelTime when the rates are not statistically significantly different. The median rate difference was 5% for many deep metazoan lineages for Erwin et al. (2011) dataset, so the rate equality was not rejected. In fact, RelTime analysis with and without the option to test rate differences produced very similar time estimates. We found that the Bayesian time estimates vary widely depending on the root priors assigned, and that the use of less restrictive priors produce Bayesian divergence times that are concordant with those from RelTime for Erwin et al. (2011) dataset. Therefore, it is prudent to discuss Bayesian estimates obtained under a range of priors in any discourse about molecular dating, including method comparisons.
Household Members Do Not Contact Each Other at Random: Implications for Infectious Disease Modelling
Authors: Goeyvaerts Nele , Santermans Eva , Potter Gail , Torneri Andrea , Van Kerckhove Kim , Willem Lander , Aerts Marc , Beutels Philippe , Hens Niel
Published: November 2017

Airborne infectious diseases such as influenza are primarily transmitted from human to human by means of social contacts and thus easily spread within households. Epidemic models, used to gain insight in infectious disease spread and control, typically rely on the assumption of random mixing within households. Until now there was no direct empirical evidence to support this assumption. Here, we present the first social contact survey specifically designed to study contact networks within households. The survey was conducted in Belgium (Flanders and Brussels) in 2010-2011. We analyzed data from 318 households totaling 1266 individuals with household sizes ranging from 2 to 7 members. Exponential-family random graph models (ERGMs) were fitted to the within-household contact networks to reveal the processes driving contact between household members, both on weekdays and weekends. The ERGMs showed a high degree of clustering and, specifically on weekdays, decreasing connectedness with increasing household size. Furthermore, we found that the odds of a contact between father and child is smaller than for any other pair except for older siblings. Epidemic simulation results suggest that within-household contact density is the main driver of differences in epidemic spread between complete and empirical-based household contact networks. The homogeneous mixing assumption may therefore be an adequate characterization of the within-household contact structure for the purpose of epidemic simulation. However, ignoring the contact density when inferring from an epidemic model will result in biased estimates of within-household transmission rates. Further research on the implementation of within-household contact networks in epidemic models is necessary.

Significance Statement

Households have a pivotal role in the spread of airborne infectious diseases. Households are bridging units between schools and workplaces, and social contacts within households are frequent and intimate, allowing for rapid disease spread. Infectious disease models typically assume that members of a household contact each other randomly. Until now there was no direct empirical evidence to support this assumption. In this paper, we present the first social contact survey specifically designed to study contact networks within households with young children. We investigate which factors drive contacts between household members on one particular day by means of a statistical model. Our results suggest the importance of connectedness within households over heterogeneity in number of contacts.
Per-sample immunoglobulin germline inference from B cell receptor deep sequencing data
Authors: Ralph Duncan K. , Matsen Frederick A.
Published: November 2017

The collection of immunoglobulin genes in an individual’s germline, which gives rise to B cell receptors via recombination, is known to vary significantly across individuals. In humans, for example, each individual has only a fraction of the several hundred known V alleles. Furthermore, the currently-accepted set of known V alleles is both incomplete (particularly for non-European samples), and contains a significant number of spurious alleles. The resulting uncertainty as to which immunoglobulin alleles are present in any given sample results in inaccurate B cell receptor sequence annotations, and in particular inaccurate inferred naive ancestors. In this paper we first show that the currently widespread practice of aligning each sequence to its closest match in the full set of IMGT alleles results in a very large number of spurious alleles that are not in the sample’s true set of germline V alleles. We then describe a new method for inferring each individual’s germline gene set from deep sequencing data, and show that it improves upon existing methods by making a detailed comparison on a variety of simulated and real data samples. This new method has been integrated into the partis annotation and clonal family inference package, available at https://github.com/psathyrella/partis, and is run by default without affecting overall run time.

