bluuebunny/crossref_metadata_2025 huggingface dataset:
Risks of harm with cannabinoids, cannabis, and cannabis-based medicine for pain management relevant to patients receiving pain treatment: protocol for an overview of systematic reviews
Authors: Gilron Ian , Blyth Fiona M. , Degenhardt Louisa , Di Forti Marta , Eccleston Christopher , Haroutounian Simon , Moore Andrew , Rice Andrew S.C. , Wallace Mark
Published: May 2019

Introduction:

With the increasing availability of cannabis and cannabinoids and their potential utility for pain treatment, there is a growing need to evaluate the risk-benefit considerations of cannabinoids for the management of pain. As part of the IASP Cannabis and Cannabinoids Task Force, this protocol describes a planned overview of systematic reviews summarizing the risks of harm with cannabinoids that are relevant to patients receiving pain treatment.

Methods:

This overview will involve literature searches of several databases and a defined search strategy that will target systematic reviews or meta-analyses of cannabinoids where harms are the primary focus. Data extraction will include various features of the cannabinoid(s) and the harm(s) being studied as well as other methodological features of each included systematic review. Methodological quality of each included review will be assessed using AMSTAR-2 as well as compliance with the PRISMA harms checklist. Prospero registration pending.

Discussion:

The broad overview of reviews defined by this protocol is expected to synthesize available good quality evidence of harms that will help inform risk-benefit considerations about the use of cannabinoids for pain management.
Do Quality Improvement Initiatives Improve Outcomes for Patients in Antiretroviral Programs in Low- and Middle-Income Countries? A Systematic Review
Authors: Hargreaves Sally , Rustage Keiran , Nellums Laura B. , Bardfield Joshua E. , Agins Bruce , Barker Pierre , Massoud M. Rashad , Ford Nathan P. , Doherty Meg , Dougherty Gillian , Singh Satvinder
Published: May 2019

Background:

There have been a range of quality improvement (QI) and quality assurance initiatives in low- and middle-income countries to improve antiretroviral therapy (ART) treatment outcomes for people living with HIV. To date, these initiatives have not been systematically assessed and little is known about how effective, cost-effective, or sustainable these strategies are in improving clinical outcomes.

Methods:

We conducted a systematic review adhering to PRISMA guidelines (PROSPERO ID: CRD42017071848), searching PubMed, MEDLINE, Embase, Web of Science, and the Cochrane database of controlled trials for articles reporting on the effectiveness of QI and quality assurance initiatives in HIV programs in low- and middle-income countries in relation to ART uptake, retention in care, adherence, viral load suppression, mortality, and other outcomes including cost-effectiveness and long-term sustainability.

Results:

One thousand eight hundred sixty articles were found, of which 29 were included. QI approaches were categorized as follows: (1) health system approaches using QI methods; (2) QI learning networks including collaboratives; (3) standard-based methods that use QI tools to improve performance gaps; and (4) campaigns using QI methods. The greatest improvements were seen in ART uptake [median increase of 14.0%; interquartile range (IQR) −9.0 to 29.3], adherence [median increase of 22.0% (IQR −7.0 to 25.0)], and viral load suppression [median increase 26.0% (IQR −8.0 to 26.0)].

Conclusions:

QI interventions can be effective in improving clinical outcomes; however, there was significant variability, making it challenging to identify which aspects of interventions lead to clinical improvements. Standardizing reporting and assessment of QI initiatives is needed, supported by national quality policies and directorates, and robust research.
7 Tesla MRI of the ex vivo human brain at 100 micron resolution
Authors: Edlow Brian L. , Mareyam Azma , Horn Andreas , Polimeni Jonathan R. , Witzel Thomas , Tisdall M. Dylan , Augustinack Jean , Stockmann Jason P. , Diamond Bram R. , Stevens Allison , Tirrell Lee S. , Folkerth Rebecca D. , Wald Lawrence L. , Fischl Bruce , van der Kouwe Andre
Published: May 2019

We present an ultra-high resolution MRI dataset of an ex vivo human brain specimen. The brain specimen was donated by a 58-year-old woman who had no history of neurological disease and died of non-neurological causes. After fixation in 10% formalin, the specimen was imaged on a 7 Tesla MRI scanner at 100 μm isotropic resolution using a custom-built 31-channel receive array coil. Single-echo multi-flip Fast Low-Angle SHot (FLASH) data were acquired over 100 hours of scan time (25 hours per flip angle), allowing derivation of a T1 parameter map and synthesized FLASH volumes. This dataset provides an unprecedented view of the three-dimensional neuroanatomy of the human brain. To optimize the utility of this resource, we warped the dataset into standard stereotactic space. We now distribute the dataset in both native space and stereotactic space to the academic community via multiple platforms. We envision that this dataset will have a broad range of investigational, educational, and clinical applications that will advance understanding of human brain anatomy in health and disease.
Using multiple reference genomes to identify and resolve annotation inconsistencies
Authors: Monnahan Patrick J. , Michno Jean-Michel , O’Connor Christine H. , Brohammer Alex B. , Springer Nathan M. , McGaugh Suzanne E. , Hirsch Candice N.
Published: May 2019

