bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeting hotspots to reduce transmission of malaria in Senegal: modeling of the effects of human mobility
Authors: Sallah Kankoé , Giorgi Roch , Ba El Hadj , Piarroux Martine , Piarroux Renaud , Griffiths Karolina , Cisse Badara , Gaudart Jean
Published: September 2018

Background

In central Senegal malaria incidences have declined in recent years in response to scaling-up of control measures, but now remains stable, making elimination improbable. Additional control measures are needed to reduce transmission.

Methods

By using a meta-population mathematical model, we evaluated chemotherapy interventions targeting stable malaria hotspots, using a differential equation framework and incorporating human mobility, and fitted to weekly malaria incidences from 45 villages, over 5 years. Three simulated approaches for selecting intervention targets were compared: a) villages with at least one malaria case during the low transmission season of the previous year; b) villages ranked highest in terms of incidence during the high transmission season of the previous year; c) villages ranked based on the degree of connectivity with adjacent populations.

Results

Our mathematical modeling, taking into account human mobility, showed that the intervention strategies targeting hotspots should be effective in reducing malaria incidence in both treated and untreated areas.

Conclusions

Mathematical simulations showed that targeted interventions allow increasing malaria elimination potential.
Association between long-term air pollution exposure and DNA methylation: the REGICOR study
Authors: Sayols-Baixeras Sergi , Fernández-Sanlés Alba , Prats Albert , Subirana Isaac , Plusquin Michelle , Künzli Nino , Marrugat Jaume , Basagaña Xavier , Elosua Roberto
Published: September 2018

Background

Limited evidence suggests that epigenetic mechanisms may partially mediate the adverse effects of air pollution on health. Our aims were to identify new genomic loci showing differential DNA methylation associated with long-term exposure to air pollution and to replicate loci previously identified in other studies.

Methods

A two-stage epigenome-wide association study was designed: 630 individuals from the REGICOR study were included in the discovery and 454 participants of the EPIC-Italy study in the validation stage. DNA methylation was assessed using the Infinium HumanMethylation450 BeadChip. NOX, NO2, PM10, PM2.5, PMcoarse, traffic intensity and traffic load exposure were measured according to the ESCAPE protocol. A systematic review was undertaken to identify those cytosine-phosphate-guanine (CpGs) associated with air pollution in previous studies and we screened for them in the discovery study.

Results

In the discovery stage of the epigenome-wide association study, 81 unique CpGs were associated with air pollution (p-value <10−5) but none of them were validated in the replication sample. Furthemore, we identified 12 CpGs in the systematic review showing differential methylation with a p-value fulfilling the Bonferroni criteria and 1642 CpGs fulfilling the false discovery rate criteria, all of which were related to PM2.5or NO2. None of them was replicated in the discovery study, in which the top hits were located in an intergenic region on chromosome 1 (cg10893043, p-value=6.79·10−5) and in thePXKandARSAgenes (cg16560256, p-value=2.23·10−04; cg11953250, p-value=3.64·10−04).

Conclusions

Neither new genomic loci associated with long-term air pollution were identified, nor previously identified loci were replicated. Continued efforts to test this potential association are warranted.
The direct costs of overdiagnosed asthma in a longitudinal population-based study
Authors: Ng Bryan C. , Sadatsafavi Mohsen , Safari Abdollah , FitzGerald J. Mark , Johnson Kate M.
Published: September 2018

Objectives

A current diagnosis of asthma cannot be objectively confirmed in many patients with physician-diagnosed asthma. Estimates of resource use in overdiagnosed cases of asthma are necessary to measure the burden of overdiagnosis and evaluate strategies to reduce this burden. We assessed the difference in asthma-related healthcare resource use between patients with a confirmed asthma diagnosis and those with asthma ruled out.

Design

Population-based prospective cohort study.

Setting

Participants were recruited through random-digit dialling of both landlines and mobile phones in BC, Canada.

Participants

We included 345 individuals ≥12 years of age with a self-reported physician diagnosis of asthma which was confirmed by a bronchodilator reversibility or methacholine challenge test at the end of the 12-month follow-up.

Primary and secondary outcome measures

Self-reported annual asthma-related direct healthcare costs (2017 Canadian dollars), outpatient physician visits, and medication use from the Canadian healthcare system perspective.

Results

Asthma was ruled out in 86 (24.9%) participants. Average annual asthma-related direct healthcare costs for participants with confirmed asthma were $497.9 (SD $677.9), and $307.7 (SD $424.1) for participants with asthma ruled out. In the adjusted analyses, a confirmed diagnosis was associated with higher direct healthcare costs (Relative Ratio [RR]=1.60, 95%CI 1.14-2.22), increased rate of specialist visits (RR=2.41, 95%CI 1.05-5.40) and reliever medication use (RR=1.62, 95%CI 1.09-2.35), but not primary care physician visits (p=0.10) or controller medication use (p=0.11).

Conclusions

A quarter of individuals with a physician diagnosis of asthma did not have asthma after objective re-evaluation. These participants still consumed a significant amount of asthma-related healthcare resources. The population-level economic burden of asthma overdiagnosis could be substantial.

Strengths and limitations of this study

Participants were recruited through random sampling of the general population in the province of British Columbia.