Author Summary

Antibodies are an important component of the adaptive immune system, which itself determines our response to both pathogens and vaccines. They are produced by B cells through somatic recombination of germline DNA, which results in a vast diversity of antigen binding affinities across the B cell repertoire. We typically learn about the development of this repertoire, and its history of interaction with antigens, by sequencing large numbers of the DNA sequences from which antibodies are derived. In order to understand such data, it is necessary to determine the combination of germline V, D, and J genes that was rearranged to form each such B cell receptor sequence. This is difficult, however, because the immunoglobulin locus exhibits an extraordinary level of diversity across individuals – encompassing both allelic variation and gene duplication, deletion, and conversion – and because the locus’s large size and repetitive structure make germline sequencing very difficult. In this paper we describe a new computational method that avoids this difficulty by inferring each individual’s set of immunoglobulin germline genes directly from expressed B cell receptor sequence data.
Analysis of Spounaviruses as a Case Study for the Overdue Reclassification of Tailed Bacteriophages
Authors: Barylski Jakub , Enault François , Dutilh Bas E. , Schuller Margo B.P. , Edwards Robert A. , Gillis Annika , Klumpp Jochen , Knezevic Petar , Krupovic Mart , Kuhn Jens H. , Lavigne Rob , Oksanen Hanna M. , Sullivan Matthew B. , Wittmann Johannes , Tolstoy Igor , Rodney Brister J. , Kropinski Andrew M. , Adriaenssens Evelien M.
Published: November 2017

It is almost a cliché that tailed bacteriophages of the order Caudovirales are the most abundant and diverse viruses in the world. Yet, their taxonomy still consists of a single order with just three families: Myoviridae, Siphoviridae, and Podoviridae. Thousands of newly discovered phage genomes have recently challenged this morphology-based classification, revealing that tailed bacteriophages are genomically even more diverse than once thought. Here, we evaluate a range of methods for bacteriophage taxonomy by using a particularly challenging group as an example, the Bacillus phage SPO1-related viruses of the myovirid subfamily Spounavirinae. Exhaustive phylogenetic and phylogenomic analyses indicate that the spounavirins are consistent with the taxonomic rank of family and should be divided into at least five subfamilies. This work is a case study for virus genomic taxonomy and the first step in an impending massive reorganization of the tailed bacteriophage taxonomy.
Widespread Genotype-Phenotype Correlations in Intellectual Disability
Authors: Casanova Emily L. , Gerstner Zachary , Sharp Julia L. , Casanova Manuel F. , Feltus F. Alex
Published: November 2017

Background

Linking genotype to phenotype is a major aim of genetics research, yet many complex conditions continue to hide their underlying biochemical mechanisms. Recent research provides evidence that relevant gene-phenotype associations are discoverable in the study of intellectual disability (ID). Here we expand on that work, identifying distinctive gene interaction modules with unique enrichment patterns reflective of associated clinical features in ID.

Methods

Two hundred twelve forms of monogenic ID were curated according to comorbidities with autism and epilepsy. These groups were further subdivided according to secondary clinical symptoms of complex versus simple facial dysmorphia and neurodegenerative-like features due to their clinical prominence, modest symptom overlap, and probable etiological divergence. An aggregate gene interaction ID network for these phenotype subgroups was discovered using via a public database of known gene interactions: protein-protein, genetic, and mRNA coexpression. Additional annotation resources (Gene Ontology, Human Phenotype Ontology, TRANSFAC/JASPAR, and KEGG/WikiPathways) were utilized to assess functional and phenotypic enrichment modules within the full ID network.

Results

Phenotypic analysis revealed high rates of complex facial dysmorphia in ID with comorbid autism. In contrast, neurodegenerative-like features were overrepresented in ID with epilepsy. Network analysis subsequently showed that gene groups divided according to clinical features of interest resulted in distinctive interaction clusters, with unique functional enrichments according to module.

Conclusions

These data suggest that specific comorbid and secondary clinical features in ID are predictive of underlying genotype. In summary, ID form unique clusters, which are comprised of individual conditions with remarkable genotypic and phenotypic overlap.
Comparative ‘omics analyses differentiateMycobacterium tuberculosisandMycobacterium bovisand reveal distinct macrophage responses to infection with the human and bovine tubercle bacilli
Authors: Malone Kerri M. , Rue-Albrecht Kévin , Magee David A. , Conlon Kevin , Schubert Olga T. , Nalpas Nicolas C. , Browne John A. , Smyth Alicia , Gormley Eamonn , Aebersold Ruedi , MacHugh David E. , Gordon Stephen V.
Published: November 2017

