bluuebunny/crossref_metadata_2025 huggingface dataset:
Gene expression in cord blood links genetic risk for neurodevelopmental disorders with maternal psychological distress and adverse childhood outcomes
Authors: Breen Michael S. , Wingo Aliza P. , Koen Nastassja , Donald Kirsten A. , Nicol Mark , Zar Heather J. , Ressler Kerry J. , Buxbaum Joseph D. , Stein Dan J.
Published: November 2017

Prenatal exposure to maternal stress and depression has been identified as a risk factor for adverse behavioral and neurodevelopmental outcomes in early childhood. However, the molecular mechanisms through which maternal psychopathology shapes offspring development remain poorly understood. We applied transcriptome-wide screens to 149 umbilical cord blood samples from neonates born to mothers with posttraumatic stress disorder (PTSD;n=20), depression (n=31) and PTSD with comorbid depression (n=13), compared to carefully matched trauma exposed controls (n=23) and healthy mothers (n=62). Analyses by maternal diagnoses revealed a clear pattern of gene expression signatures distinguishing neonates born to mothers with a history of psychopathology from those without. Co-expression network analysis identified distinct gene expression perturbations across maternal diagnoses, including two depression-related modules implicated in axon-guidance and mRNA stability, as well as two PTSD-related modules implicated in TNF signaling and cellular response to stress. Notably, these disease-related modules were enriched with brain-expressed genes and genetic risk loci for autism spectrum disorder and schizophrenia, which may imply a causal role for impaired developmental outcomes. These molecular alterations preceded changes in clinical measures at twenty-four months, including reductions in cognitive and socio-emotional outcomes in affected infants. Collectively, these findings indicate that prenatal exposure to maternal psychological distress induces neuronal, immunological and behavioral abnormalities in affected offspring and support the search for early biomarkers of exposures to adversein uteroenvironments and the classification of children at risk for impaired development.
Aquaporin-4 dependent glymphatic solute transport in rodent brain
Authors: Mestre Humberto , Kress Benjamin T. , Zou Wenyan , Pu Tinglin , Murlidharan Giridhar , Rivera Ruth M. Castellanos , Simon Matthew J. , Pike Martin M. , Plog Benjamin A , Xavier Anna L. R. , Thrane Alexander S. , Lundgaard Iben , Thomas John H. , Xiao Ming , Asokan Aravind , Miff Jeffrey J. , Nedergaard Maiken
Published: November 2017

The glymphatic system is a brain-wide metabolite clearance pathway, impairment of which in post-traumatic and ischemic brain or healthy aging is proposed to contribute to intracerebral accumulation of amyloid-β and tau proteins. Glymphatic perivascular influx of cerebrospinal fluid (CSF) depends upon the expression and perivascular localization of the astroglial water channel aquaporin-4 (AQP4). Prompted by a recent publication that failed to find an effect of Aqp4 knockout on perivascular CSF tracer influx and interstitial fluid (ISF) tracer dispersion, four independent research groups have herein re-examined the importance of Aqp4 in glymphatic fluid transport. We concur in finding that CSF tracer influx, as well as fluorescently-tagged amyloid-β efflux, are significantly faster in wild-type mice than in three different transgenic lines featuring disruption of the Aqp4 gene and one line in which AQP4 expression lacks the critical perivascular localization (Snta1 knockout). These data validate the role of AQP4 in supporting fluid and solute transport and efflux in brain in accordance with the glymphatic system model.
Visual attention is not always spatially coupled to subsequent oculomotor program
Authors: Wollenberg Luca , Deubel Heiner , Szinte Martin
Published: November 2017

The premotor theory of attention postulates that spatial attention arises from the activation of saccade areas and that the deployment of attention is the consequence of motor programming. Yet, attentional and oculomotor processes have been shown to be dissociable at the neuronal level in covert attention tasks. To investigate a potential dissociation at the behavioral level, we instructed human participants to saccade towards one of two nearby, competing saccade cues. The spatial distribution of visual attention was determined using oriented Gabor stimuli presented either at the cue locations, between them or at several other equidistant locations. Results demonstrate that accurate saccades towards one of the cues were associated with presaccadic enhancement of visual sensitivity at the respective saccade endpoint compared to the non-saccaded cue location. In contrast, averaging saccades, landing between the two cues, were not associated with attentional facilitation at the saccade endpoint, ruling out an obligatory coupling of attentional deployment to the oculomotor program. Rather, attention before averaging saccades was equally distributed to the two cued locations. Taken together, our results reveal a spatial dissociation of visual attention and saccade programming. They suggest that the oculomotor program depends on the state of attentional selection before saccade onset, and that saccade averaging arises from unresolved attentional selection.
MRIQC Web-API: Crowdsourcing image quality metrics and expert quality ratings of structural and functional MRI
Authors: Esteban O. , Blair RW. , Nielson DM. , Varada JC. , Marrett S. , Thomas AG. , Poldrack RA. , Gorgolewski KJ.
Published: November 2017