Asthma diagnosis was confirmed or ruled out using sequential guideline-recommended objective airway tests.

Healthcare resource use was self-reported, potential recall bias may have led to reduced accuracy.

The study was unable to evaluate the indirect costs of overdiagnosis or the cost-savings from correcting the diagnosis.

The generalizability of the results may be limited by regional differences in medical costs and practices.
Cardelino: Integrating whole exomes and single-cell transcriptomes to reveal phenotypic impact of somatic variants
Authors: McCarthy Davis J. , Rostom Raghd , Huang Yuanhua , Kunz Daniel J. , Danecek Petr , Bonder Marc Jan , Hagai Tzachi ,   HipSci Consortium, Wang Wenyi , Gaffney Daniel J. , Simons Benjamin D. , Stegle Oliver , Teichmann Sarah A.
Published: September 2018

Decoding the clonal substructures of somatic tissues sheds light on cell growth, development and differentiation in health, ageing and disease. DNA-sequencing, either using bulk or using single-cell assays, has enabled the reconstruction of clonal trees from frequency and co-occurrence patterns of somatic variants. However, approaches to systematically characterize phenotypic and functional variations between individual clones are not established. Here we present cardelino (https://github.com/PMBio/cardelino), a computational method for inferring the clone of origin of individual cells that have been assayed using single-cell RNA-seq (scRNA-seq). After validating our model using simulations, we apply cardelino to matched scRNA-seq and exome sequencing data from 32 human dermal fibroblast lines, identifying hundreds of differentially expressed genes between cells from different somatic clones. These genes are frequently enriched for cell cycle and proliferation pathways, indicating a key role for cell division genes in non-neutral somatic evolution.

Key findings

A novel approach for integrating DNA-seq and single-cell RNA-seq data to reconstruct clonal substructure for single-cell transcriptomes.

Evidence for non-neutral evolution of clonal populations in human fibroblasts.

Proliferation and cell cycle pathways are commonly distorted in mutated clonal populations.
PISDis a mitochondrial disease gene causing skeletal dysplasia, cataracts, and white matter changes
Authors: Zhao Tian , Goedhart Caitlin M. , Sam Pingdewinde , Lingrell Susanne , Cornish Adam J. , Lamont Ryan E , Bernier Francois P , Sinasac David , Parboosingh Jillian S ,   Care4Rare Canada Consortium, Vance Jean E. , Claypool Steven M. , Innes A Micheil , Shutt Timothy E
Published: September 2018

Exome sequencing of two sisters with congenital cataracts, short stature and white matter changes identified compound heterozygous variants in thePISDgene, encoding the phosphatidylserine decarboxylase enzyme that converts phosphatidylserine (PS) to phosphatidylethanolamine (PE) in the inner mitochondrial membrane (IMM). Decreased conversion of PS to PE, and depletion of total cellular PE levels in patient fibroblasts are consistent with impaired PISD enzyme activity. Meanwhile, as evidence for mitochondrial dysfunction, patient fibroblasts exhibited more fragmented mitochondrial networks, enlarged lysosomes, decreased maximal oxygen consumption rates and increased sensitivity to 2-deoxyglucose. Moreover, treatment with lyso-PE, which can replenish the mitochondrial pool of PE, restored mitochondrial and lysosome morphology in patient fibroblasts. Functional characterization of thePISDmutations demonstrates that the maternal variant causes an alternative splice product. Meanwhile, the paternal variant impairs autocatalytic self-processing of the PISD protein required for its activity. Finally, evidence for impaired activity of mitochondrial IMM proteases explains why the phenotypes of thesePISDpatients resemble recently described “mitochondrial chaperonopathies”. Collectively, these findings demonstrate thatPISDis a novel mitochondrial disease gene.
Historical biogeography of the leopard (Panthera pardus) and its extinct Eurasian populations
Authors: Paijmans Johanna L.A. , Barlow Axel , Förster Daniel W. , Henneberger Kirstin , Meyer Matthias , Nickel Birgit , Nagel Doris , Havmøller Rasmus Worsøe , Baryshnikov Gennady F. , Joger Ulrich , Rosendahl Wilfried , Hofreiter Michael
Published: September 2018

Background

Resolving the historical biogeography of the leopard(Panthera pardus)is a complex issue, because patterns inferred from fossils and from molecular data lack congruence. Fossil evidence supports an African origin, and suggests that leopards were already present in Eurasia during the Early Pleistocene. Analysis of DNA sequences however, suggests a more recent, Middle Pleistocene shared ancestry of Asian and African leopards. These contrasting patterns led researchers to propose a two-stage hypothesis of leopard dispersal out of Africa: an initial Early Pleistocene colonisation of Asia and a subsequent replacement by a second colonisation wave during the Middle Pleistocene. The status of Late Pleistocene European leopards within this scenario is unclear: were these populations remnants of the first dispersal, or do the last surviving European leopards share more recent ancestry with their African counterparts?

Results

In this study, we generate and analyse mitogenome sequences from historical samples that span the entire modern leopard distribution, as well as from Late Pleistocene remains. We find a deep bifurcation between African and Eurasian mitochondrial lineages (∼710 Ka), with the European ancient samples as sister to all Asian lineages (∼483 Ka). The modern and historical mainland Asian lineages share a relatively recent common ancestor (∼122 Ka), and we find one Javan sample nested within these.

