bluuebunny/crossref_metadata_2025 huggingface dataset:
Bedside dysphagia screens in patients with traumatic cervical injuries: An ideal tool for an under-recognized problem
Authors: Posillico Sarah E. , Golob Joseph F. , Rinker Andrea D. , Kreiner Laura A. , West Rebecca S. , Conrad-Schnetz Kristen J. , Kelly Michael L. , Claridge Jeffrey A.
Published: July 2018

BACKGROUND

We initiated a prospective interventional study using a nurse-driven bedside dysphagia screen (BDS) in patients with cervical spine injury (CI) to address three objectives: (1) determine the incidence of dysphagia, (2) determine the utility of the new BDS as a screening tool, and (3) compare patient outcomes, specifically dysphagia-related complications, in the study period with a retrospective cohort.

METHODS

All patients with CI admitted to a Level I trauma center were enrolled in a prospective 12-month study (June 2016–June 2017) and then were compared with a previous 18-month cohort of similar patients. Our new protocol mandated that every patient underwent a BDS before oral intake. If the patient failed the BDS, a modified barium swallow (MBS) was obtained. Exclusion criteria were emergency department discharge, inability to participate in a BDS, leaving against medical advice, BDS protocol violations, or death before BDS. A failed MBS was defined as a change in diet and a need for a repeat MBS. Dysphagia was defined as a failed MBS or the presence of a dysphagia-related complication.

RESULTS

Of 221 consecutive prospective patients identified, 114 met inclusion criteria. The incidence of dysphagia was 16.7% in all prospective study patients, 14.9% in patients with isolated CI, and 30.8% in patients with spinal cord injury. The BDS demonstrated 84.2% sensitivity, 95.8% specificity, 80.0% positive predictive value, and 96.8% negative predictive value. There were no dysphagia-related complications. The prospective study patients demonstrated significantly less dysphagia-related complications (p = 0.048) when compared with the retrospective cohort of 276 patients.

CONCLUSIONS

The introduction of the BDS resulted in increased dysphagia diagnoses, with a significant reduction in dysphagia-related complications. We recommend incorporating BDS into care pathways for patients with CI.

LEVEL OF EVIDENCE

Study type diagnostic test, level III.
New perspectives for the prediction and statistical quantification of extreme events in high-dimensional dynamical systems
Authors: Sapsis Themistoklis P.
Published: July 2018

We discuss extreme events as random occurrences of strongly transient dynamics that lead to nonlinear energy transfers within a chaotic attractor. These transient events are the result of finite-time instabilities and therefore are inherently connected with both statistical and dynamical properties of the system. We consider two classes of problems related to extreme events and nonlinear energy transfers, namely (i) the derivation of precursors for the short-term prediction of extreme events, and (ii) the efficient sampling of random realizations for the fastest convergence of the probability density function in the tail region. We summarize recent methods on these problems that rely on the simultaneous consideration of the statistical and dynamical characteristics of the system. This is achieved by combining available data, in the form of second-order statistics, with dynamical equations that provide information for the transient events that lead to extreme responses. We present these methods through two high-dimensional, prototype systems that exhibit strongly chaotic dynamics and extreme responses due to transient instabilities, the Kolmogorov flow and unidirectional nonlinear water waves.

This article is part of the theme issue ‘Nonlinear energy transfer in dynamical and acoustical systems’.
A fully passive nonlinear piezoelectric vibration absorber
Authors: Lossouarn B. , Deü J.-F. , Kerschen G.
Published: July 2018

The objective of this study is to develop the first fully passive nonlinear piezoelectric tuned vibration absorber (NPTVA). The NPTVA is designed to mitigate a specific resonance of a nonlinear host structure. To avoid the use of synthetic inductors which require external power, closed magnetic circuits in ferrite material realize the large inductance values required by vibration mitigation at low frequencies. The saturation of an additional passive inductor is then exploited to build the nonlinearity in the NPTVA. The performance of the proposed device is demonstrated both numerically and experimentally.

This article is part of the theme issue ‘Nonlinear energy transfer in dynamical and acoustical systems’.
Evidence accumulation and change rate inference in dynamic environments
Authors: Radillo Adrian E , Veliz-Cuba Alan , Josic Kresimir , Kilpatrick Zachary
Published: July 2018

In a constantly changing world, animals must account for environmental volatility when making decisions. To appropriately discount older, irrelevant information, they need to learn the rate at which the environment changes. We develop an ideal observer model capable of inferring the present state of the environment along with its rate of change. Key to this computation is updating the posterior probability of all possible changepoint counts. This computation can be challenging, as the number of possibilities grows rapidly with time. However, we show how the computations can be simplified in the continuum limit by a moment closure approximation. The resulting low-dimensional system can be used to infer the environmental state and change rate with accuracy comparable to the ideal observer. The approximate computations can be performed by a neural network model via a rate-correlation based plasticity rule. We thus show how optimal observers accumulates evidence in changing environments, and map this computation to reduced models which perform inference using plausible neural mechanisms.
MSAP In Tiger Snakes: Island Populations Are Epigenetically More Divergent
Authors: Rodriguez Lopez Carlos M , Konate Moumouni , Thomson Vicki A
Published: July 2018

