bluuebunny/crossref_metadata_2025 huggingface dataset:
MHC Genetic Variation Influences both Olfactory Signals and Scent Discrimination in Ring-Tailed Lemurs
Authors: Grogan Kathleen E. , Harris Rachel L. , Boulet Marylène , Drea Christine M.
Published: June 2018

Diversity at the Major Histocompatibility Complex (MHC) is critical to health and fitness, such that MHC genotype may predict an individual’s quality or compatibility as a competitor, ally, or mate. Moreover, because MHC products can influence the components of bodily secretions, an individual’s body odor may signal its MHC and influence partner identification or mate choice. To investigate MHC-based signaling and recipient sensitivity, we test for odor-gene covariance and behavioral discrimination of MHC diversity and pairwise dissimilarity, under the good genes and good fit paradigms, in a strepsirrhine primate, the ring-tailed lemur (Lemur catta). First, we coupled genotyping with gas chromatography-mass spectrometry to investigate if diversity of the MHC-DRB gene is signaled by the chemical diversity of lemur genital scent gland secretions. We also assessed if the chemical similarity between individuals correlated with their MHC similarity. Next, we assessed if lemurs discriminated this chemically encoded, genetic information in opposite-sex conspecifics. We found that both sexes signaled overall MHC diversity and pairwise MHC similarity via genital secretions, but in a sex- and season-dependent manner. Additionally, both sexes discriminated absolute and relative MHC-DRB diversity in the genital odors of opposite-sex conspecifics, supporting previous findings that lemur genital odors function as advertisement of genetic quality. In this species, genital odors provide honest information about an individual’s absolute and relative MHC quality. Complementing evidence in humans and Old World monkeys, our results suggest that reliance on scent signals to communicate MHC quality may be important across the primate lineage.
TuxNet: A simple interface to process RNA sequencing data and infer gene regulatory networks
Authors: Luis Balaguer Maria Angels de , Spurney Ryan J. , Clark Natalie M. , Fisher Adam P. , Sozzani Rosangela
Published: June 2018

Predicting gene regulatory networks (GRNs) from gene expression profiles has become a common approach for identifying important biological regulators. Despite the increase in the use of inference methods, existing computational approaches do not integrate RNA-sequencing data analysis, are often not automated, and are restricted to users with bioinformatics and programming backgrounds. To address these limitations, we have developed TuxNet, an integrated user-friendly platform, which, with just a few selections, allows to process raw RNA-sequencing data (using the Tuxedo pipeline) and infer GRNs from these processed data. TuxNet is implemented as a graphical user interface and, using expression data from any organism with an existing reference genome, can mine the regulations among genes either by applying a dynamic Bayesian network inference algorithm, GENIST, or a regression tree-based pipeline that uses spatiotemporal data, RTP-STAR. To illustrate the use of TuxNet while getting insight into the regulatory cascade downstream of the Arabidopsis root stem cell regulator PERIANTHIA (PAN), we obtained time course gene expression data of a PAN inducible line and inferred a GRN using GENIST. Using RTP-STAR, we then inferred the network of a PAN secondary downstream gene, ATHB13, for which we obtained wildtype and mutant expression profiles. Our case studies feature the versatility of TuxNet to infer networks using different types of gene expression data (i.e time course and steady-state data) as well as how inference networks are used to identify important regulators.

TuxNet offers a simple interface for non-computational biologists to infer GRNs from raw RNA-seq data.
β-cyclocitral is a conserved root growth regulator
Authors: Dickinson Alexandra J. , Lehner Kevin , Mi Jianing , Jia Kun-Peng , Mijar Medhavinee , Dinneny José , Al-Babili Salim , Benfey Philip N.
Published: June 2018

Natural compounds capable of increasing root depth and branching are desirable tools for enhancing stress tolerance in crops. We devised a sensitized screen to identify natural metabolites capable of regulating root traits in Arabidopsis. β-cyclocitral, an endogenous root compound, was found to promote cell divisions in root meristems and stimulate lateral root branching. β-cyclocitral rescued meristematic cell divisions inccd1ccd4biosynthesis mutants and β-cyclocitral-driven root growth was found to be independent of auxin, brassinosteroid, and ROS signaling pathways. β-cyclocitral had a conserved effect on root growth in tomato and rice and generated significantly more compact crown root systems in rice. Moreover, β-cyclocitral treatment enhanced plant vigor in rice plants exposed to salt-contaminated soil. These results indicate that β-cyclocitral is a broadly effective root growth promoter in both monocots and eudicots and could be a valuable tool to enhance crop vigor under environmental stress.