Conclusions

The phylogenetic placement of the ancient European leopard as sister group to Asian leopards suggests that these populations originate from the same out-of-Africa dispersal which founded the Asian lineages. The coalescence time found for the mitochondrial lineages aligns well with the earliest undisputed fossils in Eurasia, and thus encourages a re-evaluation of the identification of the much older putative leopard fossils from the region. The relatively recent ancestry of all mainland Asian leopard lineages suggests that these populations underwent a severe population bottleneck during the Pleistocene. Finally, although only based on a single sample, the unexpected phylogenetic placement of the Javan leopard could be interpreted as evidence for exchange of mitochondrial lineages between Java and mainland Asia, calling for further investigation into the evolutionary history of this subspecies.
The community structure of functional brain networks exhibits scale-specific patterns of variability across individuals and time
Authors: Betzel Richard F. , Bertolero Maxwell A. , Gordon Evan M. , Gratton Caterina , Dosenbach Nico U.F. , Bassett Danielle S.
Published: September 2018

The network organization of the human brain varies across individuals, changes with development and aging, and differs in disease. Discovering the major dimensions along which this variability is displayed remains a central goal of both neuroscience and clinical medicine. Such efforts can be usefully framed within the context of the brain’s modular network organization, which can be assessed quantitatively using powerful computational techniques and extended for the purposes of multi-scale analysis, dimensionality reduction, and biomarker generation. Though the concept of modularity and its utility in describing brain network organization is clear, principled methods for comparing multi-scale communities across individuals and time are surprisingly lacking. Here, we present a method that uses multi-layer networks to simultaneously discover the modular structure of many subjects at once. This method builds upon the well-known multi-layer modularity maximization technique, and provides a viable and principled tool for studying differences in network communities across individuals and within individuals across time. We test this method on two datasets and identify consistent patterns of inter-subject community variability, demonstrating that this variability – which would be undetectable using past approaches – is associated with measures of cognitive performance. In general, the multi-layer, multi-subject framework proposed here represents an advancement over current approaches by straighforwardly mapping community assignments across subjects and holds promise for future investigations of inter-subject community variation in clinical populations or as a result of task constraints.
Combined effects of migration distance, foraging method vegetation density, and population density on wing shapes of boreal songbirds
Authors: Noreau Flavie , Desrochers André
Published: September 2018

In birds, migration distance is known to influence morphological attributes that influence flight performance, especially wing shape. However, wing shape is under the likely influence of less documented factors such as foraging method, vegetation density and isolation of individuals and populations. To better understand factors leading to interspecific differences in wing shape, we measured the pointedness of wings (Kipp’s distance) of 1017 live birds of 22 species in an eastern Canadian boreal forest. We modeled wing pointedness as a function of migration distances from eBird records, foraging, habitat, and population density data fromBirds of North Americamonographs. Long-distance migrants and species living in low-density vegetation had more pointed wings than shorter-distance migrants and dense-vegetation dwellers, in accordance to our predictions. After accounting for vegetation density and migration distance, we found no link between the extent of aerial foraging or mean breeding population density, an indicator of isolation, and wing pointedness. Those results are consistent with a tradeoff between sustained flight efficiency and maneuverability, but suggest that interspecific variation in wing shape due specifically to foraging method or habitat isolation is nonexistent or obscured by other factors.
An Open-Source Plate Reader
Authors: Szymula Karol , Magaraci Michael S. , Patterson Michael , Clark Andrew , Mannickarottu Sevile G. , Chow Brian Y.
Published: September 2018

Microplate readers are foundational instruments in experimental biology and bioengineering that enable multiplexed spectrophotometric measurements. To enhance their accessibility, we here report the design, construction, validation, and benchmarking of an open-source microplate reader. The system features full-spectrum absorbance and fluorescence emission detection, in situ optogenetic stimulation, and stand-alone touch screen programming of automated assay protocols. The total system costs <$3500, a fraction of the cost of commercial plate readers, and can detect the fluorescence of common dyes down to ∼10 nanomolar concentration. Functional capabilities were demonstrated in context of synthetic biology, optogenetics, and photosensory biology: by steady-state measurements of ligand-induced reporter gene expression in a model of bacterial quorum sensing, and by flavin photocycling kinetic measurements of a LOV (light-oxygen-voltage) domain photoreceptor used for optogenetic transcriptional activation. Fully detailed guides for assembling the device and automating it using the custom Python-based API (Application Program Interface) are provided. This work contributes a key technology to the growing community-wide infrastructure of open-source biology-focused hardware, whose creation is facilitated by rapid prototyping capabilities and low-cost electronics, optoelectronics, and microcomputers.