Members of theMycobacterium tuberculosiscomplex (MTBC) are the causative agents of tuberculosis in a range of mammals, including humans. A key feature of MTBC pathogens is their high degree of genetic identity, yet distinct host tropism. Notably, whileMycobacterium bovisis highly virulent and pathogenic for cattle, the human pathogenM. tuberculosisis attenuated in cattle. Previous research also suggests that host preference amongst MTBC members has a basis in host innate immune responses. To explore MTBC host tropism, we present in-depth profiling of the MTBC reference strainsM. bovisAF2122/97 andM. tuberculosisH37Rv at both the global transcriptional and translational level via RNA-sequencing and SWATH mass spectrometry. Furthermore, a bovine alveolar macrophage infection time course model was employed to investigate the shared and divergent host transcriptomic response to infection withM. tuberculosisorM. bovis. Significant differential expression of virulence-associated pathways between the two bacilli was revealed, including the ESX-1 secretion system. A divergent transcriptional response was observed betweenM. tuberculosisandM. bovisinfection of bovine alveolar macrophages, in particular cytosolic DNA-sensing pathways at 48 hours post-infection, and highlights a distinct engagement ofM. boviswith the bovine innate immune system. The work presented here therefore provides a basis for the identification of host innate immune mechanisms subverted by virulent host-adapted mycobacteria to promote their survival during the early stages of infection.

Importance

TheMycobacterium tuberculosiscomplex (MTBC) includes the most important global pathogens for humans and animals, namelyMycobacterium tuberculosisandMycobacterium bovis,respectively. These two exemplar mycobacterial pathogens share a high degree of genetic identity, but the molecular basis for their distinct host preference is unknown. In this work we integrated transcriptomic and proteomic analyses of the pathogens to elucidate global quantitative differences between them at the mRNA and protein level. We then integrated this data with transcriptome analysis of the bovine macrophage response to infection with either pathogen. Increased expression of the ESX-1 virulence system inM. bovisappeared a key driver of an increased cytosolic nucleic acid sensing and interferon response in bovine macrophages infected withM. boviscompared toM. tuberculosis.Our work demonstrates the specificity of host-pathogen interaction and how the subtle interplay between mycobacterial phenotype and host response may underpin host specificity amongst MTBC members.
Zika: An ongoing threat to women and infants
Authors: Coimbra Beatriz Macedo , Coelho Flávio Codeço , Armstrong Margaret , Saraceni Valeria , Lemos Cristina
Published: November 2017

Recent data from Rio de Janeiro shows a sharp drop in the number of notified cases of Zika in the summer of 2016-17, compared to the previous summer. This is probably due to herd immunity built up after the previous year's epidemic. There is still a much higher incidence among women than men, almost certainly due to sexual transmission. An unexpected feature of the new data is that there are proportionally far more cases in children under 15 months than in older age classes. By comparing the incidence for 2016-17 with that of 2015-16, we can deduce the proportion of reported cases for men and women, and also verify that the disparity of incidence between them is still present. Women and children still represent risk groups with regard to Zika infection, even during a non-epidemic season.
Conversion between parallel and antiparallel β-sheets in wild-type and Iowa mutant fibrils
Authors: Xi Wenhui , Hansmann Ulrich H.E.
Published: November 2017

Using a variant of Hamilton-Replica-Exchange we study for wild type and Iowa mutant Aβ40the conversion between fibrils with antiparallel β-sheets, and such with parallel β-sheets. We show that wild type and mutant form distinct salt bridges that in turn stabilize different fibril organizations. The conversion between the two fibril forms leads to the release of small aggregates that in the Iowa mutant may shift the equilibrium from fibrils to more toxic oligomers.
Fungal communities associated with the eastern larch beetle: diversity and variation within developmental stages
Authors: Durand Audrey-Anne , Buffet Jean-Philippe , Constant Philippe , Déziel Eric , Guertin Claude
Published: November 2017

Bacterial and fungal communities associated with bark beetles, especially some Dendroctonus species, mediate challenging aspects of the subcortical habitat for their hosts. Filamentous fungi and yeasts are important in various metabolic processes of certain bark beetles, with involvement in nutrition, protection and detoxification of plant defense compounds. The eastern larch beetle, Dendroctonus simplex, is recognized as a serious forest pest in the upper part of North America. Although D. simplex is well studied, the fungal communities and their ecological role remain to be investigated. Here, using 18S rRNA gene pyrosequencing, we provide a comprehensive overview of the yeasts and filamentous fungi associated with the eastern larch beetle and compare fungal communities between different developmental stages and microenvironments. Fungal mycobiome associated with the galleries was also investigated. Our study has unveiled an unexpected fungal diversity associated with the developmental stages. Significant differences in species richness between the developmental stages were determined. Yeasts were found to be predominant in the adult and larval stages, whereas filamentous fungi were most prevalent in the pupae. Our results indicate a possible implication of yeasts in the eastern larch beetle nutrition.
Dynamics of the upper airway microbiome in the pathogenesis of asthma-associated persistent wheeze in preschool children
Authors: Teo Shu Mei , Tang Howard HF , Mok Danny , Judd Louise M , Watts Stephen C , Pham Kym , Holt Barbara J. , Kusel Merci , Serralha Michael , Troy Niamh , Bochkov Yury A , Grindle Kristine , Lemanske Robert F , Johnston Sebastian L , Gern James E , Sly Peter D , Holt Patrick G , Holt Kathryn E , Inouye Michael
Published: November 2017