Background

Advances in sequencing technologies have led to the release of reference genomes and annotations for multiple individuals within more well-studied systems. While each of these new genome assemblies shares significant portions of synteny between each other, the annotated structure of gene models within these regions can differ. Of particular concern are split-gene misannotations, in which a single gene is incorrectly annotated as two distinct genes or two genes are incorrectly annotated as a single gene. These misannotations can have major impacts on functional prediction, estimates of expression, and many downstream analyses.

Results

We developed a high-throughput method based on pairwise comparisons of annotations that detect potential split-gene misannotations and quantifies support for whether the genes should be merged into a single gene model. We demonstrate the utility of our method using gene annotations of three reference genomes from maize (B73, PH207, and W22), a difficult system from an annotation perspective due to the size and complexity of the genome. On average, we find several hundred of these potential split-gene misannotations in each pairwise comparison, corresponding to 3-5% of gene models across annotations. To determine which state (i.e. one gene or multiple genes) is biologically supported, we utilize RNAseq data from 10 tissues throughout development along with a novel metric and simulation framework. The methods we have developed require minimal human interaction and can be applied to future assemblies to aid in annotation efforts.

Conclusions

Split-gene misannotations occur at appreciable frequency in maize annotations. We have developed a method to easily identify and correct these misannotations. Importantly, this method is generic in that it can utilize any type of short-read expression data. Failure to account for split-gene misannotations has serious consequences for biological inference, particularly for expression-based analyses.
Repetitive DNA content in the maize genome is uncoupled from population stratification at SNP loci
Authors: Renny-Byfield Simon , Baumgarten Andy
Published: May 2019

Motivation

Repetitive DNA is a major component of plant genomes and is thought to be a driver of evolutionary novelty. Describing variation in repeat content among individuals and between populations is key to elucidating the evolutionary significance of repetitive DNA. However, the cost of producing references genomes has limited large-scale intraspecific comparisons to a handful of model organisms where multiple reference genomes are available.

Results

We examine repeat content variation in the genomes of 94 elite inbred maize lines using graph-based repeat clustering, a reference-free and rapid assay of repeat content. We examine population structure using genome-wide repeat profiles and demonstrate the stiff-stalk and non-stiff-stalk heterotic populations are homogenous with regard to global repeat content. In contrast and similar to previously reported results, the same individuals show clear differentiation, and aggregate into two populations, when examining population structure using genome-wide SNPs. Additionally, we develop a novel kmer based technique to examine the chromosomal distribution of repeat clusters in silico and show a cluster dependent statistically significant association with gene density.

Conclusion

Our results indicate that repeat content variation in the heterotic populations of maize has not diverged and is uncoupled from population stratification at SNP loci. We also show that repeat families exhibit divergent patterns with regard to chromosomal distribution, some repeat clusters accumulate in regions of high gene density, whereas others aggregate in regions of low gene density.

Author’s contributions

SRB and AB conceived the study, SRB performed the bioinformatic analysis, SRB wrote the paper with input from AB. email contacts: Simon Renny-Byfield: simon.renny-byfield@corteva.com, Andy Baumgarten: andy.baumgarten@corteva.com
Depth-resolved ultra-high field fMRI reveals feedback contributions to surface motion perception
Authors: Marquardt Ingo , De Weerd Peter , Schneider Marian , Gulban Omer Faruk , Ivanov Dimo , Uludağ Kâmil
Published: May 2019