Table of Contents Graphic:
Molecular Subtyping reveals Immune Alterations associated with Progression of Bronchial Premalignant Lesions
Authors: Beane Jennifer , Mazzilli Sarah A. , Campbell Joshua D. , Duclos Grant , Krysan Kostyantyn , Moy Christopher , Perdomo Catalina , Schaffer Michael , Liu Gang , Zhang Sherry , Liu Hangqio , Vick Jessica , Dhillon Samjot S. , Platero Suso J. , Dubinett Steven M. , Stevenson Christopher , Reid Mary E. , Lenburg Marc E. , Spira Avrum E.
Published: September 2018

Bronchial premalignant lesions (PMLs) are precursors of lung squamous cell carcinoma, but have variable outcome, and we lack tools to identify and treat PMLs at highest risk for progression to invasive cancer. Profiling endobronchial biopsies of PMLs obtained from high-risk smokers by RNA-Seq identified four PML subtypes with differences in epithelial and immune processes. One molecular subtype (Proliferative) is enriched with dysplastic lesions and exhibits up-regulation of metabolic and cell cycle pathways and down-regulation of ciliary processes. RNA-Seq profiles from normal-appearing uninvolved large airway brushings could identify subjects with Proliferative lesions with high specificity. Expression of interferon signaling and antigen processing/presentation pathways are decreased in progressive/persistent Proliferative lesions and immunofluorescence indicates a depletion of innate and adaptive immune cells in these lesions. Molecular biomarkers measured in PMLs or the uninvolved airway can enhance histopathological grading and suggests that immunoprevention strategies may be effective in intercepting the progression of PMLs to lung cancer.
Increasing metadata coverage of SRA BioSample entries using deep learning based Named Entity Recognition
Authors: Klie Adam , Tsui Brian Y , Mollah Shamim , Skola Dylan , Dow Michelle , Hsu Chun-Nan , Carter Hannah
Published: September 2018

High quality metadata annotations for data hosted in large public repositories are essential for research reproducibility, and for conducting fast, powerful and scalable meta-analyses. Currently, a majority of sequencing samples in the National Center for Biotechnology Information’s (NCBI’s) Sequence Read Archive (SRA) are missing metadata across several categories. In an effort to improve the metadata coverage of these samples, we leveraged almost 44 million attribute-value pairs from SRA BioSample to train a scalable, recurrent neural network that predicts missing metadata via Named Entity Recognition (NER). The network was first trained to classify short text phrases according to 11 metadata categories and achieved an overall accuracy and area under the receiver operating characteristic (AUROC) curve of 85.2% and 0.977 respectively. We then applied our classifier to predict 11 metadata categories from the longer TITLE attribute of samples, evaluating performance on a set of samples withheld from model training. Prediction accuracies were high when extracting sample Species (94.85%), Condition/Disease (95.65%) and Strain (82.03%) from TITLEs, with lower accuracies and lack of predictions for other categories highlighting multiple issues with the current metadata annotations in BioSample. These results indicate the utility of recurrent neural networks for NER-based metadata prediction and the potential for models such as the one presented here to increase metadata coverage in BioSample while minimizing the need for manual curation.

Availability

All the analyses, environments, and Jupyter notebooks pertaining to this manuscript are available on Github: https://github.com/cartercompbio/PredictMEE.
Distinct evolutionary dynamics of horizontal gene transfer in drug resistant and virulent clones ofKlebsiella pneumoniae
Authors: Wyres Kelly L , Wick Ryan R , Judd Louise M , Froumine Roni , Tokolyi Alex , Gorrie Claire L , Lam Margaret M C , Duchêne Sebastián , Jenney Adam , Holt Kathryn E
Published: September 2018

Klebsiella pneumoniae(Kp) has emerged as an important cause of two distinct public health threats: multidrug resistant (MDR) healthcare-associated infections1and community-acquired invasive infections, particularly pyogenic liver abscess2. The majority of MDR hospital outbreaks are caused by a subset ofKpclones with a high prevalence of acquired antimicrobial resistance (AMR) genes, while the majority of community-acquired invasive infections are caused by ‘hypervirulent’ clones that rarely harbour acquired AMR genes but have high prevalence of key virulence loci3–5. Worryingly, the last few years have seen increasing reports of convergence of MDR and the key virulence genes within individualKpstrains6, but it is not yet clear whether these represent a transient phenomenon or a significant ongoing threat. Here we perform comparative genomic analyses for 28 distinctKpclones, including 6 hypervirulent and 8 MDR, to better understand their evolutionary histories and the risks of convergence. We show that MDR clones are highly diverse with frequent chromosomal recombination and gene content variability that far exceeds that of the hypervirulent clones. Consequently, we predict a much greater risk of virulence gene acquisition by MDRKpclones than of resistance gene acquisition by hypervirulent clones.
Structural basis for recruitment of DAPK1 to the KLHL20 E3 ligase
Authors: Chen Zhuoyao , Picaud Sarah , Filippakopoulos Panagis , D’Angiolella Vincenzo , Bullock Alex N.
Published: September 2018