Synopsis

The MRIQC Web-API is a resource for scientists to train new automatic quality classifiers. The MRIQC Web-API has collected more than 30K sets of image quality measures automatically extracted from BOLD and T1-weighted scans using MRIQC. MRIQC is an automated MRI Quality Control tool, and here we present an extension to crowdsource these quality metrics along with anonymized metadata and manual quality ratings. This new resource will allow a better understanding of the normative values and distributions of these quality metrics, help determine the relationships between image quality and metadata such as acquisition parameters and finally, provide a cost-effective, easy way to annotate the quality of a large number of cross-site MR scans.
Failure of in vitro differentiation of Plasmodium falciparum gametocytes into ookinetes arises because of poor gamete fertilisation
Authors: Delves Michael J , Marques Sara R , Ruecker Andrea , Straschil Ursula , Miguel-Blanco Celia , López-Barragá María J , Lelièvre Joël , Molina Irene , Wree Melanie , Okitsu Shinji L , Winzeler Elizabeth , Li Fengwu , Vinetz Joseph , Sheppard Sam , Guedes Joana , Guerra Nadia , Herreros Esperanza , Sinden Robert E , Baum Jake
Published: November 2017

A critical step towards malaria elimination will be the interruption of Plasmodium transmission from the human host to the mosquito. At the core of the transmission cycle lies Plasmodium sexual reproduction leading to zygote formation and mosquito midgut colonisation by ookinetes. Whilst in vitro ookinete culture from the murine and avian malaria parasites, Plasmodium berghei and P. gallinaceum, has greatly increased our knowledge of transmission biology; efforts to mimic the process in the human parasite P. falciparum have, to date, had only limited success. Using fluorescence microscopy and flow cytometry with antibodies specific to the male gametocyte and developing ookinetes, we sought to evaluate P. falciparum ookinete production using previously published in vitro protocols. We then compared in vitro versus in vivo ookinete production in both P. falciparum and P. berghei parasites, exploring potential barriers to complete development. Finally, we sought to test a wide range of literature-led culture conditions towards further optimisation of in vitro P. falciparum ookinete production. Despite extensive testing, our efforts to replicate published methods did not produce appreciable quantities of fully formed P. falciparum ookinetes in vitro. In parallel, however, gametocyte cultures that failed to differentiate fully in vitro successfully developed into ookinetes in vivo with an efficiency approximating that of P. berghei. Flow cytometry analysis showed that this disparity likely lies with the poor fertilization of P. falciparum gametes in vitro. Attempts to improve gametocyte fertility or define conditions more permissive to fertilisation/ookinete survival in vitro were also unsuccessful. Current in vitro conditions for P. falciparum ookinete production are not optimal for gamete fertilisation either due to the lack of parasite-species-specific mosquito factors missing from in vitro culture, or non-permissive cues contaminating culture preparations.
The utility of mortality hazard rates in population analyses
Authors: Ergon Torbjørn , Borgan Ørnulf , Nater Chloé Rebecca , Vindenes Yngvild
Published: November 2017

Mortality is a key process in ecology and evolution, and much effort is spent on development and application of statistical and theoretical models involving mortality. Mortality takes place in continuous time, and a fundamental representation of mortality risks is the mortality hazard rate, which is the intensity of deadly events that an individual is exposed to at any point in time. In discrete-time population models, however, the mortality process is represented by survival or mortality probabilities, which are aggregate functions of the mortality hazard rates within given intervals. In this commentary, we argue that focussing on mortality hazard rates, also when using discrete-time models, aids the construction of biologically reasonable models and improves ecological inference.

We discuss three topics in population ecology where hazard rates can be particularly useful for biological inference, but are nevertheless often not used: (i) modelling of covariate effects, (ii) modelling of multiple sources of mortality and competing risks, and (iii) elasticity analyses of population growth rate with respect to demographic parameters. To facilitate estimation of cause-specific mortality hazard rates, we provide extensions to the R package ‘marked’.

Using mortality hazard rates sometimes makes it easier to formulate biologically reasonable models with more directly interpretable parameterizations and more explicit assumptions. In particular, interpretations about relative differences between mortality hazard rates, or effects of relative changes in mortality hazard rates on population growth (elasticities), are often more meaningful than interpretations involving relative differences in survival (or mortality) probabilities or odds.

The concept of hazard rates is essential for understanding ecological and evolutionary processes and we give an intuitive explanation for this, using several examples. We provide some practical guidelines and suggestions for further methods developments.
Exportin Crm1 is repurposed as a docking protein to generate microtubule organizing centers at the nuclear pore
Authors: Bao Xun X. , Spanos Christos , Kojidani Tomoko , Lynch Eric M. , Rappsilber Juri , Hiraoka Yasushi , Haraguchi Tokuko , Sawin Kenneth E.
Published: November 2017