Research on changes in phenotypic plasticity within wild animal populations is centuries old, however far fewer studies have investigated the role that epigenetics play in the development or persistence of natural variation in response to environmental change. Tiger snakes (Notechis scutatus) are an ideal study organism to investigate the link between epigenetics and phenotypic responses to environmental change, as they live on a range of offshore islands with different environments and prey types while exhibiting gigantism and dwarfism in body and head size. In this study, we have generated methylation sensitive amplified polymorphism (MSAP) data and found that, in general, Tiger Snakes are more epigenetically differentiated than genetically differentiated. Each island group has a distinctive epigenetic signal, suggesting the Tiger Snakes on each island group have adapted to their specific environment. This is also supported by the strong positive relationship between epigenetic differentiation and isolation age, as well as between epigenetic/genetic signal and both temperature and precipitation. The Tiger Snakes from Kangaroo Island, which has a complex landscape/environment like the mainland rather than the simple landscape/environment of each of the smaller islands, are both genetically and epigenetically more like the mainland. As the MSAP loci are randomly distributed across the genome, we believe a closer examination of the epigenetic modifications near genes involved in growth, development, and lipid metabolism will allow us to investigate the epigenetic basis for the natural variation in head size and body size on the islands.
Cellular labelling favours unfolded proteins
Authors: Minde David-Paul , Ramakrishna Manasa , Lilley Kathryn S.
Published: July 2018

Folded enzymes are essential for life, but there is limited in vivo information about how locally unfolded protein regions contribute to biological functions. Intrinsically Disordered Regions (IDRs) are enriched in disease-linked and multiply post-translationally modified proteins. The extent of foldability of predicted IDRs is difficult to measure due to significant technical challenges to survey in vivo protein conformations on a proteome-wide scale. We reasoned that IDRs should be more accessible to targeted in vivo biotinylation than more ordered protein regions, if they retain their flexibility in vivo. Indeed, we observed a positive correlation of predicted IDRs and biotinylation density across four independent large-scale proximity proteomics studies that together report >20 000 biotinylation sites. We show that biotin ‘painting’ is a promising approach to fill gaps in knowledge between static in vitro protein structures, in silico disorder predictions and in vivo condition-dependent subcellular plasticity using the 80S ribosome as an example.
Presence of midline cilia supersedes the expression of Lefty1 in forming the midline barrier during the establishment of left-right asymmetry
Authors: Shylo Natalia A , Ramrattan Dylan A , Weatherbee Scott D
Published: July 2018

Cilia in the vertebrate left-right organizer are required for the original break in left-right (L-R) symmetry. Subsequently, proper L-R patterning relies on asymmetric expression of Nodal in the lateral plate mesoderm (LPM). Lefty1, expressed in the embryonic midline, has been defined as the midline barrier, restricting the expression of Nodal to the left LPM. Here we use the mouse ciliary transition zone mutant Mks1krc, that has left isomerism and bilateral expression of the NODAL target Pitx2, to reveal that the expression of Lefty1 in the midline is insufficient for the establishment of the midline barrier. We further show through a comparison of two Tmem107 mutants that cilia in the midline are required to supplement Lefty1 expression and establish the functional midline barrier. Tmem107null mutants have no cilia in the midline and display left isomerism due to the loss of the midline barrier, whereas Tmem107schlei hypomorphic mutants have numerous cilia in the node and the midline, leading to normal Lefty1 expression and L-R patterning. This study reveals a novel role for cilia in the maintenance of L-R asymmetry.
Bat trypanosomatids (first report of T. wauwau) in Triângulo Mineiro, Brazil
Authors: Pegorari Pablo de Oliveira , Gómez-Hernández César , Barbosa Cecilia G. , Rezende-Oliveira Karine , Pedrosa André Luiz , Ramirez Juan David , Ramirez Luis E.
Published: July 2018

In this study, trypanosomatids commonly found in bats, including Trypanosoma cruzi marinkellei, T. dionisii, and Leishmania braziliensis, were identified. Additionally, T. wauwau was identified in one specimen of Anoura caudifer, and represents the first report of this parasite from the Central West region of Brazil. T. wauwau was previously identified by other researchers in the North of the country, in only three species of bats in the genus Pteronotus: P. parnellii (Pará and Rondônia states), and P. personatus and P. gymnonotus (Rondônia). The identification of T. wauwau indicates how different trypanosomatids are able to adapt to new host species of bats. This is owing to bats’ high mobility, wide geographic distribution, social behavior, and ability to coexist in large colonies. These characteristics may facilitate the transmission of infectious agents in nature, which are responsible for outbreaks of some zoonoses. Therefore, health authorities should focus on both vertebrates and vectors associated with the environments where these bats are found.