One Sentence Summary

β-cyclocitral is a metabolite of β-carotene that was identified using a sensitized chemical screen and acts broadly across plants to enhance root growth and branching.
An examination of the evolve-and-resequence method usingDrosophila simulans
Authors: Kelly John K. , Hughes Kimberly A.
Published: June 2018

We develop a set of analytical and simulation tools for Evolve-and-Resequence (E&R) experiments and apply them to a new study of rapid evolution inDrosophila simulans. Likelihood based test statistics applied to pooled population sequencing data suggest parallel evolution of 138 polymorphisms (SNPs) across the genome. This number is reduced by orders of magnitude from previous studies (thousands or tens of thousands), owing to differences in both experimental design and statistical analysis. Whole genome simulations calibrated from several Drosophila genetic datasets support the contention that the observed genome-wide response could be generated by as few as 30 loci under strong directional selection, with a corresponding hitch-hiking effect. Finally, the SNPs that showed strong parallel evolution in the novel laboratory environment exhibit an (initial) allele frequency spectrum indicative of balancing in nature. These loci also exhibit elevated differentiation among natural populations ofD. simulans.
Life history trade-offs in ectotherms impart a pseudo-hormetic response, not hormesis
Authors: McCallum Malcolm L. , Mary Michelle , Trauth Stanley E.
Published: June 2018

All organisms are faced with survival and fitness challenges. However, differences in how ectotherms and endotherms deal with these challenges causes confusion when theoretical explanations are proposed. Herein, an immunochallenged, immature ectothermic vertebrate increased growth in the face of immunochallenge, reminiscent of up-regulated physiological efficiency termed hormesis. The immunochallenged subjects increased food intake relative to control animals, a largely ignored possibility in previous studies. This likely led to an energy surplus that fueled additional growth. Although there was increased resource demand from the immune response that exceeded internal stores, the acceptably sized food items contained more resources than immunologically-driven demand required. We theorize that because ectotherms lack significant internally-stored resources compared to endotherms, they must feed to fuel increased physiological demand. This can lead to excess resource intake because the minimum acceptably sized prey contains more available resources than upregulation required. This creates a pseudo-hormetic hormetic response, fueled by excess food intake rather than significant improved physiological efficiency. Further, we speculate that lifespan and/or maturity may interact with resource management ectotherms, though our data are inconclusive on this matter. Ultimately, our data suggest additional growth when ectotherms face stressors is a pseudo-hormetic response stemming from increased food intake instead of upregulated physiological efficiency.
Competition and Synergy BetweenProchlorococcusandSynechococcusUnder Ocean Acidification Conditions
Authors: Knight Margaret A. , Morris J. Jeffrey
Published: June 2018

Anthropogenic CO2emissions are projected to lower the pH of the open ocean by 0.2 to 0.3 units over the next century. Laboratory experiments show that different phytoplankton taxa exhibit a wide variety of responses, with some strains having higher fitness under projected future conditions, and others being negatively impacted. Previous studies have suggested thatProchlorococcusandSynechococcus, the numerically dominant picophytoplankton in the oceans, have very different responses to elevated CO2that may result in a dramatic shift in their relative abundances in future oceans. Here we show that these two genera experience faster exponential growth rates under future CO2conditions, similar to most other cyanobacteria that have been studied. However,Prochlorococcusstrains have significantly lower realized growth rates due to more extreme lag periods after exposure to fresh culture media. Surprisingly, however,Synechococcuswas unable to outcompeteProchlorococcusin co-culture at elevated CO2. Under these conditions,Prochlorococcus’ poor response to elevated CO2disappeared, and it showed negative frequency dependence in its relative fitness compared toSynechococcus, with a significant fitness advantage when it was initially rare. Moreover, bothSynechococcusandProchlorococcushad faster growth rates in co-culture with each other than either had in unialgal culture. We speculate that this negative frequency dependence is an outgrowth of reductive Black Queen evolution operating on both taxa that has resulted in a passively mutualistic relationship analogous to that connectingProchlorococcuswith the “helper” heterotrophic microbes in its environment.
Nitrogen utilization and transformation ofStenotrophomonas maltophiliaW-6 with nitrogen-fixing ability
Authors: Wang Shutong , Xu Yi , Li Zhenlun
Published: June 2018

Strain W-6 was isolated from the purple soil and successfully identifed asStenotrophomonas maltophiliaand used for the investigation on nitrogen utilization. Strain W-6 was monitored with the ability of biological nitrogen fixation when N2was used for the sole nitrogen source, and yet nitrogenase activity would be inhibited in the presence of extra nitrogen. Moreover, Strain W-6 could utilize NO3−, NO2−and NH4+for cell growth through assimilation, but unable to convert them to atmospheric nitrogen. Meantime, accumulation of nitrite was observed during the nitrate removal process, and the optimal conditions for nitrate removal were temperature of 20°C, shaking speed of 150 rpm, sodium succinate as the carbon source and C/N of 12. The experimental results indicate thatStenotrophomonas maltophiliautilize W-6 could utilize not only N2but also other nitrogen sources directly as its N substance. Therefore, heterotrophicAzotobactermay possess a great significance to nitrogen cycle except in biological nitrogen fixation.