Non-centrosomal microtubule organizing centers (MTOCs) are important for microtubule organization in many cell types. In fission yeastSchizosaccharomyces pombe, the protein Mto1, together with partner protein Mto2 (Mto1/2 complex), recruits the γ-tubulin complex to multiple non-centrosomal MTOCs, including the nuclear envelope (NE). Here, we develop a comparative-interactome mass spectrometry approach to determine how Mto1 localizes to the NE. Surprisingly, we find that Mto1, a constitutively cytoplasmic protein, docks at nuclear pore complexes (NPCs), via interaction with exportin Crm1 and cytoplasmic FG-nucleoporin Nup146. Although Mto1 is not a nuclear export cargo, it binds Crm1 via a nuclear export signal-like sequence, and docking requires both Ran in the GTP-bound state and Nup146 FG repeats. In addition to determining the mechanism of MTOC formation at the NE, our results reveal a novel role for Crm1 and the nuclear export machinery in the stable docking of a cytoplasmic protein complex at NPCs.
Auditory Figure-Ground Segregation is Impaired by High Visual Load
Authors: Molloy Katharine , Lavie Nilli , Chait Maria
Published: November 2017

Figure-ground segregation is fundamental to listening in complex acoustic environments. An ongoing debate pertains to whether segregation requires attention or is ‘automatic’ and pre-attentive. In this magnetoencephalography (MEG) study we tested a prediction derived from Load Theory of attention1 that segregation requires attention, but can benefit from the automatic allocation of any ‘leftover’ capacity under low load. Complex auditory scenes were modelled with Stochastic Figure Ground stimuli (SFG2) which occasionally contained repeated frequency component ‘figures’. Naive human subjects passively listened to these signals while performing a visual attention task of either low or high load. Whilst clear figure-related neural responses were observed under conditions of low load, high visual load essentially abolished the neural response to the figure in auditory cortex (Planum Temporale, Heschl’s gyrus). We conclude that fundamental figure-ground segregation in hearing is not automatic but draws on shared resources across vision and audition.
Stringency of synthetic promoter sequences inClostridiumrevealed and circumvented by tuning promoter library mutation rates
Authors: Mordaka Paweł M. , Heap John T.
Published: November 2017

Collections of characterized promoters of different strengths are key resources for synthetic biology, but are not well established for many important organisms, including industrially-relevantClostridiumspp. When generating promoters, reporter constructs are used to measure expression, but classical fluorescent reporter proteins are oxygen-dependent and hence inactive in anaerobic bacteria likeClostridium. We directly compared oxygen-independent reporters of different types inClostridium acetobutylicumand found that glucuronidase (GusA) fromE. coliperformed best. Using GusA, a library of synthetic promoters was first generated by a typical approach entailing complete randomization of a constitutive thiolase gene promoter (Pthl) except for the consensus -35 and -10 elements. In each synthetic promoter, the chance of each degenerate position matching Pthlwas 25%. Surprisingly, none of the synthetic promoters from this library were functional inC. acetobutylicum, even though they functioned as expected inE. coli. Next, instead of complete randomization, we specified lower promoter mutation rates using oligonucleotide primers synthesized using custom mixtures of nucleotides. Using these primers, two promoter libraries were constructed in which the chance of each degenerate position matching Pthlwas 79% or 58%, instead of 25% as before. Synthetic promoters from these ‘stringent’ libraries functioned well inC. acetobutylicum, covering a wide range of strengths. The promoters functioned similarly in the distantly-related speciesClostridium sporogenes, and allowed predictable metabolic engineering ofC. acetobutylicumfor acetoin production. Besides generating the desired promoters and demonstrating their useful properties, this work indicates an unexpected ‘stringency’ of promoter sequences inClostridium, not reported previously.

GRAPHICAL ABSTRACT
Tumorcode - A framework to simulate vascularized tumors
Authors: Fredrich Thierry , Welter Michael , Rieger Heiko
Published: November 2017

During the past years our group published several articles using computer simulations to address the complex interaction of tumors and the vasculature as underlying transport network. Advances in imaging and lab techniques pushed in vitro research of tumor spheroids forward and animal models as well as clinical studies provided more insights to single processes taking part in tumor growth, however, an overall picture is still missing. Computer simulations are a none-invasive option to cumulate current knowledge and form a quasi in vivo system. In our software, several known models were assembled into a multi-scale approach which allows to study length scales relevant for clinical applications.

We release our code to the public domain, together with a detailed description of the implementation and several examples, with the hope of usage and futher development by the community. Justification for the included algorithms and the biological models was obtained in previous publications, here we summarize technical aspects following the workflow of a typical simulation procedure.
Hepatitis C Virus (HCV) diagnosis, epidemiology and access to treatment in a UK cohort
Authors: Adland Emily , Jesuthasan Gerald , Downs Louise , Wharton Victoria , Wilde Gemma , McNaughton Anna , Collier Jane , Barnes Eleanor , Klenerman Paul , Andersson Monique , Jeffery Katie , Matthews Philippa C.
Published: November 2017

Background

As direct acting antiviral (DAA) therapy is progressively rolled out for patients with hepatitis C virus (HCV) infection, careful scrutiny of HCV epidemiology, diagnostic testing, and access to care is crucial to underpin improvements in delivery of treatment.

Methods

We performed a retrospective study of HCV infection in a UK teaching hospital to evaluate the performance of different diagnostic laboratory tests, to describe the population with active HCV infection, and to determine the proportion of these individuals who access clinical care.