Author summary

The prevalence of Trypanosoma in bats is high, with T. cruzi, T. cruzi marinkellei, and T. dionisii as the most prevalent infective species. This study reports for the first time the presence of T. wauwau in the southeast region of Brazil in the bat Anoura caudifer. Although this species of Trypanosoma has been found in bats of the genus Pteronotus, it was not detected in any other genus, including in the bats that share the same shelter with Pteronotus. The species T. wauwau was found infecting bats only in Brazil. Its occurrence was restricted to the northern region of the country, in the states of Pará, infecting the species P. parnellii and in Rondônia infecting P. personatus, P. gymnonotus as well as P. parnellii. Although its morphology is similar to that of T. cruzi, little is known about the development of T. wauwau, both in its vertebrate host and the existence of a plausible invertebrate vector. Its characteristics include its inability to develop in mammalian cells and its non-infectiousness in mice and triatomine insects. Further research, through molecular studies, may provide important and valuable data for understanding the origin, evolution, and global distribution of, and the association between the different species of Trypanosoma and their hosts.
Cyborg Groups Enhance Face Recognition in Crowded Environments
Authors: Valeriani Davide , Poli Riccardo
Published: July 2018

Recognizing a person in a crowded environment is a challenging, yet critical, visual-search task for both humans and machine-vision algorithms. This paper explores the possibility of combining a residual neural network (ResNet), brain-computer interfaces (BCIs) and human participants to create “cyborgs” that improve decision making. Human participants and a ResNet undertook the same face-recognition experiment. BCIs were used to decode the decision confidence of humans from their EEG signals. Different types of cyborg groups were created, including either only humans (with or without the BCI) or groups of humans and the ResNet. Cyborg groups decisions were obtained weighing individual decisions by confidence estimates. Results show that groups of cyborgs are significantly more accurate (up to 35%) than the ResNet, the average participant, and equally-sized groups of humans not assisted by technology. These results suggest that melding humans, BCI, and machine-vision technology could significantly improve decision-making in realistic scenarios.
Seroprevalence of fourteen human polyomaviruses determined in blood donors
Authors: Kamminga Sergio , van der Meijden Els , Feltkamp Mariet C.W. , Zaaijer Hans L.
Published: July 2018

The polyomavirus family currently includes thirteen human polyomavirus (HPyV) species. In immunocompromised and elderly persons HPyVs are known to cause disease, such as progressive multifocal leukoencephalopathy (JCPyV), haemorrhagic cystitis and nephropathy (BKPyV), Merkel cell carcinoma (MCPyV), and trichodysplasia spinulosa (TSPyV). Some recently discovered polyomaviruses are of still unknown prevalence and pathogenic potential. Because HPyVs infections persist and might be transferred by blood components to immunocompromised patients, we studied the seroprevalence of fourteen polyomaviruses in adult Dutch blood donors. For most polyomaviruses the observed seroprevalence was high (60–100%), sometimes slightly increasing or decreasing with age. Seroreactivity increased with age for JCPyV, HPyV6 and HPyV7 and decreased for BKPyV and TSPyV. The most recently identified polyomaviruses HPyV12, NJPyV and LIPyV showed low overall seroprevalence (∼5%) and low seroreactivity, questioning their human tropism. Altogether, HPyV infections are common in Dutch blood donors, with an average of nine polyomaviruses per subject.
Effects of chronic spinal cord injury on relationships among ion channel and receptor mRNAs in mouse lumbar spinal cord
Authors: Garcia Virginia B. , Abbinanti Matthew D. , Harris-Warrick Ronald M. , Schulz David J.
Published: July 2018

Spinal cord injury (SCI) causes widespread changes in gene expression of the spinal cord, even in the undamaged spinal cord below the level of the lesion. Less is known about changes in the correlated expression of genes after SCI. We investigated gene co-expression networks among voltage-gated ion channel and neurotransmitter receptor mRNA levels using quantitative RT-PCR in longitudinal slices of the mouse lumbar spinal cord in control and chronic SCI animals. These longitudinal slices were made from the ventral surface of the cord, thus forming slices relatively enriched in motor neurons or interneurons. We performed absolute quantitation of mRNA copy number for 50 ion channel or receptor transcripts from each sample, and used multiple correlation analyses to detect patterns in correlated mRNA levels across all pairs of genes. The majority of channels and receptors changed in expression as a result of chronic SCI, but did so differently across slice levels. Furthermore, motor neuron enriched slices experienced an overall loss of correlated channel and receptor expression, while interneuron slices showed a dramatic increase in the number of positively correlated transcripts. These correlation profiles suggest that spinal cord injury induces distinct changes across cell types in the organization of gene co-expression networks for ion channels and transmitter receptors.
Impact of index hopping and bias towards the reference allele on accuracy of genotype calls from low-coverage sequencing
Authors: Ros-Freixedes Roger , Mara Battagin , Johnsson Martin , Gorjanc Gregor , Mileham Alan J , Rounsley Steve D , Hickey John M
Published: July 2018

Background

Inherent sources of error and bias that affect the quality of the sequence data include index hopping and bias towards the reference allele. The impact of these artefacts is likely greater for low-coverage data than for high-coverage data because low-coverage data has scant information and standard tools for processing sequence data were designed for high-coverage data. With the proliferation of cost-effective low-coverage sequencing there is a need to understand the impact of these errors and bias on resulting genotype calls.

Results

We used a dataset of 26 pigs sequenced both at 2x with multiplexing and at 30x without multiplexing to show that index hopping and bias towards the reference allele due to alignment had little impact on genotype calls. However, pruning of alternative haplotypes supported by a number of reads below a predefined threshold, a default and desired step for removing potential sequencing errors in high-coverage data, introduced an unexpected bias towards the reference allele when applied to low-coverage data. This bias reduced best-guess genotype concordance of low-coverage sequence data by 19.0 absolute percentage points.