Importance

Azotobacterspp. are found in soils worldwide, with features not simply for the nitrogen fixation, but for the energy metabolism relevant to agriculture. However, the role ofAzotobacterpotential in the function of nitrogen cycle except in biological nitrogen fixation is largely unknown. As such, whether bacteria utilize either inorganic nitrogen or organic nitrogen has remained obscure. The present studies indicate thatStenotrophomonas maltophiliaW-6 could highly efficient utilize nitrate, nitrite and ammonium etc. N substance and detect NH4+as final product. The transport velocities of nitrate-N to nitrite-N was quickly without gaseous nitrogen was produced. We probed the relationship between biological nitrogen fixation and N cycle via N conversion processes byS. maltophiliaW-6 with nitrogen-fixing ability
Impact of efavirenz, ritonavir-boosted lopinavir and nevirapine based antiretroviral regimens on the pharmacokinetics of lumefantrine and safety of artemether-lumefantrine in falciparum-negative HIV-infected Malawian adults stabilized on antiretroviral therapy
Authors: Banda Clifford George , Dzinjalamala Fraction , Mukaka Mavuto , Mallewa Jane , Maiden Victor , Terlouw Dianne J , Lalloo David G. , Khoo Saye H. , Mwapasa Victor
Published: June 2018

There is conflicting evidence of the impact of commonly used antiretroviral therapies (ARTs) on the pharmacokinetics of lumefantrine and safety profile of artemether-lumefantrine. We compared the area under the concentration-time curve (AUC0-14 days) of lumefantrine and safety profile of artemether-lumefantrine in malaria-negative human immunodeficiency virus (HIV) infected adults in two steps. In step 1, a half-dose adult course of artemether-lumefantrine was administered as a safety check in four groups (n = 6/group): (i) antiretroviral-naïve, (ii) on nevirapine-based ART, (iii) on efavirenz-based ART and (iv) on ritonavir-boosted lopinavir-based ART. In step 2, a standard-dose adult course of artemether-lumefantrine was administered to a different cohort in three groups (n = 10–15/group): (i) antiretroviral-naïve, (ii) on efavirenz-based ART and (iii) on ritonavir-boosted lopinavir-based ART. In step 1, lumefantrine’s AUC0-14 days was 53% [95% CI: 0.27-0.82] lower in the efavirenz-based ART group than the ART-naïve group and was 2.4 [95% CI: 1.58-3.62] and 2.9 [95% CI: 1.75-4.72] times higher in the nevirapine and ritonavir-boosted lopinavir groups, respectively. In step 2, lumefantrine’s AUC0-14 days was 1.9 [95% CI: 1.26-3.00] times higher in the ritonavir-boosted lopinavir group and not significantly different between the efavirenz-and ART-naïve groups (0.99 [95% CI: 0.63-1.57]). Frequent cases of haematological abnormalities (thrombocytopenia and neutropenia) were observed in the nevirapine group in step 1, leading to a recommendation from the data and safety monitoring board not to include a nevirapine group in step 2. Artemether-lumefantrine was well tolerated in the other groups. The therapeutic implications of these findings need to be evaluated among HIV-malaria co-infected adults.
Genome plasticity in Papillomaviruses andde novoemergence ofE5oncogenes
Authors: Willemsen Anouk , Félez-Sánchez Marta , Bravo Ignacio G.
Published: June 2018

The clinical presentations of papillomavirus (PV) infections come in many different flavors. While most PVs are part of a healthy skin microbiota and are not associated to physical lesions, other PVs cause benign lesions, and only a handful of PVs are associated to malignant transformations linked to the specific activities of theE5,E6andE7oncogenes. The functions and origin ofE5remain to be elucidated. TheseE5ORFs are present in the genomes of a few polyphyletic PV lineages, located between the early and the late viral gene cassettes. We have computationally assessed whether theseE5ORFs have a common origin and whether they display the properties of a genuine gene. Our results suggest that during the evolution ofPapillomaviridae, at least four events lead to the presence of a long non-coding DNA stretch between theE2and theL2genes. In three of these events, the novel regions evolved coding capacity, becoming the extantE5ORFs. We then focused on the evolution of theE5genes inAlphaPVsinfecting humans. The sharp match between the type of E5 protein encoded inAlphaPVsand the infection phenotype (cutaneous warts, genital warts or anogenital cancers) supports the role of E5 in the differential oncogenic potential of these PVs. In our analyses, the best-supported scenario is that the five types of extant E5 proteins within theAlphaPVgenomes may not have a common ancestor. However, the chemical similarities between E5s regarding amino acid composition prevent us from confidently rejecting the model of a common origin. Our evolutionary interpretation is that an originally non-coding region entered the genome of the ancestralAlphaPVs. This genetic novelty allowed to explore novel transcription potential, triggering an adaptive radiation that yielded three main viral lineages encoding for different E5 proteins, and that display distinct infection phenotypes. Overall, our results provide an evolutionary scenario for thede novoemergence of viral genes and illustrate the impact of such genotypic novelty in the phenotypic diversity of the viral infections.
Broad geographic sampling reveals predictable, pervasive, and strong seasonal adaptation inDrosophila
Authors: Machado Heather E. , Bergland Alan O. , Taylor Ryan , Tilk Susanne , Behrman Emily , Dyer Kelly , Fabian Daniel K. , Flatt Thomas , González Josefa , Karasov Talia L. , Kim Bernard , Kozeretska Iryna , Lazzaro Brian P. , Merritt Thomas JS , Pool John E. , O’Brien Katherine , Rajpurohit Subhash , Roy Paula R. , Schaeffer Stephen W. , Serga Svitlana , Schmidt Paul , Petrov Dmitri A.
Published: June 2018