Human visual surface perception has neural correlates in early visual cortex, but the extent to which feedback contributes to this activity is not well known. Feedback projections preferentially enter superficial and deep anatomical layers, while avoiding the middle layer, which provides a hypothesis for the cortical depth distribution of fMRI activity related to feedback in early visual cortex. Here, we presented human participants uniform surfaces on a dark, textured background. The grey surface in the left hemifield was either perceived as static or moving based on a manipulation in the right hemifield. Physically, the surface was identical in the left visual hemifield, so any difference in percept likely was related to feedback. Using ultra-high field fMRI, we report the first evidence for a depth distribution of activation in line with feedback during the (illusory) perception of surface motion. Our results fit with a signal re-entering in superficial depths of V1, followed by a feedforward sweep of the re-entered information through V2 and V3, as suggested by activity centred in the middle-depth levels of the latter areas. This positive modulation of the BOLD signal due to illusory surface motion was on top of a strong negative BOLD response in the cortical representation of the surface stimuli, which depended on the presence of texture in the background. Hence, the magnitude and sign of the BOLD response to the surface strongly depended on background properties, and was additionally modulated by the presence or absence of illusory motion perception in a manner compatible with feedback. In summary, the present study demonstrates the potential of depth resolved fMRI in tackling biomechanical questions on perception that so far were only within reach of invasive animal experimentation.
Trans-omic analysis reveals allosteric and gene regulation-axes for altered glucose-responsive liver metabolism associated with obesity
Authors: Kokaji Toshiya , Hatano Atsushi , Ito Yuki , Yugi Katsuyuki , Eto Miki , Ohno Satoshi , Fujii Masashi , Hironaka Ken-ichi , Egami Riku , Inoue Hiroshi , Uda Shinsuke , Kubota Hiroyuki , Suzuki Yutaka , Ikeda Kazutaka , Arita Makoto , Matsumoto Masaki , Nakayama Keiichi I. , Hirayama Akiyoshi , Soga Tomoyoshi , Kuroda Shinya
Published: May 2019

Impaired glucose tolerance associated with obesity causes postprandial hyperglycemia and can lead to type 2 diabetes. To study the differences in liver metabolism in the healthy and obese states, we constructed and analyzed trans-omic glucose-responsive metabolic networks with layers for metabolites, expression data for metabolic enzyme genes, transcription factors, and insulin signaling proteins from the livers of healthy and obese mice. We integrated multi-omic time-course data from wild-type (WT) and leptin-deficient obese (ob/ob) mice after orally administered glucose. In WT mice, metabolic reactions were rapidly regulated (within 10 minutes of oral glucose administration) primarily by glucose-responsive metabolites, especially ATP and NADP+, which functioned as allosteric regulators and substrates of metabolic enzymes, and by Akt-dependent glucose-responsive genes encoding metabolic enzymes. Inob/obmice, most rapid regulation by glucose-responsive metabolites was absent; instead, glucose administration produced slow changes in the expression of metabolic enzyme-encoding genes to alter metabolic reactions in a time scale of hours. Few common regulatory events occurred in both the healthy and obese mice. Thus, our trans-omic network analysis revealed regulation of liver metabolism in response to glucose is mediated through different mechanisms in the healthy and obese states: Rapid changes in allosteric regulators and substrates and in gene expression dominate the healthy state, and slow transcriptional regulation dominates the obese state.

One Sentence Summary

Rapid changes in regulatory metabolites and gene expression dominate the healthy state, and slow transcriptional regulation dominates the obese state.
Characterization of the untranslated region of lymphocytic choriomeningitis virus S segment
Authors: Taniguchi Satoshi , Yoshikawa Tomoki , Shimojima Masayuki , Fukushi Shuetsu , Kurosu Takeshi , Tani Hideki , Fukuma Aiko , Kato Fumihiro , Nakayama Eri , Maeki Takahiro , Tajima Shigeru , Lim Chang-Kweng , Ebihara Hideki , Kyuwa Shigeru , Morikawa Shigeru , Saijo Masayuki
Published: May 2019

Lymphocytic choriomeningitis virus (LCMV) is a prototypic arenavirus. The viral genome consists of two RNA segments, L and S. The 5’- and 3’-termini of both L and S segments are highly conserved among arenaviruses. These regions consist of 19 complementary base pairs and are essential for viral genome replication and transcription. In addition to these 19 nucleotides in the 5’- and 3’-termini, there are untranslated regions (UTRs) composed of 58 and 41 nucleotide residues in the 5’ and 3’ UTRs, respectively, in the LCMV S segment. Their functional roles, however, have yet to be elucidated. In this study, a reverse genetics and a minigenome system for the LCMV strain WE were established and used to analyze the function of these regions. The results obtained from these analyses, plus RNA secondary structure prediction, revealed that not only these 19 nucleotides but also the 20th–40th and 20th–38th nucleotides located downstream of the 19 nucleotides in the 5’- and 3’-termini, respectively, are heavily involved in viral genome replication and transcription. Furthermore, the introduction of mutations in these regions depressed viral propagationin vitroand enhanced attenuationin vivo. Conversely, recombinant LCMVs (rLCMVs), which had various deletions in the other UTRs, propagated as well as wild-type LCMVin vitrobut were attenuatedin vivo. Most mice previously infected with rLCMVs with mutated UTRs, when further infected with a lethal dose of wild-type LCMV, survived. These results suggest that rLCMVs with mutated UTRs could be candidates for an LCMV vaccine.