Repeated cycles of infection-associated lower airway inflammation drives the pathogenesis of persistent wheezing disease in children. Tracking these events across a birth cohort during their first five years, we demonstrate that >80% of infectious events indeed involve viral pathogens, but are accompanied by a shift in the nasopharyngeal microbiome (NPM) towards dominance by a small range of pathogenic bacterial genera. Unexpectedly, this change in NPM frequently precedes the appearance of viral pathogens and acute symptoms. In non-sensitized children these events are associated only with “transient wheeze” that resolves after age three. In contrast, in children developing early allergic sensitization, they are associated with ensuing development of persistent wheeze, which is the hallmark of the asthma phenotype. This suggests underlying pathogenic interactions between allergic sensitization and antibacterial mechanisms.
Within host selection for faster replicating bacterial symbionts
Authors: Chrostek Ewa , Teixeira Luis
Published: November 2017

Wolbachiais a widespread, intracellular symbiont of arthropods, able to induce reproductive distortions and antiviral protection in insects.Wolbachiacan also be pathogenic, as is the case withwMelPop, a virulent variant of the endosymbiont ofDrosophila melanogaster. An extensive genomic amplification of the 20kb region encompassing eightWolbachiagenes, called Octomom, is responsible forwMelPop virulence. The Octomom copy number inwMelPop can be highly variable between individualD. melanogasterflies, even when comparing siblings arising from a single female. Moreover, Octomom copy number can change rapidly between generations. These data suggest an intra-host variability in Octomom copy number betweenWolbachiacells. SincewMelPopWolbachiawith different Octomom copy numbers grow at different rates, we hypothesized that selection could act on this intra-host variability. Here we tested if total Octomom copy number changes during the lifespan of individualDrosophilahosts, revealing selection for differentWolbachiapopulations. We performed a time course analysis of Octomom amplification in flies whose mothers were controlled for Octomom copy number. We show that despite the Octomom copy number being relatively stable it increases slightly throughoutD. melanogasteradult life. This indicates that there is selection acting on the intra-host variation in the Octomom copy number over the lifespan of individual hosts. This within host selection for faster replicating bacterial symbionts may be in conflict with between host selection against highly pathogenicWolbachia.
iterative Random Forests to discover predictive and stable high-order interactions
Authors: Basu Sumanta , Kumbier Karl , Brown James B. , Yu Bin
Published: November 2017

Genomics has revolutionized biology, enabling the interrogation of whole transcriptomes, genome-wide binding sites for proteins, and many other molecular processes. However, individual genomic assays measure elements that interactin vivoas components of larger molecular machines. Understanding how these high-order interactions drive gene expression presents a substantial statistical challenge. Building on Random Forests (RF), Random Intersection Trees (RITs), and through extensive, biologically inspired simulations, we developed the iterative Random Forest algorithm (iRF). iRF trains a feature-weighted ensemble of decision trees to detect stable, high-order interactions with same order of computational cost as RF. We demonstrate the utility of iRF for high-order interaction discovery in two prediction problems: enhancer activity in the earlyDrosophilaembryo and alternative splicing of primary transcripts in human derived cell lines. InDrosophila, among the 20 pairwise transcription factor interactions iRF identifies as stable (returned in more than half of bootstrap replicates), 80% have been previously reported as physical interactions. Moreover, novel third-order interactions, e.g. between Zelda (Zld), Giant (Gt), and Twist (Twi), suggest high-order relationships that are candidates for follow-up experiments. In human-derived cells, iRF re-discovered a central role of H3K36me3 in chromatin-mediated splicing regulation, and identified novel 5th and 6th order interactions, indicative of multi-valent nucleosomes with specific roles in splicing regulation. By decoupling the order of interactions from the computational cost of identification, iRF opens new avenues of inquiry into the molecular mechanisms underlying genome biology.
Attomol-level quantification of chemically modified ribonucleosides enabled by capillary porous graphitic carbon columns in nano LC-MS
Authors: Sarin L. Peter , Kienast Sandra D. , Leufken Johannes , Ross Robert L. , Limbach Patrick A. , Fufezan Christian , Drexler Hannes C. A. , Leidel Sebastian A.
Published: November 2017