Results

Over a total time period of 33 months between 2013 and 2016, we tested 38,510 individuals for HCV infection and confirmed a new diagnosis of active HCV infection (HCV-Ag+ and/or HCV RNA+) in 359 (positive rate 0.9%). Our in-house HCV-Ab test had a positive predictive value of 87% when compared to repeat HCV-Ab testing in a regional reference laboratory, highlighting the potential for false positives to arise based on a single round of antibody-based screening. Of those confirmed Ab-positive, 70% were HCV RNA positive. HCV-Ag screening performed well, with 100% positive predictive value compared to detection of HCV RNA. There was a strong correlation between quantitative HCV-Ag and HCV RNA viral load (p<0.0001). Among the 359 cases of infection, the median age was 37 years, 85% were male, and 36% were in prison. Among 250 infections for which genotype was available, HCV genotype-1 (n=110) and genotype-3 (n=111) accounted for the majority. 117/359 (33%) attended a clinic appointment and 48 (13%) had curative treatment defined as sustained virologic response at 12 weeks (SVR12).

Conclusions

HCV-Ab tests should be interpreted with caution as an indicator of population prevalence of HCV infection, both as a result of the detection of individuals who have cleared infection and due to false positive test results. We demonstrate that active HCV infection is over-represented among men and in the prison population. A minority of patients with a diagnosis of HCV infection access clinical care and therapy; enhanced efforts are required to target diagnosis and providing linkage to clinical care within high risk populations.

ABBREVIATIONS

DAA

Direct Acting Antiviral

ELISA

Enzyme linked immunosorbent assay

HCV

Hepatitis C Virus

HCV-Ab

IgG antibody to Hepatitis C virus

HCV-Ag

Hepatitis C virus core antigen

HCV RNA

Hepatitis C ribonucleic acid (viral load)

MSM

men who have sex with men

NAT

nucleic acid testing

PCR

polymerase chain reaction (test for viral load)

PPV

positive predictive value

PWID

people who inject drugs

SDG

Sustainable Development Goals

SVR

sustained virologic response

WHO

World Health Organisation
Diversity loss selects for altered plant phenotypic responses to local arbuscular mycorrhizal communities
Authors: Hahl Terhi , van Moorsel Sofia Julia , Schmid Marc W. , Zuppinger-Dingley Debra , Schmid Bernhard , Wagg Cameron
Published: November 2017

1. Biodiversity loss not only impairs ecosystem functioning but can also alter the selection for traits in plant communities. At high diversity selection favours traits that allow for greater niche partitioning, whereas at low diversity selection may favour greater defence against pathogens. However, it is unknown whether changes in plant diversity also select for altered interactions with soil organisms.
2. We assessed whether the responses in plant growth and functional traits to their local arbuscular mycorrhizal fungal (AMF) communities have been altered by the diversity of the plant communities from which both plants and AMF communities were obtained. We grew plants with AMF communities that originated from either plant monocultures or mixtures in a fully factorial design that included both negative and positive controls, by inoculating no AMF or a foreign AMF respectively.
3. We found that AMF from plant mixtures were more beneficial than monoculture AMF for two out of five plant species. Plants from mixtures generally grew better than those from monocultures, but suffered greater damage by leaf pathogens. Although plant growth and phenotypic responses were dependent on the AMF communities with which they associated, we found little evidence for plant growth responses specific to their local AMF communities and results differed between species and traits.
4. Our results show that plants from mixtures were selected for increased growth at the expense of reduced defence and vice versa for plants from monocultures, providing evidence for plant diversity-dependent selection on competitive growth vs. defence. Furthermore, our study suggests that effects of a common history between plants and AMF do not follow a general pattern leading to increased or decreased mutualism.
5. Synthesis: Here we provide evidence that biodiversity loss can alter evolutionary trajectories of plant phenotypes and responses to their local AMF communities. However, the selection for altered plant-AMF interactions differ between plant species. To understand how plant communities respond and evolve under a changing environment requires further knowledge about life strategies of plant species and their above-belowground interactions.
DNA methylation estimation using methylation-sensitive restriction enzyme bisulfite sequencing (MREBS)
Authors: Bonora Giancarlo , Rubbi Liudmilla , Morselli Marco , Chronis Constantinos , Plath Kathrin , Pellegrini Matteo
Published: November 2017

Whole-genome bisulfite sequencing (WGBS) and reduced representation bisulfite sequencing (RRBS) are widely used for measuring DNA methylation levels on a genome-wide scale(1). Both methods have limitations: WGBS is expensive and prohibitive for most large-scale projects; RRBS only interrogates 6-12% of the CpGs in the human genome(16,19). Here, we introduce methylation-sensitive restriction enzyme bisulfite sequencing (MREBS) which has the reduced sequencing requirements of RRBS, but significantly expands the coverage of CpG sites in the genome. We built a multiple regression model that combines the two features of MREBS: the bisulfite conversion ratios of single cytosines (as in WGBS and RRBS) as well as the number of reads that cover each locus (as in MRE-seq(12)). This combined approach allowed us to estimate differential methylation across 60% of the genome using read count data alone, and where counts were sufficiently high in both samples (about 1.5% of the genome), our estimates were significantly improved by the single CpG conversion information. We show that differential DNA methylation values based on MREBS data correlate well with those based on WGBS and RRBS. This newly developed technique combines the sequencing cost of RRBS and DNA methylation estimates on a portion of the genome similar to WGBS, making it ideal for large-scale projects of mammalian genomes.
A tangled tale of convergence and divergence: archaeal chromosomal proteins and Chromo-like domains in bacteria and eukaryotes
Authors: Kaur Gurmeet , Iyer Lakshminarayan M. , Subramanian Srikrishna , Aravind L.
Published: November 2017