BTB-Kelch proteins form the largest subfamily of Cullin-RING E3 ligases, yet their substrate complexes are mapped and structurally characterized only for KEAP1 and KLHL3. KLHL20 is a related CUL3-dependent ubiquitin ligase linked to autophagy, cancer and Alzheimer’s disease that promotes the ubiquitination and degradation of substrates including DAPK1, PML and ULK1. We identified a ‘LPDLV’-containing recruitment site in the DAPK1 death domain and determined the 1.1 Å crystal structure of a KLHL20-DAPK1 complex. DAPK1 binds to KLHL20 as a loose helical turn that inserts deeply into the central pocket of the Kelch domain to contact all six blades of the β-propeller. Here, KLHL20 forms a salt bridge as well as hydrophobic interactions that include a tryptophan and cysteine residue ideally positioned for covalent inhibitor development. The structure highlights the diverse binding modes of circular substrate pockets versus linear grooves and suggests a novel E3 ligase for protac-based drug design.
Analysis of a large data set reveals haplotypes carrying putatively recessive lethal alleles with pleiotropic effects on economically important traits in beef cattle
Authors: Jenko Janez , McClure Matthew C , Matthews Daragh , McClure Jennifer , Johnsson Martin , Gorjanc Gregor , Hickey John M
Published: September 2018

Background

Deleterious recessive alleles can result in reduced economic performance in livestock in multiple ways in homozygous individuals: from early embryonic death, death soon after birth, to being non-lethal but causing reduced viability. While death is an easy phenotype to score, reduced viability is not as easy to identify. However, it can sometimes be observed as reduced artificial insemination (AI) conception rates, longer calving intervals, or higher hazard for live born animals.

Methods

In this paper, we searched for haplotypes carrying putatively recessive lethal alleles in 132,725 genotyped Irish beef cattle from five breeds: Aberdeen Angus, Charolais, Hereford, Limousin, and Simmental. We phased the genotypes in sliding windows along the genome and used five tests to identify haplotypes with absence of or reduced homozygosity. We then corroborated the identified haplotypes with reproduction records, indicating early embryonic death, and postnatal survival records. Finally, we assessed haplotype pleiotropy by estimating substitution effects on national estimates of breeding values for 15 economically important traits in beef production.

Results

We found support for three haplotypes with carrying putatively recessive lethal alleles. The haplotypes were located on chromosome 14 in Aberdeen Angus, chromosome 19 in Charolais and chromosome 16 in Simmental. Their population frequencies is 15.2%, 14.4%, and 8.8%, respectively. All of the haplotypes showed pleiotropic effects on economically important traits for beef production. Their allele substitution effects are €3.23, €1.47, and €2.30 for the terminal index and -€3.15, -€0.75, and €1.12 for the replacement index, where one standard deviations are €18.32, €22.54, and €22.33 for terminal index and €29.52, €35.62, and €30.97 for the replacement index. We identified ZFAT as the candidate gene for lethality in Aberdeen Angus, several candidate genes for the Simmental haplotype, and no candidate genes for the Charolais haplotype.

Conclusions

We analysed genotype, reproduction, survival, and production data to discover haplotypes carrying putatively recessive lethal alleles in Irish beef cattle. We found support for three haplotypes. All three haplotypes have pleiotropic effects on economically important traits in beef production.
Differential impact of endogenous and exogenous attention on activity in human visual cortex
Authors: Dugué Laura , Merriam Elisha P. , Heeger David J. , Carrasco Marisa
Published: September 2018

How do endogenous (voluntary) and exogenous (involuntary) attention modulate activity in visual cortex? Using ROI-based fMRI analysis, we measured fMRI activity for valid and invalid trials (target at cued/un-cued location, respectively), pre- or post-cueing endogenous or exogenous attention, while participants performed the same orientation discrimination task. We found stronger modulation in contralateral than ipsilateral visual regions, and higher activity in valid-than invalid-trials. For endogenous attention, modulation of stimulus-evoked activity due to a pre-cue increased along the visual hierarchy, but was constant due to a post-cue. For exogenous attention, modulation of stimulus-evoked activity due to a pre-cue was constant along the visual hierarchy, but was not modulated due to a post-cue. These findings reveal that endogenous and exogenous attention distinctly modulate activity in visuo-occipital areas during orienting and reorienting; endogenous attention facilitates both the encoding and the readout of visual information whereas exogenous attention only facilitates the encoding of information.
Overestimation of the prevalence of eosinophilic colitis with reliance on a single billing code
Authors: Muir AB , Jensen ET , Wechsler JB , Menard-Katcher P , Falk GW , Aceves SS , Furuta GT , Dellon ES , Rothenberg ME , Spergel JM
Published: September 2018

Eosinophilic colitis (EC) is a rare disorder characterized by eosinophilic inflammation of the colon causing diarrhea, bloody stool, nausea, constipation and abdominal pain. The Consortium for Eosinophilic Gastrointestinal Disease Research sought to undertake the first multi-center study of the EC population, but faced challenges with meeting enrollment goals that were based on initial estimates. To understand the reason for this, we performed chart review of patients with ICD codes for EC at 8 tertiary care centers. Chart review revealed that the isolated use of ICD codes overestimated EC rates in the pediatric population.
Neural responses to heartbeats as a mechanism for distinguishing self from other during imagination
Authors: Babo-Rebelo Mariana , Buot Anne , Tallon-Baudry Catherine
Published: September 2018

Imagination is an internally-generated process, where one can make oneself or other people appear as protagonists of a scene. How does the brain tag the protagonist of an imagined scene, as being oneself or someone else? Crucially, neither external stimuli nor motor feedback are available during imagination to disentangle imagining oneself from imagining someone else. Here, we test the hypothesis that an internal mechanism based on the neural monitoring of heartbeats could distinguish between self and other. 23 participants imagined themselves (from a first-person perspective) or a friend (from a third-person perspective) in various scenarios, while their brain activity was recorded with magnetoencephalography and their cardiac activity was simultaneously monitored. We measured heartbeat-evoked responses, i.e. transients of neural activity occurring in response to each heartbeat, during imagination. The amplitude of heartbeat-evoked responses differed between imagining oneself and imagining a friend, in the precuneus, mid and posterior cingulate regions bilaterally. Effect size was modulated by the general daydreaming frequency of participants but not by their interoceptive abilities. These results could not be accounted for by other characteristics of imagination (e.g., the ability to adopt the perspective, valence or arousal), nor by cardiac parameters (e.g., heart rate) or arousal levels. Heartbeat-evoked responses thus appear as a neural marker distinguishing self from other during imagination.