IMPORTANCE

The function of untranslated regions (UTRs) of the arenavirus genome has not well been studied except for the 19 nucleotides of the 5’- and 3’-termini. In this study the function of the UTRs of the LCMV S segment was analyzed. It was found that not only the 19 nucleotides of the 5’- and 3’-termini but also the 20th–40th and 20th–38th nucleotides located downstream of the 19 nucleotides in the 5’- and 3’-termini, respectively, were involved in viral genome replication and transcription. Furthermore, other UTRs in the S segment were involved in virulencein vivo. The introduction of mutations to these regions makes it possible to establish attenuated LCMV and potentially develop LCMV vaccine candidates.
Time of day is associated with paradoxical reductions in global signal fluctuation and functional connectivity
Authors: Orban Csaba , Kong Ru , Li Jingwei , Chee Michael W.L. , Yeo B. T. Thomas
Published: May 2019

1.

The brain exhibits substantial diurnal variation in physiology and function but neuroscience studies rarely report or consider the effects of time of day. Here, we examined variation in resting-state fMRI in around 900 subjects scanned between 8am to 10pm on two different days. Multiple studies across animals and humans have demonstrated that the brain’s global signal amplitude (henceforth referred to as “fluctuation”) increases with decreased arousal. Thus, in accord with known circadian variation in arousal, we hypothesised that global signal fluctuation would be lowest in the morning, increase in the mid-afternoon and dip in the early evening. Instead, we observed a cumulative decrease (22% between 9am to 9pm) in global signal fluctuation as the day progressed. To put the magnitude of this decrease in context, we note that task-evoked fMRI responses are typically in the order of 1% to 3%. Respiratory variation also decreased with time of day, although control analyses suggested that this did not account for the reduction in GS fluctuation. Finally, time of day was associated with marked decreases in resting state functional connectivity across the whole brain. The magnitude of decrease was significantly stronger than associations between functional connectivity and behaviour (e.g., fluid intelligence). These findings reveal unexpected effects of time of day on the resting human brain, which challenge the prevailing notion that the brain’s global signal reflects mostly arousal and physiological artefacts. We conclude by discussing potential mechanisms for the observed diurnal variation in resting brain activity and the importance of accounting for time of day in future studies.
Deep learning does not outperform classical machine learning for cell-type annotation
Authors: Köhler Niklas D. , Büttner Maren , Andriamanga Niry , Theis Fabian J.
Published: May 2019

Deep learning has revolutionized image analysis and natural language processing with remarkable accuracies in prediction tasks, such as image labeling and semantic segmentation or named-entity recognition and semantic role labeling. Specifically, the combination of algorithmic and hardware advances with the appearance of large and well-labeled datasets has led up to seminal contributions in these fields.

The emergence of large amounts of data from single-cell RNA-seq and the recent global effort to chart all cell types in the Human Cell Atlas has attracted an interest in deep-learning applications. However, all current approaches are unsupervised,i.e., learning of latent spaces without using any cell labels, even though supervised learning approaches are often more powerful in feature learning and the most popular approach in the current AI revolution by far. Here, we ask why this is the case. In particular we ask whether supervised deep learning can be used for cell annotation,i.e.to predict cell-type labels from single-cell gene expression profiles. After evaluating 10 classification methods across 14 datasets, we notably find that deep learning does not outperform classical machine-learning methods in the task. Thus, cell-type prediction based on gene-signature derived cell-type labels is potentially too simplistic a task for complex non-linear methods, which demands better labels of functional single-cell readouts.
Rapid learning and unlearning of predicted sensory delays in self-generated touch
Authors: Kilteni Konstantina , Houborg Christian , Ehrsson H. Henrik
Published: May 2019

Self-generated touch feels less intense and less ticklish than identical externally generated touch. This somatosensory attenuation occurs because the brain predicts the tactile consequences of our self-generated movements. To produce attenuation, the tactile predictions need to be time-locked to the movement, but how the brain maintains this temporal tuning remains unknown. Using a bimanual self-touch paradigm, we demonstrate that people can rapidly unlearn to attenuate touch immediately after their movement and learn to attenuate delayed touch instead, after repeated exposure to a systematic delay between the movement and the resulting touch. The magnitudes of the unlearning and learning effects are correlated and dependent on the number of trials that participants have been exposed to. We further show that delayed touches feel less ticklish and non-delayed touches more ticklish after exposure to the systematic delay. These findings demonstrate that the attenuation of self-generated touch is adaptive.
Immune disease variants modulate gene expression in regulatory CD4+ T cells and inform drug targets
Authors: Bossini-Castillo Lara , Glinos Dafni A. , Kunowska Natalia , Golda Gosia , Lamikanra Abigail , Spitzer Michaela , Soskic Blagoje , Cano-Gamez Eddie , Smyth Deborah J. , Cattermole Claire , Alasoo Kaur , Mann Alice , Kundu Kousik , Soranzo Nicole , Dunham Ian , Roberts David , Trynka Gosia
Published: May 2019