To advance our understanding of adaptation to temporally varying selection pressures, we identified signatures of seasonal adaptation occurring in parallel amongDrosophila melanogasterpopulations. Specifically, we estimated allele frequencies genome-wide from flies sampled early and late in the growing season from 20 widely dispersed populations. We identified parallel seasonal allele frequency shifts across North America and Europe, demonstrating that seasonal adaptation is a general phenomenon of temperate fly populations. Seasonally fluctuating polymorphisms are enriched in large chromosomal inversions and we find a broad concordance between seasonal and spatial allele frequency change. The direction of allele frequency change at seasonally variable polymorphisms can be predicted by weather conditions in the weeks prior to sampling, linking the environment and the genomic response to selection. Our results suggest that fluctuating selection is an important evolutionary force affecting patterns of genetic variation inDrosophila.
Molecular evolution of juvenile hormone esterase-like proteins in a socially exchanged fluid
Authors: LeBoeuf Adria C. , Cohanim Amir B. , Stoffel Céline , Brent Colin S. , Waridel Patrice , Privman Eyal , Keller Laurent , Benton Richard
Published: June 2018

Socially exchanged fluids are a direct means for organisms to influence conspecifics. When orally feeding larval offspring via trophallaxis, Camponotus floridanus ant workers were shown to transfer Juvenile Hormone (JH), a key developmental regulator, as well as paralogs of JH esterase (JHE), an enzyme that hydrolyzes JH. We combine proteomic, phylogenetic and selection analyses to investigate the evolution of this esterase subfamily. We show that Camponotus JHE-like proteins have sustained multiple duplications, positive selection, and changed localization to become abundantly and selectively present in trophallactic fluid. To assess their potential role in larval development, we fed workers a JHE-specific inhibitor to introduce it into the trophallactic network. This increased the proportion larvae reared to metamorphosis by these workers, similar to supplementation with JH. Together these findings suggest that JHE-like proteins have evolved new roles in inter-individual regulation of larval development in Camponotus.
Combining Multi-Site/Multi-Study MRI Data: Linked-ICA Denoising for Removing Scanner and Site Variability from Multimodal MRI Data
Authors: Li Huanjie , Smith Stephen M. , Gruber Staci , Lukas Scott E. , Silveri Marisa M. , Hill Kevin P. , S Killgore William D. , Nickerson Lisa D.
Published: June 2018

Large multi-site studies that pool magnetic resonance imaging (MRI) data across research sites or studies, or that utilize shared data from imaging repositories, present exceptional opportunities to advance neuroscience and enhance reproducibility of neuroimaging research. However, both scanner and site variability are confounds that hinder pooling data collected across different sites or across different operating systems on the same scanner, even when all acquisition protocols are harmonized. These confounds degrade statistical analyses and can lead to spurious findings. Unfortunately, methods to address this problem are scant. In this study, we propose a novel denoising approach for multi-site multimodal MRI data that implements a data-driven linked independent component analysis (LICA) to efficiently identify scanner/site-related effects for removal. Removing these effects results in denoised data that can then be combined across sites/studies to improve modality-specific statistical processing. We use data from six different studies collected on the same scanner across major hardware (gradient and head coil) and software upgrades to demonstrate our LICA-based denoising approach. The proposed method is superior compared to the existing methods we tested and has great potential for large-scale multi-site studies to produce combined data free from study/site confounds.
FADU: A Feature Counting Tool for Prokaryotic RNA-Seq Analysis
Authors: Chung Matthew , Adkins Ricky S. , Shetty Amol C. , Sadzewicz Lisa , Tallon Luke J. , Fraser Claire M. , Rasko David A. , Mahurkar Anup , Dunning Hotopp Julie C.
Published: June 2018

Motivation

The major algorithms for quantifying transcriptomics data for differential gene expression analysis were designed for analyzing data from human or human-like genomes, specifically those with single gene transcripts and distinct transcriptional boundaries that extend beyond the coding sequence (CDS) as identified through expressed sequence tags (ESTs) or EST-like sequence data. Some eukaryotic genomes and all, or nearly all, bacterial genomes require alternate methods of quantification since they lack annotation of transcriptional boundaries with EST or EST-like data, have overlapping transcriptional boundaries, and/or have polycistronic transcripts.

Results

An algorithm was developed and tested that better quantifies transcriptomics data for differential gene expression analysis in organisms with overlapping transcriptional units and polycistronic transcripts. Using data from standard libraries originating from Escherichia coli and Ehrlichia chaffeensis, and strand-specific libraries from the Wolbachia endosymbiont wBm, FADU can derive counts for genes that are missed by HTSeq and featurecounts. Using the default parameters with the E. coli data, FADU can detect transcription of 51 more genes than HTSeq in union mode and 21 genes more than featurecounts, with 42 and 18 of these features being <300 bp, respectively. Due to its ability to derive counts for otherwise unrepresented genes without overstating their abundance, we believe FADU to be an improved tool for quantifying transcripts in prokaryotic systems for RNA-Seq analyses.

Availability and implementation

FADU is available at https://github.com/adkinsrs/FADU. FADU was implemented using Python3 and requires the PySAM module (version 0.12.0.1 or later).