Highlights

- Heartbeat-evoked responses differentiate self from other during imagination.

- These effects were located in the precuneus and mid- to posterior cingulate.

- The neural monitoring of the body could be a mechanism for self/other distinction.
DeepProteomics: Protein family classification using Shallow and Deep Networks
Authors: Vazhayil Anu , Vinayakumar R , Soman KP
Published: September 2018

The knowledge regarding the function of proteins is necessary as it gives a clear picture of biological processes. Nevertheless, there are many protein sequences found and added to the databases but lacks functional annotation. The laboratory experiments take a considerable amount of time for annotation of the sequences. This arises the need to use computational techniques to classify proteins based on their functions. In our work, we have collected the data from Swiss-Prot containing 40433 proteins which is grouped into 30 families. We pass it to recurrent neural network(RNN), long short term memory(LSTM) and gated recurrent unit(GRU) model and compare it by applying trigram with deep neural network and shallow neural network on the same dataset. Through this approach, we could achieve maximum of around 78% accuracy for the classification of protein families.
Transient intracellular acidification regulates the core transcriptional heat shock response
Authors: Triandafillou Catherine G. , Katanski Christopher D. , Dinner Aaron R. , Drummond D. Allan
Published: September 2018

Heat shock induces a conserved transcriptional program regulated by heat shock factor 1 (Hsf1) in eukaryotic cells. Activation of this heat-shock response is triggered by heat-induced misfolding of newly synthesized polypeptides, and so has been thought to depend on ongoing protein synthesis. Here, using the the budding yeastSaccharomyces cerevisiae, we report the discovery that Hsf1 can be robustly activated when protein synthesis is inhibited, so long as cells undergo cytosolic acidification. Heat shock has long been known to cause transient intracellular acidification which, for reasons which have remained unclear, is associated with increased stress resistance in eukaryotes. We demonstrate that acidification is required for heat shock response induction in translationally inhibited cells, and specifically affects Hsf1 activation. Physiological heat-triggered acidification also increases population fitness and promotes cell cycle reentry following heat shock. Our results uncover a previously unknown adaptive dimension of the well-studied eukaryotic heat shock response.
Multiple QTL underlie milk phenotypes at the CSF2RB locus
Authors: Lopdell Thomas J , Tiplady Kathryn , Couldrey Christine , Johnson Thomas JJ , Keehan Michael , Davis Stephen R , Harris Bevin L , Spelman Richard J , Snell Russell G , Littlejohn Mathew D
Published: September 2018

Background

Bovine milk provides an important source of nutrition in much of the Western world, forming components of many food products. Over many years, artificial selection has substantially improved milk production by cows. However, the genes underlying milk production quantitative trait loci (QTL) remain relatively poorly characterised. Here, we investigate a previously-reported QTL located at theCSF2RBlocus, for several milk production phenotypes, to better understand its underlying genetic and molecular causes.

Results

Using a population of 29,350 taurine dairy cattle, we conducted association analyses for milk yield and composition traits, and identified highly significant QTL for milk yield, milk fat concentration, and milk protein concentration. Strikingly, protein concentration and milk yield appear to show co-located yet genetically distinct QTL. To attempt to understand the molecular mechanisms that might be mediating these effects, gene expression data were used to investigate eQTL for eleven genes in the broader interval. This analysis highlighted genetic impacts onCSF2RBandNCF4expression that share similar association signatures to those observed for lactation QTL, strongly implicating one or both of these genes as the cause of these effects. Using the same gene expression dataset representing 357 lactating cows, we also identified 38 novel RNA editing sites in the 3′UTR ofCSF2RBtranscripts. The extent to which two of these sites were edited also appears to be genetically co-regulated with lactation QTL, highlighting a further layer of regulatory complexity implicating theCSF2RBgene.