Identifying cellular functions dysregulated by disease associated variants could implicate novel pathways for drug targeting or modulation in cell therapies. Variants associated with immune diseases point towards the role of CD4+ regulatory T cells (Tregs), cell type critical for immune homeostasis. To translate the effects of immune disease alleles on Treg function we mapped genetic regulation (QTL) of gene expression and chromatin activity in Tregs. We identified 123 loci where Treg QTLs colocalized with immune disease variants. These colocalizations indicated that dysregulation of key Treg pathways, including cell activation via CD28 and IL-2 signalling mediated by STAT5A contribute to the shared pathobiology of immune diseases. Finally, using disease GWAS signals colocalizing with Treg QTLs, we identified 34 known drug targets and 270 targets with drug tractability evidence. Our study is the first in-depth characterization of immune disease variant effects on Treg gene expression modulation and dysregulation of Treg function.
Human Auditory Ossicles as an Alternative Optimal Source of Ancient DNA
Authors: Sirak Kendra , Fernandes Daniel , Cheronet Olivia , Harney Eadaoin , Mah Matthew , Mallick Swapan , Rohland Nadin , Adamski Nicole , Broomandkhoshbacht Nasreen , Callan Kimberly , Candilio Francesca , Lawson Ann Marie , Mandl Kirsten , Oppenheimer Jonas , Stewardson Kristin , Zalzala Fatma , Anders Alexandra , Bartík Juraj , Coppa Alfredo , Tumen Dashtseveg , Évinger Sándor , Farkaš Zdeněk , Hajdu Tamás , Bayarsaikhan Jamsranjav , McIntyre Lauren , Moiseyev Vyacheslav , Pap Ildikó , Pietrusewsky Michael , Raczky Pál , Šefčáková Alena , Soficaru Andrei , Szeniczey Tamás , Szőke Béla Miklós , Tuvshinjargal Tumurbaatar , Van Gerven Dennis , Vasilyev Sergey , Bell Lynne , Reich David , Pinhasi Ron
Published: May 2019

DNA recovery from ancient human remains has revolutionized our ability to reconstruct the genetic landscape of the past. Ancient DNA research has benefited from the identification of skeletal elements, such as the cochlear part of the osseous inner ear, that provide optimal contexts for DNA preservation; however, the rich genetic information obtained from the cochlea must be counterbalanced against the loss of valuable morphological information caused by its sampling. Motivated by similarities in developmental processes and histological properties between the cochlea and auditory ossicles, we evaluated the efficacy of ossicles as an alternative source of ancient DNA. We demonstrate that ossicles perform comparably to the cochlea in terms of DNA recovery, finding no substantial reduction in data quality, quantity, or authenticity across a range of preservation conditions. Ossicles can be sampled from intact skulls or disarticulated petrous bones without damage to surrounding bone, and we argue that, when available, they should be selected over the cochlea to reduce damage to skeletal integrity. These results identify a second optimal skeletal element for ancient DNA analysis and add to a growing toolkit of sampling methods that help to better preserve skeletal remains for future research while maximizing the likelihood that ancient DNA analysis will produce useable results.
Structural characterization of covalently stabilized human cystatin C oligomers
Authors: Chrabąszczewska Magdalena , Sieradzan Adam K. , Rodziewicz-Motowidło Sylwia , Grubb Anders , Dobson Christopher M. , Kumita Janet R. , Kozak Maciej
Published: May 2019

Human cystatin C (HCC), a cysteine-protease inhibitor, exists as a folded monomer under physiological conditions but has the ability to self-assemble via domain swapping into multimeric states, including oligomers with a doughnut-like structure. The structure of the monomeric HCC has been solved by X-ray crystallography, and a covalently linked version of HCC (stab-1 HCC) is able to form stable oligomeric species containing 10-12 monomeric subunits. We have performed molecular modeling, and in conjunction with experimental parameters obtained from AFM, TEM and SAXS measurements, we observe that the structures are essentially flat, with a height of about 2 nm, and the distance between the outer edge of the ring and the edge of the central cavity is ~5.1 nm. These dimensions correspond to the height and diameter of one stab-1 HCC subunit and we present a dodecamer model for stabilized cystatin C oligomers using molecular dynamics simulations and experimentally measured parameters. Given that oligomeric species in protein aggregation reactions are often transient and very highly heterogeneous, the structural information presented here on these isolated stab-1 HCC oligomers may provide useful to further explore the physiological relevance of different structural species of cystatin C in relationship to protein misfolding disease
GATA3 mutation disrupts a functional network governed by estrogen receptor, FOXA1 and GATA3
Authors: Takaku Motoki , Grimm Sara A. , Kumar Bony De , Bennett Brian D. , Wade Paul A.
Published: May 2019