The Chromo-like superfamily of SH3-fold β-barrel domains recognize epigenetic marks in eukaryotic proteins. Their provenance has been placed either in archaea, based on apparent structural similarity to chromatin-compacting Sul7d and Cren7 proteins, or in bacteria based on the presence of sequence homologs. Using sequence and structural evidence we establish that the archaeal Cren7/Sul7 proteins emerged from a zinc ribbon (ZnR) ancestor. Further, we show that the ancestral eukaryotic Chromo-like domains evolved from bacterial precursors acquired from early endosymbioses, which already possessed an aromatic cage for recognition of modified amino-groups. These bacterial versions are part of a radiation of secreted SH3-fold domains, which spawned both chromo-like domains and classical SH3 domains in the context of peptide-recognition in the peptidoglycan. This establishes that Cren7/Sul7 converged to a "SH3”-like state from a ZnR precursor via the loss of metal-chelation and acquisition of stronger hydrophobic interactions; it is unlikely to have participated in the evolution of the chromo-like domains. We show that archaea possess several Cren7/Sul7-related proteins with intact Zn-chelating ligands, which we predict to play previously unstudied roles in cell-division comparable to the PRC barrel.
Recurrent network model for learning goal-directed sequences through reverse replay
Authors: Haga Tatsuya , Fukai Tomoki
Published: November 2017

Reverse replay of hippocampal place cells occurs frequently at rewarded locations, suggesting its contribution to goal-directed pathway learning. Symmetric spike-timing dependent plasticity (STDP) in CA3 likely potentiates recurrent synapses for both forward (start to goal) and reverse (goal to start) replays during sequential activation of place cells. However, how reverse replay selectively strengthens forward pathway is unclear. Here, we show computationally that firing sequences bias synaptic transmissions to the opposite direction of propagation under symmetric, but not asymmetric, STDP in the co-presence of short-term synaptic plasticity. We demonstrate that a significant bias can be created in biologically realistic simulation settings, and that this bias enables reverse replay to enhance goal-directed spatial memory on a T-maze. Our model for the first time provides the mechanistic account for the way reverse replay contributes to hippocampal sequence learning for reward-seeking spatial navigation.
Feed-forward inhibition conveys time-varying stimulus information in a collision detection circuit
Authors: Wang Hongxia , Dewell Richard B. , Zhu Ying , Gabbiani Fabrizio
Published: November 2017

Feed-forward inhibition is ubiquitous as a motif in the organization of neuronal circuits. During sensory information processing, it is traditionally thought to sharpen the responses and temporal tuning of feed-forward excitation onto principal neurons. As it often exhibits complex time-varying activation properties, feed-forward inhibition could also convey information used by single neurons to implement dendritic computations on sensory stimulus variables. We investigated this possibility in a collision detecting neuron of the locust optic lobe that receives both feed-forward excitation and inhibition. We identified a small population of neurons mediating feed-forward inhibition, with wide visual receptive fields and whose responses depend both on the size and speed of moving stimuli. By studying responses to simulated objects approaching on a collision course, we determined that they jointly encode the angular size of expansion of the stimulus. Feed-forward excitation on the other hand encodes a function of the angular velocity of expansion and the targeted collision detecting neuron combines these two variables non-linearly in its firing output. Thus, feed-forward inhibition actively contributes to the detailed firing rate time course of this collision detecting neuron, a feature critical to the appropriate execution of escape behaviors. These results suggest that feed-forward inhibition could similarly convey time-varying stimulus information in other neuronal circuits.
Unequal contributions of species’ persistence and migration on plant communities’ response to climate warming throughout forests
Authors: Bertrand Romain
Published: November 2017

Community reshuffling is lagging behind climate warming for many taxa, thereby generating a climatic debt. However, only few studies have attempted to assess the underlying factors that explain this debt, and none has gone further to explore this issue from a biogeographical perspective. Here I examine how effects of species’ migration and persistence on the current climatic debt vary spatially in forest herbaceous communities throughout the French territory. I show that Mediterranean communities are responding to climate warming through both high species’ migration and persistence effects, while alpine forest is the only ecosystem where species’ migration overtakes species’ persistence mechanisms. Such an approach seems promising in assessing the underlying mechanisms of the biodiversity response to climate change locally, and it can be applied for conservation issues to assess biodiversity sensitivity and optimize its management.
Presence of Atopy Increases the Risk of Asthma Relapse
Authors: Teoh Laurel , Mackay Ian , Van Asperen Peter P , Acworth Jason , Hurwitz Mark , Upham John W , Siew Weng Hou , Wang Claire YT , Sloots Theo P , Neeman Teresa , Chang Anne B
Published: November 2017

Objectives

In children with hospitalised and non-hospitalised asthma exacerbations, to: (a) describe the point prevalence of respiratory viruses/atypical bacteria using polymerase chain reaction (PCR) and; (b) evaluate the impact of respiratory viruses/atypical bacteria and atopy on acute severity and clinical recovery.