Conclusions

This chromosome 5 locus presents a diversity of molecular and lactation QTL, likely representing multiple overlapping effects that, at a minimum, highlight theCSF2RBgene as having a causal role in these processes.
Laboratory evolution reveals a two-dimensional rate-yield tradeoff in microbial metabolism
Authors: Cheng Chuankai , O’Brien Edward J. , McCloskey Douglas , Utrilla Jose , Olson Connor , LaCroix Ryan A. , Sandberg Troy E. , Feist Adam M. , Palsson Bernhard O. , King Zachary A.
Published: September 2018

Growth rate and yield are fundamental features of micro-bial growth. However, we lack a mechanistic and quantita-tive understanding of the rate-yield relationship. Studies pairing computational predictions with experiments have shown the importance of maintenance energy and proteome allocation in explaining rate-yield tradeoffs and overflow metabolism. Recently, adaptive evolution experiments ofEs-cherichia colireveal a phenotypic diversity beyond what has been explained using simple models of growth rate versus yield. Here, we identify a two-dimensional rate-yield trade-off in adaptedE. colistrains where the dimensions are (A) a tradeoff between growth rate and yield and (B) a tradeoff between substrate (glucose) uptake rate and growth yield. We employ a multi-scale modeling approach, combining a previously reported coarse-grained small-scale proteome allocation model with a fine-grained genome-scale model of metabolism and gene expression (ME-model), to develop a quantitative description of the full rate-yield relationship forE. coliK-12 MG1655. The multi-scale analysis resolves the complexity of ME-model which hindered its practical use in proteome complexity analysis, and provides a mecha-nistic explanation of the two-dimensional tradeoff. Further, the analysis identifies modifications to the P/O ratio and the flux allocation between glycolysis and pentose phosphate pathway as potential mechanisms that enable the tradeoff between glucose uptake rate and growth yield. Thus, the rate-yield tradeoffs that govern microbial adaptation to new environments are more complex than previously reported, and they can be understood in mechanistic detail using a multi-scale modeling approach.
Rates of increase of antibiotic resistance and ambient temperature in Europe: a cross-national analysis of 28 countries between 2000-2016
Authors: McGough Sarah F. , MacFadden Derek R. , Hattab Mohammad W. , Mølbak Kåre , Santillana Mauricio
Published: September 2018

Background

Widely recognized as a major public health threat globally, the rapid increase of antibiotic resistance in bacteria could soon render our most effective method to combat infections obsolete. Factors influencing the burden of resistance in human populations remain poorly described, though temperature is known to play an important role in mechanisms at the bacterial level.

Methods

We performed an ecologic analysis of country level antibiotic resistance prevalence in 3 common bacterial pathogens across 28 countries in Europe, and used multivariable models to evaluate associations with minimum temperature and other predictors over a 17-year period (2000-2016). We quantified the effects of minimum temperature, population density, and antibiotic consumption on the rate of change of antibiotic resistance across geographies.

Findings

For three common bacterial pathogens and four classes of antibiotics, we found evidence of a long-term effect of ambient minimum temperature on rates of increase of antibiotic resistance across 28 countries in Europe between 2000-2016. Specifically, we show that across all antibiotic classes for the pathogensE. coliandK. pneumoniae, European countries with 10°C warmer ambient temperatures have experienced more rapid increases in antibiotic resistance over the 17-year period, ranging between 0.33%/year (95% CI 0.2, 0.5) and 1.2%/year (0.4, 1.9), even after accounting for recognized drivers of resistance including antibiotic consumption and population density. We found a decreasing relationship forS. aureusand methicillin of −0.4%/year (95% CI −0.7, 0.0), reflecting widespread declines in MRSA across Europe over the study period.

Interpretation

Ambient temperature may be an important modulator of the rate of change of antibiotic resistance. Our findings suggest that rising temperatures globally may hasten the spread of resistance and complicate efforts to mitigate it.

Funding

Canadian Institutes of Health Research Fellowship (D.R.M.).
Metagenomics Analyses of Cellulose and Volatile Fatty Acids Metabolism by Microorganisms in the Cow Rumen
Authors: Wang Lijun , Jiang Xin , Xu Hongjian , Zhang Yonggen
Published: September 2018

The purpose of this study was to evaluate the effects of different forage-to-concentrate (F:C) ratios (7:3 high-forage, 3:7 high-concentrate) on rumen microflora and fiber degradation mechanism. Compared with the high-concentrate (HC) group, the high-forage(HF) group showed improved fiber degradation and a sustained high level of carboxymethyl cellulose (CMCase), β-glucosidase and β-xylosidase activities, but the total VFAs decreased. Among bacteria at the family level,LachnospiraceaeandSuccinivibrionaceaein HF groups were 2-fold and 4-fold more abundant than in the HC group, respectively. A KEGG analysis revealed that succinate-CoA synthetase (EC: 6.2.1.5) and propionate-CoA transferase (EC: 2.8.3.1) leading directly to propionate production were more abundant in HC group. Conversely, butyryl-CoA dehydrogenase (EC: 1.3.8.1) was directly related to butyrate production and was higher in the HF group. A gene expression analysis showed that the relative content ofFibrobacter succinogenesandButyrivibrio fibrisolvenswas higher in the HF group and contributed more to fiber degradation and VFA production.Prevotella ruminicola, Selenomonas ruminantium, andVeillonella alkalescenscontributed more to starch degradation and propionate production, which relative content was higher in the HC group. This research gave a further explanation of the fiber degradation parameters and microbiota under different F:C ration. The fiber-degrading bacteria in the roughage group have a high content level, and the corresponding cellulase activity is also high. These results supported the potential of diets for microbial manipulation, which can increase feed digestibility and explored new fibrinolytic bacteria.