Post-transcriptional chemical modifications of (t)RNA molecules are crucial in fundamental biological processes, such as translation. Despite their biological importance and accumulating evidence linking them to various human diseases, technical challenges have limited the development of methods for reliable detection and accurate quantification of these modifications. Here, we present a sensitive capillary nanoflow liquid chromatography mass spectrometry (nLC-MS) pipeline for quantitative high-resolution analysis of ribonucleoside modifications from complex biological samples. We evaluated two porous graphitic carbon (PGC) materials as stationary phases for reversed-phase separation of ribonucleosides and found that both PGC matrices have excellent retention and separation characteristics, as well as the capability to separate structural isomers. Using PGC matrices in nLC-MS yielded excellent signal-to-noise ratios in a detection range spanning up to six orders of magnitude, allowing for the analysis of individual ribonucleosides down to attomol concentrations. Furthermore, normalizing the obtained signal intensities to a stable isotope labeled spike-in enabled direct comparison of ribonucleoside levels between different samples. In conclusion, capillary PGC columns coupled to nLC-MS constitute a powerful and sensitive tool for quantitative analysis of chemically modified ribonucleosides in complex biological samples. This setup will be invaluable for further unraveling the intriguing and multifaceted biological roles of RNA modifications.
Chaos and the (un)predictability of evolution in a changing environment
Authors: Rego-Costa Artur , Débarre Florence , Chevin Luis-Miguel
Published: November 2017

Among the factors that may reduce the predictability of evolution, chaos, characterized by a strong dependence on initial conditions, has received much less attention than randomness due to genetic drift or environmental stochasticity. It was recently shown that chaos in phenotypic evolution arises commonly under frequency-dependent selection caused by competitive interactions mediated by many traits. This result has been used to argue that chaos should often make evolutionary dynamics unpredictable. However, populations also evolve largely in response to external changing environments, and such environmental forcing is likely to influence the outcome of evolution in systems prone to chaos. We investigate how a changing environment causing oscillations of an optimal phenotype interacts with the internal dynamics of an eco-evolutionary system that would be chaotic in a constant environment. We show that strong environmental forcing can improve the predictability of evolution, by reducing the probability of chaos arising, and by dampening the magnitude of chaotic oscillations. In contrast, weak forcing can increase the probability of chaos, but it also causes evolutionary trajectories to track the environment more closely. Overall, our results indicate that, although chaos may occur in evolution, it does not necessarily undermine its predictability.
Identification of key pathways and metabolic fingerprints of longevity in C. elegans
Authors: Gao Arwen W. , Smith Reuben L. , van Weeghel Michel , Kamble Rashmi , Houtkooper Riekelt H.
Published: November 2017

Impaired insulin/IGF-1 signaling (IIS) pathway and caloric restriction (CR) are two well-established interventions to prolong lifespan in worm C. elegans. However, a cross comparison of these longevity pathways using a multi-omics integration approach is lacking. In this study, we aimed to identify key pathways and metabolite fingerprints of longevity that are shared between IIS and CR worm models using a multi-omics integration approach. We generated transcriptomics and metabolomics data from two long-lived mutant worm strains, i.e. daf-2 (impaired IIS pathway) and eat-2 (CR model) and compared them with the N2 strain. Transcriptional profiling identified shared longevity signatures between the two strains, such as an upregulation of lipid storage and defense responses and downregulation of macromolecule synthesis and developmental processes. The shared longevity signatures revealed by metabolomics profiling included an increase in the levels of glycerol-3P, ademine, xanthine, and AMP, and a decrease in the levels of the amino acid pool, the C18:0 and C17:1 fatty acids. After we integrated transcriptomics and metabolomics data based on the annotations in KEGG, our results highlighted a downregulation of pyrimidine metabolism and upregulation of purine metabolism as a commonality between the two longevity mechanisms. Overall, our findings point towards the existence of shared metabolic pathways that are likely important for lifespan extension and provide novel insights into potential regulators and metabolic fingerprints for longevity.
Decachlorocyclopentasilanes coordinated by pairs of chloride anions, with different cations, but the same solvent molecules
Authors: Moxter Maximilian , Teichmann Julian , Lerner Hans-Wolfram , Bolte Michael , Wagner Matthias
Published: November 2017