Design

This was a prospective study performed during 2009-2011.

Setting

The study was performed in the Emergency Departments of 2 hospitals.

Patients

244 children aged 2-16 years presenting with acute asthma to the Emergency Departments were recruited. A nasopharyngeal aspirate and allergen skin prick test were performed.

Main outcome measures

The outcomes were divided into (a) acute severity outcomes [Australian National Asthma Council assessment, hospitalisation, Functional Severity Scale, acute asthma score, asthma quality of life questionnaires for parents (PACQLQ) on presentation, asthma diary scores (ADS) on presentation and length of hospitalisation] and (b) recovery outcomes (PACQLQ for 21 days, ADS for 14 days and representation for asthma for 21 days).

Results

PCR for viruses/atypical bacteria was positive in 81.7% of children (75.1% human rhinovirus, co-detection in 14.2%).M. pneumoniaeandC. pneumoniaewere rarely detected. The presence of micro-organisms had little impact on acute asthma or recovery outcomes. Children with atopy were significantly more likely to relapse and represent for medical care by day-14 (OR 1.11, 95%CI 1.00,1.23).

Conclusions

The presence of any viruses is associated with asthma exacerbations but does not appear to influence asthma recovery. In contrast, atopy is associated with asthma relapse.M. pneumoniaeandC. pneumoniaeare rare triggers of acute asthma in young children.
Multi-Omics factor analysis - a framework for unsupervised integration of multi-omic data sets
Authors: Argelaguet Ricard , Velten Britta , Arnol Damien , Dietrich Sascha , Zenz Thorsten , Marioni John C. , Huber Wolfgang , Buettner Florian , Stegle Oliver
Published: November 2017

Multi-omic studies promise the improved characterization of biological processes across molecular layers. However, methods for the unsupervised integration of the resulting heterogeneous datasets are lacking. We present Multi-Omics Factor Analysis (MOFA), a computational method for discovering the principal sources of variation in multi-omic datasets. MOFA infers a set of (hidden) factors that capture biological and technical sources of variability. It disentangles axes of heterogeneity that are shared across multiple modalities and those specific to individual data modalities. The learnt factors enable a variety of downstream analyses, including identification of sample subgroups, data imputation, and the detection of outlier samples. We applied MOFA to a cohort of 200 patient samples of chronic lymphocytic leukaemia, profiled for somatic mutations, RNA expression, DNA methylation and ex-vivo drug responses. MOFA identified major dimensions of disease heterogeneity, including immunoglobulin heavy chain variable region status, trisomy of chromosome 12 and previously underappreciated drivers, such as response to oxidative stress. In a second application, we used MOFA to analyse single-cell multiomics data, identifying coordinated transcriptional and epigenetic changes along cell differentiation.
Use-dependent plasticity in human primary motor hand area: Synergistic interplay between training and immobilisation
Authors: Raffin Estelle , Siebner Hartwig Roman
Published: November 2017

Training and immobilization are powerful drivers of use-dependent plasticity in human primary motor hand area (M1HAND). Here we used transcranial magnetic stimulation to clarify how training and immobilisation of a single finger interact within M1HAND. Healthy volunteers trained to track a moving target with a finger for one week. The tracking skill acquired with the trained finger was transferred to a non-trained finger of the same hand. The cortical representations of the trained and non-trained finger muscle converged in proportion with skill transfer. Finger immobilisation alone attenuated the corticomotor representation and pre-existing tracking skill of the immobilized finger. The detrimental effects of finger immobilization were blocked by concurrent training of the non-immobilized finger. Conversely, immobilization of the non-trained fingers accelerated learning during the first two days of training. The results provide novel insight into use-dependent cortical plasticity, revealing synergistic rather than competitive interaction patterns within M1HAND.
Natural genetic variation inC. elegansreveals genomic loci controlling metabolite levels
Authors: Gao Arwen W. , Sterken Mark G. , Bos Jelmi uit de , Creij Jelle van , Kamble Rashmi , Snoek Basten L. , Kammenga Jan E. , Houtkooper Riekelt H.
Published: November 2017

Metabolic homeostasis is sustained by complex biological networks responding to nutrient availability. Disruption of this equilibrium involving intricate interactions between genetic and environmental factors can lead to metabolic disorders, including obesity and type 2 diabetes. To identify the genetic factors controlling metabolism, we applied a quantitative genetic strategy using aCaenorhabditis eleganspopulation consisting of 199 recombinant inbred lines (RILs) originally derived from crossing parental strains Bristol N2 and Hawaii CB4856. We focused on the genetic factors that control metabolite levels and measured fatty acid (FA) and amino acid (AA) composition in the 199 RILs using targeted metabolomics. For both FA and AA profiles, we observed large variation in metabolite levels with 32-82% heritability between the RILs. We performed metabolite-metabolite correlation analysis and detected strongly co-correlated metabolite clusters. To identify natural genetic variants responsible for the observed metabolite variations, we performed QTL mapping and detected 36 significant metabolite QTL (mQTL). We focused on the mQTL that displayed high significant linkage and heritability, including an mQTL for the FA C14:1 on chromosome I, and another mQTL for the FA C18:2 on chromosome IV. Using introgression lines (ILs) we were able to narrow down both mQTL to a 1.4 Mbp and a 3.6 Mbp region, respectively. Overall, this systems approach provides us with a powerful platform to study the genetic basis ofC. elegansmetabolism. It also allows us to investigate additional interventions, such as nutrients and stresses that maintain or disturb the regulatory network controlling metabolic homeostasis, and identify gene-by-environment interactions.
TRUmiCount: Correctly counting absolute numbers of molecules using unique molecular identifiers
Authors: Pflug Florian G. , von Haeseler Arndt
Published: November 2017