Contact

jdhotopp@som.umaryland.edu
Codon stabilization coefficient as an index for prediction of codon bias and its potential applications
Authors: Carneiro Rodolofo L. , Requião Rodrigo D. , Rossetto Silvana , Domitrovic Tatiana , Palhano Fernando L.
Published: June 2018

Different methods of mRNA half-life measurements are available, but genome-wide measurements of mRNA half-life in yeast showed a weak correlation between the methods. Moreover, when we compared mRNA half-life determined by these methods with other cellular measurements such as mRNA and protein abundance low correlation was found. To clarify this matter, we analyzed mRNA half-life datasets from nine different groups to determine the most accurate method of measurement. Since codon optimality is one of the significant determinants of mRNA stability, we used the codon stabilization coefficient (CSC) as a reference for mRNA half-life measurement accuracy. After CSC calculation for each dataset, we find strong positive correlations between the CSC from some datasets with other parameters that reflect codon optimality such as tRNA abundance and ribosome residence time. By the use of CSC parameter, we observed that most genes contain non-optimal codons and that codon bias exists toward optimized and non-optimized genes. We also observed that stretches of non-optimal are not randomly distributed since it causes impacts on translation.
Cryo-EM structure of the benzodiazepine-sensitive α1β1γ2 heterotrimeric GABAAreceptor in complex with GABA illuminates mechanism of receptor assembly and agonist binding
Authors: Phulera Swastik , Zhu Hongtao , Yu Jie , Claxton Derek P. , Yoder Nate , Yoshioka Craig , Gouaux Eric
Published: June 2018

Fast inhibitory neurotransmission in the mammalian nervous system is largely mediated by GABAAreceptors, chloride-selective members of the superfamily of pentameric Cys-loop receptors. Native GABAAreceptors are heteromeric assemblies sensitive to many important drugs, from sedatives to anesthetics and anticonvulsive agents, with mutant forms of GABAAreceptors implicated in multiple neurological diseases, including epilepsy. Despite the profound importance of heteromeric GABAAreceptors in neuroscience and medicine, they have proven recalcitrant to structure determination. Here we present the structure of the triheteromeric α1β1γ2EMGABAAreceptor in complex with GABA, determined by single particle cryo-EM at 3.1-3.8 Å resolution, elucidating the molecular principles of receptor assembly and agonist binding. Remarkable N-linked glycosylation on the α1 subunit occludes the extracellular vestibule of the ion channel and is poised to modulate receptor assembly and perhaps ion channel gating. Our work provides a pathway to structural studies of heteromeric GABAAreceptors and a framework for the rational design of novel therapeutic agents.
A critical assessment of data quality and venous effects in ultra-high-resolution fMRI
Authors: Kay Kendrick , Jamison Keith W. , Vizioli Luca , Zhang Ruyuan , Margalit Eshed , Ugurbil Kamil
Published: June 2018

Advances in hardware, pulse sequences, and reconstruction techniques have made it possible to perform functional magnetic resonance imaging (fMRI) at sub-millimeter resolution while maintaining high spatial coverage and acceptable signal-to-noise ratio. Here, we examine whether ultra-high-resolution fMRI can be exploited for routine use in neuroscience research. We conducted fMRI in human visual cortex during a simple event-related visual experiment (7T, gradient-echo EPI, 0.8-mm isotropic voxels, 2.2-s sampling rate, 84 slices), and developed analysis and visualization tools to assess the quality of the data. We make three main observations. First, we find that the acquired fMRI images, combined with appropriate surface-based processing, provide reliable and accurate measurements of fine-scale blood oxygenation level dependent (BOLD) activity patterns. Second, we show that the highly folded structure of cortex causes substantial biases on spatial resolution and data visualization. Third, we examine the well-recognized issue of venous contributions to fMRI signals. In a systematic assessment of large sections of cortex measured at a fine scale, we show that time-averaged T2*-weighted EPI intensity is a simple, robust marker of venous effects. These venous effects are unevenly distributed across cortex, are more pronounced in gyri and outer cortical depths, and are, to a certain degree, in consistent locations across subjects relative to cortical folding. Furthermore, we show that these venous effects are strongly correlated with BOLD responses evoked by the experiment. We conclude that ultra-high-resolution fMRI can provide robust information about fine-scale BOLD activity patterns, but special care must be exercised in visualizing and interpreting these patterns, especially with regards to the confounding influence of the brain’s vasculature. To help translate these methodological findings to neuroscience research, we provide practical suggestions for both high-resolution and standard-resolution fMRI studies.
Deciphering the rules of mRNA structure differentiation in vivo and in vitro with deep neural networks in Saccharomyces cerevisiae
Authors: Yu Haopeng , Meng Wenjing , Mao Yuanhui , Zhang Yi , Sun Qing , Tao Shiheng
Published: June 2018