Conclusions

We propose a simple pipeline to correct this bias and we recommend that users of low-coverage sequencing be wary of unexpected biases produced by tools designed for high-coverage sequencing.
Prevalence and determinants of smoking status among university students: Artvin Çoruh University sample
Authors: Karadoğan Dilek , Önal Özgür , Kanbay Yalçın
Published: July 2018

Background and aim

While smoking prevalence has decreased in many developed countries, in others it is still an increasing risk factor for public health, especially among young adults. In this study we aimed to find the factors affecting university students’ smoking status.

Methods

This cross-sectional study was conducted between March and June 2017 with a simple random sampling method. A self-administered questionnaire was used to collect information on sociodemographic characteristics, cigarette smoking status, and the related risk factors. Univariate analysis and multivariate logistic regression analysis with the Backward:LR test were performed.

Results

Out of 2723 students, 2505 students’ data were available and suitable for analysis. Mean participant age was 20.9±2.5, with female dominance (58.9%). Students studying in two-year degree departments comprised 45.6% of the study population, and the remaining 54.4% of the students were in 4-year degree departments. In terms of parental smoking habits, 36.1% reported a smoker father, while that rate was 10.3% for mothers and 15.0% for siblings. Current smokers represented 27.9% of the group: 46% among males and 15.3% among females. Mean age for beginning smoking was 16.34±2.72, 15.65±2.67 for males, 16.34±2.72 for females (p<0.05). Mean Fagerströmtest score was 4.43±1.82, and female students had lower test scores than males (p<0.05). After controlling for potential confounders in multivariate analysis, it was seen that five factors were positively associated with current smoking (p<0.05): male gender (OR:3.43; 95%, CI:2.75-4.28), studying in two-year programs (OR: 1.74; 95% CI: 1.39-2.18), having at least one close family member who is a smoker (OR:1.63; 95% CI:1.31-2.04), having close friends who are all smokers (OR:1.81; 95% CI: 1.40-2.33), and alcohol consumption (OR:4.39; 95% CI: 3.51-5.49).

Conclusion

Our study showed a higher smoking rate among our study population, both compared to similar nationalstudies and the country’s overall smoking rate. Underlying factors should be evaluated via qualitative studies and preventive strategies should be implemented accordingly.
Exploring the Genetic Basis of Human Population Differences in DNA Methylation and their Causal Impact on Immune Gene Regulation
Authors: Husquin Lucas T. , Rotival Maxime , Fagny Maud , Quach Hélène , Zidane Nora , McEwen Lisa M. , MacIsaac Julia L. , Kobor Michael S , Aschard Hugues , Patin Etienne , Quintana-Murci Lluis
Published: July 2018

DNA methylation is influenced by both environmental and genetic factors and is increasingly thought to affect variation in complex traits and diseases. Yet, the extent of ancestry-related differences in DNA methylation, its genetic determinants, and their respective causal impact on immune gene regulation remain elusive. We report extensive population differences in DNA methylation between individuals of African and European descent — detected in primary monocytes that were used as a model of a major innate immunity cell type. Most of these differences (~70%) were driven by DNA sequence variants nearby CpG sites (meQTLs), which account for ~60% of the variance in DNA methylation. We also identify several master regulators of DNA methylation variation in trans, including a regulatory hub nearby the transcription factor-encoding CTCF gene, which contributes markedly to ancestry-related differences in DNA methylation. Furthermore, we establish that variation in DNA methylation is associated with varying gene expression levels following mostly, but not exclusively, a canonical model of negative associations, particularly in enhancer regions. Specifically, we find that DNA methylation highly correlates with transcriptional activity of 811 and 230 genes, at the basal state and upon immune stimulation, respectively. Finally, using a Bayesian approach, we estimate causal mediation effects of DNA methylation on gene expression in ~20% of the studied cases, indicating that DNA methylation can play an active role in immune gene regulation. Using a system-level approach, our study reveals substantial ancestry-related differences in DNA methylation and provides evidence for their causal impact on immune gene regulation.
Clinical Impact and Cost-Effectiveness of a 176-Condition Expanded Carrier Screen
Authors: Beauchamp Kyle A. , Johansen Taber Katherine A. , Muzzey Dale
Published: July 2018

Purpose

Carrier screening identifies couples at high risk for conceiving offspring affected with serious heritable conditions. Minimal screening guidelines mandate testing for cystic fibrosis and spinal muscular atrophy, but expanded carrier screening (ECS) assesses reproductive risk for hundreds of conditions simultaneously. Although medical societies consider ECS an acceptable practice, the health economics of ECS remain incompletely characterized.

Methods

The clinical impact and cost-effectiveness of a 176-condition ECS panel were investigated using a decision-tree model comparing minimal screening and ECS in a preconception setting. Carrier rates from >50,000 patients informed disease-incidence estimates, while cost and life-years-lost data were aggregated from the literature and a cost-of-care database. Model robustness was evaluated using one-way and probabilistic sensitivity analyses.