Counting DNA or RNA molecules using next-generation sequencing (NGS) suffers from amplification biases. Counting unique molecular identifiers (UMIs) instead of reads is still prone to over-estimation due to amplification and sequencing artifacts and under-estimation due to lost molecules. We present an algorithm that corrects for these errors, based on a mechanistic model of the PCR and sequencing process whose parameters have an immediate physical interpretation and are easily estimated. We demonstrate that our algorithm outputs essentially unbiased counts with substantially improved accuracy.
Acute fluoxetine differently affects aggressive display in zebrafish phenotypes
Authors: Barbosa Hellen Pereira , Lima Monica Gomes , Maximino Caio
Published: November 2017

Zebrafish have been introduced as a model organism in behavioral neuroscience and biological psychiatry, increasing the breadth of findings using fish to study the neurobiology of aggression. Phenotypic differences between leopard and longfin zebrafish were exploited in order to elucidate the role of phasic serotonin in aggressive displays on this species. The present study revealed differences in aggressive display between leopard and longfin zebrafish, and a discrepant effect of acute fluoxetine in both populations. In mirror-induced aggression, leopard animals showed higher display latencies than longfin, as well as lower display duration and frequency (Experiment 1). Moreover, 2.5 mg/kg fluoxetine decreased the duration and frequency of display in longfin, but not leopard; and 5 mg/kg fluoxetine increased display frequency in leopard, but not longfin (Experiment 2). It is suggested that zebrafish from the longfin phenotype show more aggressive motivation and readiness in the mirror-induced aggression test that leopard, and that acute fluoxetine increases aggression in leopard and decreased it in longfin zebrafish.
Hidden variation in polyploid wheat drives local adaptation
Authors: Gardiner Laura-Jayne , Joynson Ryan , Omony Jimmy , Rusholme-Pilcher Rachel , Olohan Lisa , Lang Daniel , Bai Caihong , Hawkesford Malcolm , Salt David , Spannagl Manuel , Mayer F.X.Klaus , Kenny John , Bevan Michael , Hall Neil , Hall Anthony
Published: November 2017

Wheat has been domesticated into a large number of agricultural environments and has a remarkable ability to adapt to diverse environments. To understand this process, we survey genotype, repeat content and DNA methylation across a bread wheat landrace collection representing global genetic diversity. We identify independent variation in methylation, genotype and transposon copy number. We show that these, so far unexploited, sources of variation have had a massive impact on the wheat genome and that ancestral methylation states become preferentially ‘hard coded’ as SNPs via 5-methylcytosine deamination. These mechanisms also drive local adaption, impacting important traits such as heading date and salt tolerance. Methylation and transposon diversity could therefore be used alongside single nucleotide polymorphism (SNP) based markers for breeding.
Minerva: An Alignment and Reference Free Approach to Deconvolve Linked-Reads for Metagenomics
Authors: Danko David C. , Meleshko Dmitry , Bezdan Daniela , Mason Christopher , Hajirasouliha Iman
Published: November 2017

Emerging Linked-Read technologies (aka Read-Cloud or barcoded short-reads) have revived interest in standard short-read technology as a viable way to understand large-scale structure in genomes and metagenomes. Linked-Read technologies, such as the 10X Chromium system, use a microfluidic system and a set of specially designed 3’ barcodes (aka UIDs) to tag short DNA reads which were originally sourced from the same long fragment of DNA; subsequently, these specially barcoded reads are sequenced on standard short read platforms. This approach results in interesting compromises. Each long fragment of DNA is covered only sparsely by short reads, no information about the relative ordering of reads from the same fragment is preserved, and typically each 3’ barcode matches reads from 2-20 long fragments of DNA. However, compared to long read platforms like those produced by Pacific Biosciences and Oxford Nanopore the cost per base to sequence is far lower, far less input DNA is required, and the per base error rate is that of Illumina short-reads.