The structure of mRNA in vivo is influenced by various factors involved in the translation process, resulting in significant differentiation of mRNA structure from that in vitro. Because multiple factors cause the differentiation of in vivo and in vitro mRNA structures, it was difficult to perform a more accurate analysis of mRNA structures in previous studies. In this study, we have proposed a novel application of a deep neural network (DNN) model to predict the structural stability of mRNA in vivo by fitting six quantifiable features that may affect mRNA folding: ribosome density, minimum folding free energy, GC content, mRNA abundance, ribosomal initial density and position of mRNA structure. Simulated mutations of the mRNA structure were designed and then fed into the trained DNN model to compute their structural stability. We found unique effects of these six features on mRNA structural stability in vivo. Strikingly, the ribosome density of the structural region is the most important factor affecting the structural stability of mRNA in vivo, and the strength of the mRNA structure in vitro should have a relatively small effect on its structural stability in vivo. The recruitment of DNNs provides a new paradigm to decipher the differentiation of mRNA structure in vivo and in vitro. This improved knowledge on the mechanisms of factors influencing mRNA structural stability will facilitate the design and functional analysis of mRNA structure in vivo.
Genomic meta-analysis of the interplay between 3D chromatin organization and gene expression programs under basal and stress conditions
Authors: Nurick Idan , Shamir Ron , Elkon Ran
Published: June 2018

Background

Our appreciation of the critical role of the 3D organization of the genome in gene regulation is steadily increasing. Recent 3C-based deep sequencing techniques elucidated a hierarchy of structures that underlie the spatial organization of the genome in the nucleus. At the top of this hierarchical organization are chromosomal territories and the megabase-scale A/B compartments that correlate with transcriptional activity within cells. Below them are the relatively cell-type invariant topologically associated domains (TADs), characterized by high frequency of physical contacts between loci within the same TAD and are assumed to function as regulatory units. Within TADs, chromatin loops bring enhancers and target promoters to close spatial proximity. Yet, we still have only rudimentary understanding how differences in chromatin organization between different cell types affect cell-type specific gene expression programs that are executed under basal and challenged conditions.

Results

Here, we carried out a large-scale meta-analysis that integrated Hi-C data from thirteen different cell lines and dozens of ChIP-seq and RNA-seq datasets measured on these cells, either under basal conditions or after treatment. Pairwise comparisons between cell lines demonstrated the strong association between modulation of A/B compartmentalization, differential gene expression and transcription factor (TF) binding events. Furthermore, integrating the analysis of transcriptomes of different cell lines in response to various challenges, we show that 3D organization of cells under basal conditions constrains not only gene expression programs and TF binding profiles that are active under the basal condition but also those induced in response to treatment.

Conclusions

Our results further elucidate the role of dynamic genome organization in regulation of differential gene expression between different cell types, and indicate the impact of intra-TAD enhancer-promoter interactions that are established under basal conditions on both the basal and treatment-induced gene expression programs.
circuitSNPs: Predicting genetic effects using a Neural Network to model regulatory modules of DNase-seq footprints
Authors: Shanku Alexander G. , Findley Anthony , Kalita Cynthia , Shim Heejung , Luca Francesca , Pique-Regi Roger
Published: June 2018

Motivation

Identifying and characterizing the function of non coding regions in the genome, and the genetic variants disrupting gene regulation, is a challenging question in genetics. Through the use of high throughput experimental assays that provide information about the chromatin state within a cell, coupled with modern computational approaches, much progress has been made towards this goal, yet we still lack a comprehensive characterization of the regulatory grammar. We propose a new method that combines sequence and chromatin accessibility information through a neural network framework with the goal of determining and annotating the effect of genetic variants on regulation of chromatin accessibility and gene transcription. Importantly, our new approach can consider multiple combinations of transcription factors binding at the same location when assessing the functional impact of non-coding genetic variation.

Results

Our method, circuitSNPs, generates predictions describing the functional effect of genetic variants on local chromatin accessibility. Further, we demonstrate that circuitSNPs not only performs better than other variant annotation tools, but also retains the causal motifs / transcription factors that drive the predicted regulatory effect.

Contact

fluca@wayne.edu, rpique@wayne.edu

Availability

http://github.com/piquelab/circuitSNPs
Dynamic decoupling of biomass and lipid biosynthesis by autonomously regulated switch
Authors: Santala Suvi , Efimova Elena , Santala Ville
Published: June 2018

For improving the microbial production of fuels and chemicals, gene knock-outs and overexpression are routinely applied to intensify the carbon flow from substrate to product. However, their possibilities in dynamic control of the flux between the biomass and product synthesis are limited, whereas dynamic metabolic switches can be used for optimizing the distribution of carbon and resources. The production of single cell oils is especially challenging, as the synthesis is strongly regulated, competes directly with biomass, and requires defined conditions, such as nitrogen limitation. Here, we engineered a metabolic switch for redirecting carbon flow from biomass to wax ester production in Acinetobacter baylyi ADP1 using acetate as a carbon source. Isocitrate lyase, an essential enzyme for growth on acetate, was expressed under an arabinose inducible promoter. The autonomous downregulation of the expression is based on the gradual oxidation of the arabinose inducer by a glucose dehydrogenase gcd. The depletion of the inducer, occurring simultaneously to acetate consumption, switches the cells from a biomass mode to a lipid synthesis mode, enabling the efficient channelling of carbon to wax esters in a simple batch culture. In the engineered strain, the yield and titer of wax esters were improved by 3.8 and 3.1 folds, respectively, over the control strain. In addition, the engineered strain accumulated wax esters 19% of cell dry weight, being the highest reported among microbes. The study provides important insights into the dynamic engineering of the biomass-dependent synthesis pathways for the improved production of biocompounds from low-cost, sustainable substrates.
Functional testing of a humanPBX3variant in zebrafish reveals a potential modifier role in congenital heart defects
Authors: Farr Gist H. , Imani Kimia , Pouv Darren , Maves Lisa
Published: June 2018