Results

For every 100,000 pregnancies, 300 are predicted to be affected by ECS-panel conditions, which, on average, individually incur $1,300,000 in lifetime costs and increase mortality by 26 undiscounted life-years on average. Relative to minimal screening, ECS reduces the affected-birth rate and is cost-effective (i.e., <$50,000 incremental cost per life-year), findings robust to reasonable model-parameter perturbation.

Conclusion

ECS is predicted to reduce the population burden of Mendelian disease in a cost-effective manner compared to many other common medical interventions.
Regulatory mechanism predates the evolution of ant-like swarm intelligence in simulated robots
Authors: Fujisawa Ryusuke , Ichinose Genki , Dobata Shigeto
Published: July 2018

The evolution of complexity is one of the prime features of life on Earth. Although well accepted as the product of adaptation, the dynamics underlying the evolutionary build-up of complex adaptive systems remains poorly resolved. Using simulated robot swarms that exhibit ant-like group foraging with trail pheromones, we show that their swarm intelligence paradoxically involves regulatory behavior that arises in advance. We focused on a “traffic rule” on their foraging trail as a regulatory trait. We allowed the simulated robot swarms to evolve pheromone responsiveness and behaviors simultaneously. In most cases, the traffic rule, initially arising as selectively neutral component behaviors, assisted the group foraging system to bypass a fitness valley caused by overcrowding on the trail. Our study reveals a hitherto underappreciated role of regulatory mechanisms in the origin of swarm intelligence, as well as highlights the importance of embodiment in the study of their evolution.
ParGenes: a tool for massively parallel model selection and phylogenetic tree inference on thousands of genes
Authors: Morel Benoit , Kozlov Alexey M. , Stamatakis Alexandros
Published: July 2018

Motivation

Coalescent- and reconciliation-based methods are now widely used to infer species phylogenies from genomic data. They typically use per-gene phylogenies as input, which requires conducting multiple individual tree inferences on a large set of multiple sequence alignments (MSAs). At present, no easy-to-use parallel tool for this task exists. Ad hoc scripts for this purpose do not only induce additional implementation overhead, but can also lead to poor resource utilization and long times-to-solution. We present ParGenes, a tool for simultaneously determining the best-fit model and inferring maximum likelihood (ML) phylogenies on thousands of independent MSAs using supercomputers.

Results

ParGenes executes common phylogenetic pipeline steps such as model-testing, ML inference(s), bootstrapping, and computation of branch support values via a single parallel program invocation. We evaluated ParGenes by inferring > 20, 000 phylogenetic gene trees with bootstrap support values from Ensembl Compara and VectorBase alignments in 28 hours on a cluster with 1024 nodes.

Availability

GNU GPL at https://github.com/BenoitMorel/ParGenes.

Contact

Benoit.Morel@h-its.org

Supplementary information

Supplementary material is available at Bioinformatics online.
Prediction of subgenome additive and interaction effects in allohexaploid wheat
Authors: Santantonio Nicholas , Jannink Jean-Luc , Sorrells Mark E.
Published: July 2018

1

Whole genome duplications have played an important role in the evolution of angiosperms. These events often occur through hybridization between closely related species, resulting in an allopolyploid with multiple subgenomes. With the availability of affordable genotyping and a reference genome to locate markers, breeders of allopolyploids now have the opportunity to manipulate subgenomes independently. This also presents a unique opportunity to investigate epistatic interactions between homeologous orthologs across subgenomes. We present a statistical framework for partitioning genetic variance to the subgenomes of an allopolyploid, predicting breeding values for each subgenome, and determining the importance of inter-genomic epistasis. We demonstrate using an allohexaploid wheat breeding population evaluated in Ithaca, NY and an important wheat dataset previously shown to demonstrate non-additive genetic variance. Subgenome covariance matrices were constructed and used to calculate subgenome interaction covariance matrices across subgenomes for variance component estimation and genomic prediction. We propose a method to extract population structure from all subgenomes at once before covariances are calculated to reduce collinearity between subgenome estimates. Variance parameter estimation was shown to be reliable for additive subgenome effects, but was less reliable for subgenome interaction components. Predictive ability was equivalent to current genomic prediction methods. Including only inter-genomic interactions resulted in the same increase in accuracy as modeling all pairwise marker interactions. Thus, we provide a new tool for breeders of allopolyploid crops to characterize the genetic architecture of existing populations, determine breeding goals, and develop new strategies for selection of additive effects and fixation of inter-genomic epistasis.
Information-rich localization microscopy through machine learning
Authors: Kim Taehwan , Moon Seonah , Xu Ke
Published: July 2018

While current single-molecule localization microscopy (SMLM) methods often rely on the target-specific alteration of the point spread function (PSF) to encode the multidimensional contents of single fluorophores, we argue that the details of the PSF in an unmodified microscope already contain rich, multidimensional information. We introduce a data-driven approach in which artificial neural networks (ANNs) are trained to make a direct link between an experimental PSF image and its underlying parameters. To demonstrate this concept in real systems, we decipher in fixed cells both the colors and the axial positions of single molecules in regular SMLM data.
Fast and flexible linear mixed models for genome-wide genetics
Authors: Runcie Daniel E , Crawford Lorin
Published: July 2018