The use of Linked-Reads presents a new set of algorithmic challenges. In this paper, we formally describe one particular issue common to all applications of Linked-Read technology: the deconvolution of reads with a single 3’ barcode into clusters that correspond to a single long fragment of DNA. We introduce Minerva, A graph-based algorithm that approximately solves the barcode deconvolution problem for metagenomic data (where reference genomes may be incomplete or unavailable). Additionally, we develop two demonstrations where the deconvolution of barcoded reads improves downstream results: improving the specificity of taxonomic assignments, and by improving clustering of related sequences. To the best of our knowledge, we are the first to address the problem of barcode deconvolution in metagenomics.
Role of SCN5A coding and non-coding sequences in Brugada syndrome onset: What’s behind the scenes?
Authors: Daimi Houria , Khelil Amel Haj , Neji Ali , Hamda Khaldoun Ben , Maaoui Sabri , Aranega Amelia , Chibani Jemni BE , Franco Diego
Published: November 2017

Brugada syndrome (BrS) is a rare inherited cardiac arrhythmia associated with a high risk of sudden cardiac death (SCD) due to ventricular fibrillation (VF). BrS is characterized by coved-type ST-segment elevation in the right precordial leads (V1-V3) in the absence of structural heart disease. This pattern is spontaneous, or is unmasked by intravenous administration of Class I antiarrhythmic drugs. The SCN5A-encoded α-subunit of the NaV1.5 cardiac sodium channel has been linked to BrS, and mutations in SCN5A are identified in 15–30% of BrS cases. Genetic testing of BrS patients generally involves sequencing of protein-coding portions and flanking intronic regions of SCN5A, according to recent international guidelines. This excludes the regulatory untranslated regions (5’UTR and 3’UTR) from the routine genetic testing of BrS patients. We here screened the coding sequence, the flanking intronic regions as well as the 5’ and 3’UTR regions of SCN5A gene and further five candidate genes (GPD1L, SCN1B, KCNE3, SCN4B, and MOG1) in a Tunisian family diagnosed with Brugada syndrome.

A new Q1000K mutation was identified on the SCN5A gene along with two common polymorphisms (H558R and D1819). Furthermore, multiple genetic variants were identified on the SCN5A 3’UTR, one of which is predicted to create additional microRNA (miRNAs) binding site for miR-1270. Additionally, we identified the hsa-miR-219a rs107822. No relevant coding sequence variant was identified in the remaining studied candidate genes. Although Q1000K is localized in the conserved binding site of MOG1 which predicts a functional consequence, this new mutation along with the additional variants were differentially distributed among the family members without any clear genotype-phenotype concordance. This gives extra evidences about the complexity of the disease and suggests that the occurrence and prognosis of BrS is most likely controlled by a combination of multiple genetic factors and exposures, rather than a single polymorphism/mutation. Most SCN5A polymorphisms were localized in non-coding regions hypothesizing an impact on the miRNA-target complementarities. In this regard, over-expression of miR-1270 led to a significant decrease of luciferase activity suggesting a direct role regulating SCN5A. Therefore, genetic variants that disrupt its binding affinity to SCN5A 3’UTR and/or its expression might cause loss of normal repression control and be associated to BrS.
Sleep-Dependent Memory Consolidation and Incremental Sentence Comprehension: Computational Dependencies during Language Learning as Revealed by Neuronal Oscillations
Authors: Cross Zachariah R. , Kohler Mark J. , Schlesewsky Matthias , Gaskell M. Gareth , Bornkessel-Schlesewsky Ina
Published: November 2017

We hypothesise a beneficial influence of sleep on the consolidation of the combinatorial mechanisms underlying incremental sentence comprehension. These predictions are grounded in recent work examining the effect of sleep on the consolidation of linguistic information, which demonstrate that sleep-dependent neurophysiological activity consolidates the meaning of novel words and simple grammatical rules. However, the sleep-dependent consolidation of sentence-level combinatorics has not been studied to date. Here, we propose that dissociable aspects of sleep neurophysiology consolidate two different types of combinatory mechanisms in human language: sequence-based (order-sensitive) and dependency-based (order-insensitive) combinatorics. The distinction between the two types of combinatorics is motivated both by cross-linguistic considerations and the neurobiological underpinnings of human language. Unifying this perspective with principles of sleep-dependent memory consolidation, we posit that a function of sleep is to optimise the consolidation of sequence-based knowledge (the when) and the establishment of semantic schemas of unordered items (the what) that underpin cross-linguistic variations in sentence comprehension. This hypothesis builds on the proposal that sleep is involved in the construction of predictive codes, a unified principle of brain function that supports incremental sentence comprehension. Finally, we discuss neurophysiological measures (EEG/MEG) that could be used to test these claims, such as the quantification of neuronal oscillations, which reflect basic mechanisms of information processing in the brain.
Covalent linkage of the DNA repair template to the CRISPR/Cas9 complex enhances homology-directed repair
Authors: Savic Natasa , Ringnalda Femke , Bargsten Katja , Li Yizhou , Berk Christian , Hall Jonathan , Neri Dario , Jinek Martin , Schwank Gerald
Published: November 2017

The CRISPR/Cas9 targeted nuclease technology allows the insertion of genetic modifications with single base-pair precision. The preference of mammalian cells to repair Cas9-induced DNA double-strand breaks via non-homologous end joining (NHEJ) rather than via homology-directed repair (HDR) however leads to relatively low rates of correctly edited loci. Here we demonstrate that covalently linking the DNA repair template to Cas9 increases the ratio of HDR over NHEJ up to 23-fold, and therefore provides advantages for clinical applications where high-fidelity repair is needed.