Estrogen receptors (ER) are part of the nuclear receptor superfamily of transcription factors and are activated by the steroid hormone 17β-estradiol. ER forms a regulatory network in conjunction with other transcription factors, such as FOXA1 and GATA3. GATA3 has been identified as one of the most frequently mutated genes in breast cancer and is capable of specifying chromatin localization of FOXA1 and ER. How GATA3 mutations impact this transcriptional network is unknown. Here we investigate the function of one of the recurrent patient-derived GATA3 mutations (R330fs) on this regulatory network. Genomic analysis indicates that the R330fs mutant can disrupt the cooperative action of ER, FOXA1, and GATA3, and induce a change in chromatin localization of these factors. Relocalization of ER and FOXA1 is associated with altered chromatin architecture, which leads to differential gene expression in GATA3 mutant cells. These results suggest an active role for GATA3 mutants in ER positive breast tumors.
Defects in mating behavior are the primary cause of sterility inC. elegansmales at elevated temperature
Authors: Nett Emily M. , Sepulveda Nicholas B. , Petrella Lisa N.
Published: May 2019

Reproduction is a fundamental imperative of all forms of life. For all the advantages sexual reproduction confers, it has a deeply conserved flaw: it is temperature sensitive. As temperatures rise, fertility decreases. Across species male fertility is particularly sensitive to elevated temperature. Previously we have shown in the model nematode wormC. elegans, that all males are fertile at 20°C but almost all males have lost fertility at 27°C. Male fertility is dependent on the production functional sperm, successful mating and transfer of sperm, and successful fertilization post-mating. To determine how male fertility is impacted by elevated temperature we analyzed these aspects of male reproduction at 27°C in three wild-type strains ofC. elegans: JU1171, LKC34, and N2. We found no effect of elevated temperature on the number of immature non-motile spermatids formed. There was a weak effect of elevated temperature on sperm activation that may negatively impact sperm function. In stark contrast, there was a strong effect of elevated temperature on male mating behavior and sperm transfer such that males very rarely successfully completed mating when exposed to 27°C. Therefore, we propose a model where elevated temperature reduces male fertility due to the negative impacts of temperature on the somatic tissues necessary for mating. Loss of successful mating at elevated temperature overrides any effects that temperature may have on the germline or sperm cells.
Optimizing functional groups in ecosystem models: Case study of the Great Barrier Reef
Authors: Haller-Bull Vanessa , Rovenskaya Elena
Published: May 2019

Uncertainty is inherent in ecosystem modelling, however its effects on modelling results are often poorly understood or ignored. This study addresses the issue of structural uncertainty or, more specifically, model resolution and its impact on the analysis of ecosystem vulnerability to threats. While guidelines for node assignments exist, they are not underlined with quantitative analysis. Different resolutions of a coral reef network are investigated by comparing the simulated network dynamics over time in various threat scenarios. We demonstrate that the error between a higher-resolution and a lower-resolution models increases, first slowly then rapidly with increased degree of node aggregation. This informs the choice of an optimal model resolution whereby a finer level of a food web representation yields only minimal additional accuracy, while increasing computational cost substantially. Furthermore, our analysis shows that species biomass ratio and the production ratio are important parameters to guide node aggregation to minimize the error.
Neural pathways linking hypoxia with pectoral fin movements in Danio rerio
Authors: Rosales Kaila , Yeh Chen-Min , How Javier J. , Villa-Real Reginno , DePasquale Elizabeth , Groisman Alex , Chalasani Sreekanth H.
Published: May 2019

Zebrafish larvae respond to hypoxia by increasing a number of ventilatory behaviors. During development, these animals switch from skin-resident to gill-resident neuroendocrine cells around 7 days post fertilization (d.p.f.) to detect hypoxia and drive adaptive behaviors. Here, we probe the neural pathways that receive inputs from skin-resident neuroendocrine cells and alter pectoral fin movements. We first show that a 5 d.p.f. larva increases its pectoral fin movements and heart activity upon hypoxia exposure. Next, we map the downstream neural circuitry and show that individual vagal sensory neurons receive inputs from multiple oxygen-sensing neuroendocrine cells. We then use calcium imaging to show that neurons in the second, but not third, vagal sensory ganglia show increases in the magnitude of their hypoxia-evoked responses. Finally, we link purinergic signaling between neuroendocrine cells and second vagal sensory neurons to increases in pectoral fin movements. Collectively, we suggest that vagal sensory neurons transform hypoxic stimuli into respiratory behaviors.
An Automated 3D Analysis Framework for Optical Coherence Tomography Angiography
Authors: Sarabi Mona Sharifi , Gahm Jin Kyu , Khansari Maziyar M. , Zhang Jiong , Kashani Amir H. , Shi Yonggang
Published: May 2019