Linear mixed effect models are powerful tools used to account for population structure in genome-wide association studies (GWASs) and estimate the genetic architecture of complex traits. However, fully-specified models are computationally demanding and common simplifications often lead to reduced power or biased inference. We describe Grid-LMM (https://github.com/deruncie/GridLMM), an extendable algorithm for repeatedly fitting complex linear models that account for multiple sources of heterogeneity, such as additive and non-additive genetic variance, spatial heterogeneity, and genotype-environment interactions. Grid-LMM can compute approximate (yet highly accurate) frequentist test statistics or Bayesian posterior summaries at a genome-wide scale in a fraction of the time compared to existing general-purpose methods. We apply Grid-LMM to two types of quantitative genetic analyses. The first is focused on accounting for spatial variability and non-additive genetic variance while scanning for QTL; and the second aims to identify gene expression traits affected by non-additive genetic variation. In both cases, modeling multiple sources of heterogeneity leads to new discoveries.

Author summary

The goal of quantitative genetics is to characterize the relationship between genetic variation and variation in quantitative traits such as height, productivity, or disease susceptibility. A statistical method known as the linear mixed effect model has been critical to the development of quantitative genetics. First applied to animal breeding, this model now forms the basis of a wide-range of modern genomic analyses including genome-wide associations, polygenic modeling, and genomic prediction. The same model is also widely used in ecology, evolutionary genetics, social sciences, and many other fields. Mixed models are frequently multi-faceted, which is necessary for accurately modeling data that is generated from complex experimental designs. However, most genomic applications use only the simplest form of linear mixed methods because the computational demands for model fitting can be too great. We develop a flexible approach for fitting linear mixed models to genome scale data that greatly reduces their computational burden and provides flexibility for users to choose the best statistical paradigm for their data analysis. We demonstrate improved accuracy for genetic association tests, increased power to discover causal genetic variants, and the ability to provide accurate summaries of model uncertainty using both simulated and real data examples.
Addressing challenges of high spatial resolution, UHF field fMRI for group analysis of higher-order cognitive tasks; an inter-sensory task directing attention between visual and somatosensory domains
Authors: Aquino Kevin M. , Sokoliuk Rodika , Pakenham Daisie , Panchuelo Rosa Sanchez , Hanslmayr Simon , Mayhew Stephen D. , Mullinger Karen J. , Francis Susan T.
Published: July 2018

Functional MRI at ultra-high field (UHF, ≥7T) provides significant increases in BOLD contrast-to-noise ratio (CNR) compared with conventional field strength (3T), and has been exploited for reduced field-of-view, high spatial resolution mapping of primary sensory areas. Applying these high spatial resolution methods to investigate whole brain functional responses to higher-order cognitive tasks leads to a number of challenges, in particular how to perform robust group-level statistical analyses.

This study addresses these challenges using an inter-sensory cognitive task which modulates top-down attention at graded levels between the visual and somatosensory domains. At the individual level, highly focal functional activation to the task and task difficulty (modulated by attention levels) were detectable due to the high CNR at UHF. However, to assess group level effects, both anatomical and functional variability must be considered during analysis. We demonstrate the importance of surface over volume normalization and the requirement of no spatial smoothing when assessing highly focal activity. Using novel group analysis on anatomically parcellated brain regions, we show that in higher cognitive areas (parietal and dorsal-lateral-prefrontal cortex) fMRI responses to graded attention levels were modulated quadratically, whilst in visual cortex and VIP, responses were modulated linearly. These group fMRI responses were not seen clearly using conventional second-level GLM analyses, illustrating the limitations of a conventional approach when investigating such focal responses in higher cognitive regions which are more anatomically variable. The approaches demonstrated here complement other advanced analysis methods such as multi-variate pattern analysis, allowing UHF to be fully exploited in cognitive neuroscience.
Cryo-EM Reveals Ligand Induced Allostery Underlying InsP3R Channel Gating
Authors: Fan Guizhen , Baker Mariah R. , Wang Zhao , Seryshev Alexander B. , Ludtke Steven J. , Baker Matthew L. , Serysheva Irina I.
Published: July 2018

Inositol-1,4,5-trisphosphate receptors (InsP3Rs) are cation channels that mobilize Ca2+from intracellular stores in response to a wide range of cellular stimuli. The paradigm of InsP3R activation is the coupled interplay between binding of InsP3and Ca2+that switches the ion conduction pathway between closed and open states to enable the passage of Ca2+through the channel. However, the molecular mechanism of how the receptor senses and decodes ligand-binding signals into gating motion remains unknown. Here we present the electron cryo-microscopy structure of InsP3R1 from rat cerebellum determined to 4.1 Å resolution in the presence of activating concentrations of Ca2+and adenophostin A (AdA), a structural mimetic of InsP3and the most potent known agonist of the channel. Comparison with the 3.9 Å-resolution structure of InsP3R1 in the Apo-state, also reported herein, reveals the binding arrangement of AdA in the tetrameric channel assembly and striking ligand-induced conformational rearrangements within cytoplasmic domains coupled to the dilation of a hydrophobic constriction at the gate. Together, our results provide critical insights into the mechanistic principles by which ligand-binding allosterically gates InsP3R channel.
Asgard archaea are diverse, ubiquitous, and transcriptionally active microbes
Authors: Cai Mingwei , Liu Yang , Zhou Zhichao , Yang Yuchun , Pan Jie , Gu Ji-Dong , Li Meng
Published: July 2018