Whole-genome and whole-exome sequencing efforts are increasingly identifying candidate genetic variants associated with human disease. However, predicting and testing the pathogenicity of a genetic variant remains challenging. Genome editing allows for the rigorous functional testing of human genetic variants in animal models. Congenital heart defects (CHDs) are a prominent example of a human disorder with complex genetics. An inherited sequence variant in the humanPBX3gene (PBX3p.A136V) has previously been shown to be enriched in a CHD patient cohort, indicating that thePBX3p.A136V variant could be a modifier allele for CHDs.PBXgenes encode TALE (Three Amino acid Loop Extension)-class homeodomain-containing DNA-binding proteins with diverse roles in development and disease and are required for heart development in mouse and zebrafish. Here we use CRISPR-Cas9 genome editing to directly test whether thisPBXgene variant acts as a genetic modifier in zebrafish heart development. We used a single-stranded oligodeoxynucleotide to precisely introduce the humanPBX3p.A136V variant in the homologous zebrafishpbx4gene (pbx4p.A131V). We find that zebrafish that are homozygous forpbx4p.A131V are viable as adults. However, we show that thepbx4p.A131V variant enhances the embryonic cardiac morphogenesis phenotype caused by loss of the known cardiac specification factor, Hand2. Our study is the first example of using precision genome editing in zebrafish to demonstrate a function for a human disease-associated single nucleotide variant of unknown significance. Our work underscores the importance of testing the roles of inherited variants, not justde novovariants, as genetic modifiers of CHDs. Our study provides a novel approach toward advancing our understanding of the complex genetics of CHDs.

Summary statement

Our study provides a novel example of using genome editing in zebrafish to demonstrate how a human DNA sequence variant of unknown significance may contribute to the complex genetics of congenital heart defects.
Benchmark and integration of resources for the estimation of human transcription factor activities
Authors: Garcia-Alonso Luz , Ibrahim Mahmoud M , Turei Denes , Saez-Rodriguez Julio
Published: June 2018

Prediction of transcription factor (TF) activities from the gene expression of their targets (i.e. TF regulon) is becoming a widely-used approach to characterize the functional status of transcriptional regulatory circuits. Several strategies and datasets have been proposed to link the target genes likely regulated by a TF, each one providing a different level of evidence. The most established ones are: (i) manually curated repositories, (ii) interactions derived from ChIP-seq binding data, (iii) in silico prediction of TF binding on gene promoters, and (iv) reverse-engineered regulons from large gene expression datasets. However, it is not known how these different sources of regulons affect the TF activity estimations, and thereby downstream analysis and interpretation. Here we compared the accuracy and biases of these strategies to define human TF regulons by means of their ability to predict changes in TF activities in three reference benchmark datasets. We assembled a collection of TF-target interactions among 1,541 TFs, and evaluated how the different molecular and regulatory properties of the TFs, such as the DNA-binding domain, specificities or mode of interaction with the chromatin, affect the predictions of TF activity changes. We assessed their coverage and found little overlap on the regulons derived from each strategy and better performance by literature-curated information followed by ChIP-seq data. We provide an integrated resource of all TF-target interactions derived through these strategies with a confidence score, as a resource for enhanced prediction of TF activities.
The reduced prevalence of macrolide resistance inMycoplasma pneumoniaeclinical isolates from pediatric patients in Beijing in 2016
Authors: Tian Xiujun , Wei Ran , Shao Junyan , Wang Hong , Li Jing , Zhou Wei , Qin Xuanguang , Hu Yinghui , Dou Haiwei , Guo Dongxing , Li Jingyi , Li Dan , Xu Baoping , Xin Deli
Published: June 2018

Older children especially from seven to thirteen years old are more prone to developMycoplasma pneumoniae(MP) infection; in winter children are more susceptible to infect with MP. In Beijing, China in 2016 the rates of macrolide resistance of MP were 69.48% (in total children), 61.59% (in outpatients) and 79.28% (in hospitalized patients), respectively. All the macrolide resistant isolates harbored A2063G or A2064G mutation in the 23S rRNA gene. Seven isolates showed a mixed infection. Susceptibility results showed that 73 isolates with the A2063G mutation demonstrated different levels resistance to erythromycin (MIC=8 to>256μg/ml), azithromycin (MIC=8 to>64μg/ml) and josamycin (MIC=2 to 8μg/ml). No cross-resistance was observed in the in the antibiotics of levofloxacin and tetracycline against MP.
Individual based genetic analyses support asexual hydrochory dispersal in Zostera noltei
Authors: Berković Buga , Coelho Nelson , Gouveia Licínia , Serrão Ester A. , Alberto Filipe
Published: June 2018