Optical Coherence Tomography Angiography (OCTA) is a novel, non-invasive imaging modality of retinal capillaries at micron resolution. While OCTA generates 3D image volumes, current analytic methods rely on 2Den faceprojection images for quantitative analysis. This obscures the 3D vascular geometry and prevents accurate characterization of retinal vessel networks. In this paper, we have developed an automated analysis framework that preserves the 3D geometry of OCTA data. This framework uses curvelet-based denoising, optimally oriented flux (OOF) vessel enhancement and projection artifact removal, as well as the generation of 3D vessel length from the Hamilton-Jacobi skeleton. We implement this method on a dataset of 338 OCTA scans from human subjects with diabetic retinopathy (DR) which is known to cause decrease in capillary density and compare them to healthy controls. Our results indicate that 3D vessel-skeleton-length (3D-VSL) captures differences in both superficial and deep capillary density that are not apparent in 2D vessel skeleton analyses. In statistical analysis, we show that the 3D small-vessel-skeleton-length (3D-SVSL), which is computed after the removal of the large vessels and associated projection artifacts, provides a novel metric to detect group differences between healthy controls and progressive stages of DR.

This work was supported in part by NIH grants UH3NS100614, R21EY027879, U01EY025864, K08EY027006, P41EB015922, P30EY029220, Research to Prevent Blindness, and UL1TR001855 and UL1TR000130 from the National Center for Advancing Translational Science (NCATS) of the U.S. National Institutes of Health.
The Role of Premature Evidence Accumulation in Making Difficult Perceptual Decisions under Temporal Uncertainty
Authors: Devine Ciara A. , Gaffney Christine , Loughnane Gerard , Kelly Simon P. , O’Connell Redmond G.
Published: May 2019

The computations and neural processes underpinning decision making have primarily been investigated using highly simplified tasks in which stimulus onsets cue observers to start accumulating choice-relevant information. Yet, in daily life we are rarely afforded the luxury of knowing precisely when choice-relevant information will appear. Here, we examined neural indices of decision formation while subjects discriminated subtle stimulus feature changes whose timing relative to stimulus onset (‘foreperiod’) was uncertain. Joint analysis of behavioral error patterns and neural decision signal dynamics indicated that subjects systematically began the accumulation process before any informative evidence was presented, and further, that accumulation onset timing varied systematically as a function of the foreperiod of the preceding trial. These results suggest that the brain can adjust to temporal uncertainty by strategically modulating accumulation onset timing according to statistical regularities in the temporal structure of the sensory environment with particular emphasis on recent experience.
Understanding Cognitive Impairment in Mood Disorders: Mediation Analyses in the UK Biobank Cohort
Authors: Cullen Breda , Smith Daniel J. , Deary Ian J. , Pell Jill P. , Keyes Katherine M. , Evans Jonathan J.
Published: May 2019

Background

Cognitive impairment is strongly linked with persistent disability in people with mood disorders, but the factors that explain cognitive impairment in this population are unclear.

Aims

We aimed to estimate the total effect of (i) bipolar disorder (BD) and (ii) major depression on cognitive function, and the magnitude of the effect that was explained by potentially modifiable intermediate factors.

Method

Cross-sectional study using baseline data from the UK Biobank cohort. Participants were categorised as BD (N=2,709), major depression (N=50,975), or no mood disorder (N=102,931 to 105,284). The outcomes were computerised tests of reasoning, reaction time and memory. The potential mediators were cardiometabolic disease and psychotropic medication. Analyses were informed by graphical methods, and controlled for confounding using regression, propensity score-based methods, and G-computation.

Results

Group differences of small magnitude were found on a visuospatial memory test. Z-score differences for BD were in the range −0.23 to −0.17 (95% CI range −0.39 to −0.03) across different estimation methods, and approximately −0.07 (95% CI −0.10 to −0.03) for major depression. One-quarter of the effect was mediated via psychotropic medication in the BD group (−0.05; 95% CI −0.09 to −0.01). No evidence was found for mediation via cardiometabolic disease.