We have determined the crystal structures of two decachlorocyclopentasilanes, namely bis(tetra-n-butylammonium) dichloride decachlorocyclopentasilane dichloromethane disolvate, 2C16H36N+·2Cl−·Si5Cl10·2CH2Cl2, (I), and bis(tetraethylammonium) dichloride decachlorocyclopentasilane dichloromethane disolvate, 2C8H20N+·2Cl−·Si5Cl10·2CH2Cl2, (II), both of which crystallize with discrete cations, anions, and solvent molecules. In (I), the complete decachlorocyclopentasilane ring is generated by a crystallographic twofold rotation axis. In (II), one cation is located on a general position and the other two are disordered about centres of inversion. These are the first structures featuring the structural motif of a five-membered cyclopentasilane ring coordinated from both sides by a chloride ion. The extended structures of (I) and (II) feature numerous C—H...Cl interactions. In (II), the N atoms are located on centres of inversion and as a result, the ethylene chains are disordered over equally occupied orientations.
Crystal structures of 2,6-dibromo-4-methylbenzonitrile and 2,6-dibromo-4-methylphenyl isocyanide
Authors: Noland Wayland E. , Shudy Jessica E. , Rieger Janel L. , Tu Zoe H. , Tritch Kenneth J.
Published: November 2017

In the title crystals, C8H5Br2N, which are isomorphous, the steric bulk of the methyl group causes neighboring molecules to become mutually inclined. This prevents the formation of planar or nearly planar sheets, which were observed in the trichloro and tribromo analogs. Instead of CN/NC...Br contacts, tetrameric Br...Br contacts are observed. These contacts form tetragonally puckered sheets parallel to (001). The CN/NC and methyl groups are grouped at the peaks and troughs. Both molecules lie across crystallographic mirror planes; thus, the methyl H atoms are disordered over two sets of sites with equal occupancy. The title nitrile is a redetermination. The refinement converged atR[F2> 2σ(F2)] = 0.020, whereas the original determination [Gleason & Britton, (1976).Cryst. Struct. Commun.5, 229–232] hadR= 0.112.
Crystal structure ofcis-1-phenyl-8-(pyridin-2-ylmethyl)dibenzo[1,2-c:2,1-h]-2,14-dioxa-8-aza-1-borabicyclo[4.4.0]deca-3,8-diene
Authors: Ledesma Gabriela , Signorella Sandra , Back Davi , Schulz Lang Ernesto
Published: November 2017

The title compound, C26H23BN2O2, was obtained as by product during synthetic attempts of a complexation reaction between the tripodal ligand H2L[N,N-bis(2-hydroxybenzyl)(pyridin-2-yl)methylamine] and manganese(III) acetate in the presence of NaBPh4. The isolatedB-phenyl dioxazaborocine contains an N→B dative bond with acisconformation. In the crystal, C—H...O hydrogen bonds define chains parallel to theb-axis direction. A comparative analysis with other structurally related derivatives is also included, together with a rationalization of the unexpected production of this zwitterionic heterocycle.
1-(Pyridin-2-yl)-2,4-bis[(pyridin-2-yl)carbonyl]-3,5-bis(3,4,5-trimethoxyphenyl)cyclohexanol 2.25-hydrate
Authors: Dravida Thendral Era , Gomathi S. , Mohamooda Sumaya U. , Biruntha K. , Usha G.
Published: November 2017

In the title compound, C41H41N3O9·2.25H2O, the cyclohexanol ring adopts a chair conformation. The cyclohexanol ring makes dihedral angles of 87.89 (7) and 75.53 (8)° with the mean planes of the trimethoxyphenyl rings and dihedral angles of 84.18 (8), 85.07 (7) and 82.03 (8)° with the pyridine rings. In the crystal, the packing is stabilized by C—H...O, O—H...O and O—H...N hydrogen bonds involving water molecules and methoxy O atoms, resulting in a supramolecular network. One of the methoxy groups is disordered over two sets of sites with occupancy factors of 0.63 (3) and 0.37 (3).