Asgard is a newly proposed archaeal superphylum. Phylogenetic position of Asgard archaea and its relationships to the origin of eukaryotes is attracting increasingly research interest. However, in-depth knowledge of their diversity, distribution, and activity of Asgard archaea remains limited. Here, we used phylogenetic analysis to cluster the publicly available Asgard archaeal 16S rRNA gene sequences into 13 subgroups, including five previously unknown subgroups. These lineages were widely distributed in anaerobic environments, with the majority of 16S rRNA gene sequences (92%) originating from sediment habitats. Co-occurrence analysis revealed potential relationships between Asgard, Bathyarchaeota, and Marine Benthic Group D archaea. Genomic analysis suggested that Asgard archaea are potentially mixotrophic microbes with divergent metabolic capabilities. Importantly, metatranscriptomics confirmed the versatile lifestyles of Lokiarchaeota and Thorarchaeota, which can fix CO2using the tetrahydromethanopterin Wood-Ljungdahl pathway, perform acetogenesis, and degrade organic matters. Overall, this study broadens the understandings of Asgard archaea ecology, and also provides the first evidence to support a transcriptionally active mixotrophic lifestyle of Asgard archaea, shedding light on the potential roles of these microorganisms in the global biogeochemical cycling.
A new normalization for the Nanostring nCounter gene expression assay
Authors: Molania Ramyar , Gagnon-Bartsch Johann A. , Dobrovic Alexander , Speed Terence P
Published: July 2018

The Nanostring nCounter gene expression assay uses molecular barcodes and single molecule imaging to detect and count hundreds of unique transcripts in a single reaction. These counts need to be normalized to adjust for the amount of sample, variations in assay efficiency, and other factors. Most users adopt the normalization approach described in the nSolver analysis software, which involves background correction based on the observed values of negative control probes, a within-sample normalization using the observed values of positive control probes and normalization across samples using reference (housekeeping) genes. Here we present a new normalization method, Removing Unwanted Variation-III (RUV-III), which makes vital use of technical replicates and suitable control genes. We also propose an approach using pseudo-replicates when technical replicates are not available. The effectiveness of RUV-III is illustrated on four different data sets. We also offer suggestions on the design and analysis of studies involving this technology.
On the molecular filters in cochlea transduction
Authors: Goussev Valeri
Published: July 2018

The article is devoted to the specific consideration of the cochlear transduction for the low level sound intensities, which correspond to the regions near the perception threshold. The basic cochlea mechanics is extended by the new concept of the molecular filters, which allows us to discuss the transduction mechanism on the molecular level in the space-time domain. The molecular filters are supposed to be built on the set of the stereocilia of every inner hair cell. It is hypothesized that the molecular filters are the sensors in the feedback loop, which includes also outer hair cells along with the tectorial membrane and uses the zero compensation method to evaluate the traveling wave shape on the basilar membrane. Besides the compensation, the feedback loop, being spatially distributed along the cochlea, takes control over the tectorial membrane strain field generated by the outer hair cells, and implements it as the mechanism for the automatic gain control in the sound transduction.
Two central pattern generators from the crab, Cancer borealis, respond robustly and differentially to extreme extracellular pH
Authors: Haley Jessica A. , Hampton David , Marder Eve
Published: July 2018

Animals and their neuronal circuits must maintain function despite significant environmental fluctuations. The crab, Cancer borealis, experiences daily changes in ocean temperature and pH. Here, we describe the effects of extreme changes in extracellular pH – from pH 5.5 to 10.4 – on two central pattern generating networks, the stomatogastric and cardiac ganglia of C. borealis. Given that the physiological properties of ion channels are known to be sensitive to pH within the range tested, it is surprising that these rhythms generally remained robust from pH 6.1 to pH 8.8. Unexpectedly, the stomatogastric ganglion was more sensitive to acid while the cardiac ganglion was more sensitive to base. Considerable animal-to-animal variability was likely a consequence of similar network performance arising from variable sets of underlying conductances. Together, these results illustrate the potential difficulty in generalizing the effects of environmental perturbation across circuits, even within the same animal.

Abbreviations

STG

stomatogastric ganglion

CG

cardiac ganglion

CPG

central pattern generator

AB

Anterior Burster

PD

Pyloric Dilator

LP

Lateral Pyloric

PY

Pyloric

SC

Small Cell

LC

Large Cell

lvn

lateral ventricular nerve

ANOVA

analysis of variance

PTX

picrotoxin

IPSP

inhibitory post-synaptic potential

LG

Lateral Gastric

MG

Medial Gastric

LPG

Lateral Posterior Gastric

GM

Gastric Mill

DG

Dorsal Gastric

AM

Anterior Median

Int1

Interneuron 1

mvn

medial ventricular nerve

dgn

dorsal gastric nerve

lgn

lateral gastric nerve

ion

inferior oesophageal nerve

IC

Inferior Cardiac

VD

Ventricular Dilator

MCN1

Modulatory Commissural Neuron 1

VCN

Ventral Cardiac Neuron

CPN2

Commissural Projection Neuron 2

CoG

commissural ganglion

KDE

kernel density estimate

IQR

interquartile range

CI

confidence interval
Evolutionary parallelisms of pectoral and pelvic network-anatomy from fins to limbs
Authors: Esteve-Altava Borja , Pierce Stephanie E. , Molnar Julia L. , Johnston Peter , Diogo Rui , Hutchinson John R.
Published: July 2018