IMPORTANCE

The forage of the cow’s feed occupies a large proportion. The shortage of high-quality forage in cow breeding has become an important factor limiting the China’s dairy industry. The effective measure is to improve the utilization of low-quality forage. Based on traditional nutrient metabolism, the reasons for the effects of roughage on the growth and metabolism of dairy cows can be explored, but the metabolic mechanism is not well analyzed, and the further utilization of forage is also limited. Metagenomics has proven to be a powerful tool for studying rumen microbial structures and gene function. This experiment used metagenomics to study the metabolism of cellulose and volatile acids in the rumen. Our research showed that different forage-to-concentrate shifted the composition of microorganisms and the activity of enzymes, resulting in different metabolic pathways of volatile fatty acids. This work provides a background for microbial community composition and further use of forage.
Sex differences in the behavioral and synaptic consequences of a single exposure to cannabinoid at puberty and adulthood
Authors: Borsoi Milene , Manduca Antonia , Bara Anissa , Lassalle Olivier , Pelissier-Alicot Anne-Laure , Manzoni Olivier J.
Published: September 2018

Heavy cannabis consumption among adolescents is associated with significant and lasting neurobiological, psychological and health consequences that depend on the age of first use. Chronic exposure to cannabinoid (CB) agonists during adolescence alters social behavior and prefrontal cortex (PFC) activity in adult rats. However, sex differences on social behavior as well as PFC synaptic plasticity after acute CB activation remain poorly explored. Here, we determined the consequences of a single CB activation differently affects PFC in males and females by assessing social behavior and PFC neuronal and synaptic functions in rats during pubertal or adulthood periods, 24h after a single in-vivo cannabinoid exposure (SCE). During puberty, SCE reduced play behavior in females but not males. In contrast, SCE impaired sociability in both sexes at adulthood. General exploration and memory recognition remained normal at both ages and both sexes. At the synaptic level, SCE ablated endocannabinoid-mediated long-term depression (eCB-LTD) in the PFC of females of both ages and heightened excitability of PFC pyramidal neurons at adulthood, while males were spared. In contrast, SCE was associated to impaired long-term potentiation in adult males. Together, the data indicate behavioral and synaptic sex differences in response to a single in-vivo exposure to cannabinoid at puberty and adulthood.
Detection of cell-type-specific risk-CpG sites in epigenome-wide association studies
Authors: Luo Xiangyu , Yang Can , Wei Yingying
Published: September 2018

In epigenome-wide association studies, the measured signals for each sample are a mixture of methylation profiles from different cell types. The current approaches to the association detection only claim whether a cytosine-phosphate-guanine (CpG) site is associated with the phenotype or not, but they cannot determine the cell type in which the risk-CpG site is affected by the phenotype. Here, we propose a solid statistical method, HIgh REsolution (HIRE), which not only substantially improves the power of association detection at the aggregated level as compared to the existing methods but also enables the detection of risk-CpG sites for individual cell types.
Superfolder mTurquoise2oxoptimized for the bacterial periplasm allows high efficiencyin vivoFRET of cell division antibiotic targets
Authors: Meiresonne Nils Y. , Consoli Elisa , Mertens Laureen M. Y. , Chertkova Anna , Goedhart Joachim , Blaauwen Tanneke den
Published: September 2018

Fluorescent proteins (FP)s are of vital importance to biomedical research. Many of the currently available fluorescent proteins do not fluoresce when expressed in non-native environments, such as the bacterial periplasm. This strongly limits the options for applications that employ multiple FPs, such as multiplex imaging or FRET. To address this issue, we have engineered a new cyan fluorescent protein based on mTurquoise2 (mTq2). The new variant is dubbed superfolder turquoise 2 ox (sfTq2ox) and is able to withstand challenging, oxidizing environments. sfTq2oxhas improved folding capabilities and can be expressed in the periplasm at higher concentrations without toxicity. This was tied to the replacement of native cysteines that may otherwise form promiscuous disulfide-bonds. The improved sfTq2oxhas the same spectroscopic properties as mTq2, i.e. high fluorescence lifetime and quantum yield. The sfTq2ox-mNeongreen FRET pair allows the detection of periplasmic protein-protein interactions with energy transfer rates exceeding 40 %. Employing the new FRET pair, we show the direct interaction of two essential periplasmic cell division proteins FtsL and FtsB and disrupt it by mutations, paving the way forin vivoantibiotic screening.
Competing evolutionary paths in growing populations with applications to multidrug resistance
Authors: Nicholson Michael D. , Antal Tibor
Published: September 2018

Investigating the emergence of a particular cell type is a recurring theme in models of growing cellular populations. The evolution of resistance to therapy is a classic example. Common questions are: when does the cell type first occur, and via which sequence of steps is it most likely to emerge? For growing populations, these questions can be formulated in a general framework of branching processes spreading through a graph from a root to a target vertex. Cells have a particular fitness value on each vertex and can transition along edges at specific rates. Vertices represents cell states, say genotypes or physical locations, while possible transitions are acquiring a mutation or cell migration. We focus on the setting where cells at the root vertex have the highest fitness and transition rates are small. Simple formulas are derived for the time to reach the target vertex and for the probability that it is reached along a given path in the graph. We demonstrate our results on several scenarios relevant to the emergence of drug resistance, including: the orderings of resistance-conferring mutations in bacteria and the impact of imperfect drug penetration in cancer.