Dispersal beyond the local patch in clonal plants was typically thought to result from sexual reproduction via seed dispersal. However, evidence for the separation, transport by water, and re-establishment of asexual propagules (asexual hydrochory) is mounting suggesting other important means of dispersal in aquatic plants. Using an unprecedented sampling size and microsatellite genetic identification, we describe the distribution of seagrass clones along tens of km within a coastal lagoon in Southern Portugal. Our spatially explicit individual-based sampling design covered 84 km2 and collected 3 185 Zostera noltei ramets from 803 sites. We estimated clone age, assuming rhizome elongation as the only mechanism of clone spread, and contrasted it with paleo-oceanographic sea level change. We also studied the association between a source of disturbance and the location of large clones. A total of 16 clones were sampled more than 10 times and the most abundant one was sampled 59 times. The largest distance between two samples from the same clone was 26.4 km and a total of 58 and 10 clones were sampled across more than 2 and 10 km, respectively. The number of extremely large clone sizes, and their old ages when assuming the rhizome elongation as the single causal mechanism, suggests other processes are behind the span of these clones. We discuss how the dispersal of vegetative fragments in a stepping-stone manner might have produced this pattern. We found higher probabilities to sample large clones away from the lagoon inlet, considered a source of disturbance. This study corroborates previous experiments on the success of transport and re-establishment of asexual fragments and supports the hypothesis that asexual hydrochory is responsible for the extent of these clones.
Spatial analysis of the cure rate for tuberculosis in primary health care in the municipality of Rio de Janeiro between 2012 and 2014
Authors: Prado Junior José Carlos , de Andrade Medronho Roberto
Published: June 2018

Background

Tuberculosis (TB) has a high disease burden and the World Health Organization (WHO) states it is a global emergency. TB is the most important cause of death from infectious disease in adults. It is directly related to access to health services and socioeconomic factors. Primary health care (PHC) provides greater linkage of people to health services and greater medication adherence in some chronic diseases. It also provides supervised treatment and more effective search for contactants. The PHC Reform started in 2009 in Rio de Janeiro, increasing coverage from 7% to 46.16% in 2015.

Methodology/Principal findings

This paper aims to evaluate the spatial distribution of new TB cases closed with a cure outcome in dwellers of Rio de Janeiro in the period 2012-2014, according to PHC coverage, controlling socioeconomic, demographic and epidemiological factors. Variables were obtained from the Notifiable Diseases Information System for Tuberculosis (SINAN-TB) and the socioeconomic variables from the 2010 national census at census tract level. The socioeconomic variables were selected from multivariate analysis using main factors analysis technique. The generalized additive model (GAM) was used for the spatial analysis. Association was found between TB cure and variables education, alcoholism, contacts search, HIV serology and elderly. People with family health coverage between 35 and 41 months were 1.64 more likely of cure when compared to people without coverage (95% CI 1.07-2.51). Spatial analysis identified areas with less probability of cure for tuberculosis in the municipality of Rio de Janeiro.

Author Summary

Tuberculosis is associated to social and demographic conditions. Lack of access to healthcare contributes to delay in diagnosis and in the beginning of the treatment. Primary health care improve access and adherence to treatment. This study can be useful as a public health policy, since it is possible to prioritize the region in the map to improve TB cure. We found association between tuberculosis cure and the duration of implantation of the primary health care teams. This finding corroborates the importance of treating tuberculosis in this level of care. The spatial analysis of cases of tuberculosis cure showed a significant spatial association with the cure of tuberculosis. The results of this study can contribute reinforcing the policy makers for developing primary health care to improve the access to health services and to reach better TB cure rates. Spatial analysis may be an useful tool for identifying the areas where to prioritize efforts for reaching better results.
Bridging the gap between theory and practice in management accounting
Authors: Jansen E. Pieter
Published: June 2018

Purpose

Although management accounting tools and techniques are developed to solve practical problems in organizations, there is a lot of criticism of management accounting research for not having an impact on practice. In interventionist research, the “shaping” of an intervention to solve a practical problem is an important step. The purpose of this paper is to explore how the findings of management accounting research can be reviewed to make them practically applicable in shaping an intervention.

Design/methodology/approach

The paper is based on the author’s experiences with an interventionist research project.

Findings

Systematic literature reviews, which are common in engineering and medicine, bring together the academic knowledge that can contribute to solutions for a specific practical problem, including a definition of the ways in which this knowledge can be applied. Inspired by the methodology for conducting such reviews, this paper proposes how interventionist management accounting researchers can use existing theoretical knowledge in shaping interventions that aim to solve a practical problem. After an intervention, the analysis of the intervention’s unforeseen effects can provide a basis for the refinement of the theory identified in the literature review.

Research limitations/implications

Such a literature review can be organized according to four approaches to taking theoretical knowledge into practice. Unforeseen effects of the intervention can guide the selection of additional theory that helps to interpret these effects and refine normative and academic theory.

Originality/value

In management accounting it is uncommon to review the literature with the aim of shaping a solution for a practical problem. This paper explores how literature reviews that focus on a specific practical problem can contribute to bridging the gap between theory and practice.