Pectoral and pelvic lobe-fins transformed into fore- and hindlimbs during the Devonian period, enabling the water-to-land transition in tetrapods. In the timespan of ~60 million years, transitional forms evolved, spanning a wide range of morphologies. Here we traced the evolution of well-articulated appendicular skeletons across the fins-to-limbs transition, using a network-based approach and phylogenetic tools to quantify and compare topological features of skeletal anatomy of fins and limbs. We show that the topological arrangement of bones in the pectoral and pelvic appendages evolved in parallel during the fins-to-limbs transition, occupying overlapping regions of the morphospace, following a directional mode of evolution, and decreasing their disparity over time. We identify the presence of digits as the morphological novelty triggering significant topological changes that clearly discriminated limbs from fins. The origin of digits caused an evolutionary shift towards appendages that were less densely and heterogeneously connected, but more assortative and modular. Topological disparity likewise decreased for both appendages: for the pectoral appendage, until the origin of amniotes; for the pelvic appendage, until a time concomitant with the earliest-known tetrapod tracks. Finally, we tested and rejected the presence of a pectoral-pelvic similarity bottleneck for the network-anatomy of appendages at the origin of tetrapods. We interpret our findings in the context of a dynamic compromise between possibly different functional demands in pectoral and pelvic appendages during the water-to-land transition and a shared developmental program constraining the evolvability of limbs.
SMRT long reads and Direct Label and Stain optical maps allow the generation of a high-quality genome assembly for the European barn swallow (Hirundo rustica rustica)
Authors: Formenti Giulio , Chiara Matteo , Poveda Lucy , Francoijs Kees-Jan , Bonisoli-Alquati Andrea , Canova Luca , Gianfranceschi Luca , Stephen Horner David , Saino Nicola
Published: July 2018

Background

The barn swallow (Hirundo rustica) is a migratory bird that has been the focus of a large number of ecological, behavioural and genetic studies. To facilitate further population genetics and genomic studies, here we present a reference genome assembly for the European subspecies (H. r. rustica).

Findings

As part of the Genome10K (G10K) effort on generating high quality vertebrate genomes, we have assembled a highly contiguous genome assembly using Single Molecule Real-Time (SMRT) DNA sequencing and several Bionano optical map technologies. We compared and integrated optical maps derived both from the Nick, Label, Repair and Stain and from the Direct Label and Stain (DLS) technologies. As proposed by Bionano, the DLS more than doubled the scaffold N50 with respect to the nickase. The dual enzyme hybrid scaffold led to a further marginal increase in scaffold N50 and an overall increase of confidence in the scaffolds. After removal of haplotigs, the final assembly is approximately 1.21 Gbp in size, with a scaffold N50 value of over 25.95 Mbp.

Conclusions

This high-quality genome assembly represents a valuable resource for further studies of population genetics and genomics in the barn swallow, and for studies concerning the evolution of avian genomes. It also represents one of the very first genomes assembled by combining SMRT long-read sequencing with the new Bionano DLS technology for scaffolding. The quality of this assembly demonstrates the potential of this methodology to substantially increase the contiguity of genome assemblies.
Dynamic functional connectivity changes in dementia with Lewy bodies and Alzheimer’s disease
Authors: Schumacher Julia , Peraza Luis R. , Firbank Michael , Thomas Alan J. , Kaiser Marcus , Gallagher Peter , O’Brien John T. , Blamire Andrew M. , Taylor John-Paul
Published: July 2018

We studied the dynamic functional connectivity profile of dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD) and the relationship between dynamic connectivity and the temporally transient symptoms of cognitive fluctuations and visual hallucinations in DLB.

Resting state fMRI data from 31 DLB, 29 AD, and 31 healthy control participants were analysed using dual regression to determine between-network functional connectivity. We used a sliding window approach followed by k-means clustering and dynamic network analyses to study dynamic functional connectivity changes associated with AD and DLB. Network measures that showed significant group differences were tested for correlations with clinical symptom severity.

AD and DLB patients spent more time than controls in sparse connectivity configurations with absence of strong positive and negative connections and a relative isolation of motor networks from other networks. Additionally, DLB patients spent less time in a more strongly connected state and the variability of global brain network efficiency was reduced in DLB compared to controls. However, there were no significant correlations between dynamic connectivity measures and clinical scores.

The loss of global efficiency variability in DLB might indicate the presence of an abnormally rigid brain network and the lack of economical dynamics, factors which could contribute to an inability to respond appropriately to situational demands. However, the absence of significant clinical correlations indicates that the severity of transient cognitive symptoms such as cognitive fluctuations and visual hallucinations might not be directly related to these dynamic connectivity changes observed during a short resting state scan.