Conclusions

In a large community-based sample in middle to early old age, BD and depression were associated with lower visuospatial memory performance, in part potentially due to psychotropic medication use. Mood disorders and their treatments will have increasing importance for population cognitive health as the proportion of older adults continues to grow.
Biogeographical patterns in soil bacterial communities across the Arctic region
Authors: Malard Lucie A , Anwar Muhammad Zohaib , Jacobsen Carsten S , Pearce David A
Published: May 2019

The considerable microbial diversity of soils, their variety and key role in biogeochemical cycling has led to growing interest in their global distribution and the impact that environmental change might have at the regional level. In the broadest study of Arctic soil bacterial communities to date, we used high-throughput DNA sequencing to investigate the bacterial diversity from 200 independent Arctic soil samples from 43 sites. We quantified the impact of spatial and environmental factors on bacterial community structure using variation partitioning analysis, illustrating a non-random distribution across the region. pH was confirmed as the key environmental driver structuring Arctic soil bacterial communities, while total organic carbon, moisture and conductivity were shown to have little effect. Specialist taxa were more abundant in acidic and alkaline soils while generalist taxa were more abundant in acidoneutral soils. Of 48,147 bacterial taxa, a core microbiome composed of only 13 taxa that were ubiquitously distributed and present within 95% of samples was identified, illustrating the high potential for endemism in the region. Overall, our results demonstrate the importance of spatial and edaphic factors on the structure of Arctic soil bacterial communities.
Using a collaborative data collection method to update life-history values for snapper and grouper in Indonesia’s deep-slope demersal fishery
Authors: Wibisono Elle , Mous Peter , Humphries Austin
Published: May 2019

The deep-slope demersal fishery that targets snapper and grouper species is an important fishery in Indonesia. Boats operate at depths between 50-500 m using drop lines and bottom long lines. There are few data, however, on the basic characteristics of the fishery which impedes accurate stock assessments and the establishment of harvest control rules. To address this gap, we developed a collaborative data collection and recording system for species and length composition of commercial catches. The Crew-Operated Data Recording System (CODRS) involves fishers who take photos of each individual fish in the catch along with a low-cost vessel tracking system. As it relies on fisher’s collaboration and willingness to share data, CODRS is comparable with a logbook system but enables verification of species identification with greater spatial resolution. We implemented this system from 2015 to 2018 and gathered data from 251 captains and 2,707 fishing trips, which yielded more than one million individual fish, or 2,680 tons. While there were over 100 species in the fishery, we found that the top five species accounted for approximately half of the total catch. We also unveiled fifteen species previously not associated with the fishery due to the fish being eaten on-board, used as bait, or sold prior to being recorded by traders. Using these data, we updated life-history parameters (length at maturity, optimum fishing length, asymptotic length, and maximum length) of the top 50 species in the fishery based on the maximum observed length; this study resulted in higher estimates for maximum length, most likely due to the high sampling size. For some species, the discrepancies between different sources were large, whereas others were not. This collaborative data collection method and findings are useful for scientists and managers interested in conducting length-based stock assessments to establish harvest control rules for data-poor fisheries.
Fully Interpretable Deep Learning Model of Transcriptional Control
Authors: Liu Yi , Barr Kenneth , Reinitz John
Published: May 2019

The universal expressibility assumption of Deep Neural Networks (DNNs) is the key motivation behind recent work in the system biology community to employ DNNs to solve important problems in functional genomics and molecular genetics. Because of the black box nature of DNNs, such assumptions, while useful in practice, are unsatisfactory for scientific analysis. In this paper, we give an example of a DNN in which every layer is interpretable. Moreover, this DNN is biologically validated and predictive. We derive our DNN from a systems biology model that was not previously recognized as having a DNN structure. This DNN is concerned with a key unsolved biological problem, which is to understand the DNA regulatory code which controls how genes in multicellular organisms are turned on and off. Although we apply our DNN to data from the early embryo of the fruit flyDrosophila,this system serves as a testbed for analysis of much larger data sets obtained by systems biology studies on a genomic scale.
Influence of genetic variants on gene expression in human pancreatic islets – implications for type 2 diabetes
Authors: Viñuela Ana , Varshney Arushi , van de Bunt Martijn , Prasad Rashmi B. , Asplund Olof , Bennett Amanda , Boehnke Michael , Brown Andrew , Erdos Michael R. , Fadista João , Hansson Ola , Hatem Gad , Howald Cédric , Iyengar Apoorva K. , Johnson Paul , Krus Ulrika , MacDonald Patrick E. , Mahajan Anubha , Manning Fox Jocelyn E. , Narisu Narisu , Nylander Vibe , Orchard Peter , Oskolkov Nikolay , Panousis Nikolaos I. , Payne Anthony , Stitzel Michael L. , Vadlamudi Swarooparani , Welch Ryan , Collins Francis S. , Mohlke Karen L. , Gloyn Anna L. , Scott Laura J. , Dermitzakis Emmanouil T. , Groop Leif , Parker Stephen C.J. , McCarthy Mark I.
Published: May 2019

Most signals detected by genome-wide association studies map to non-coding sequence and their tissue-specific effects influence transcriptional regulation. However, many key tissues and cell-types required for appropriate functional inference are absent from large-scale resources such as ENCODE and GTEx. We explored the relationship between genetic variants influencing predisposition to type 2 diabetes (T2D) and related glycemic traits, and human pancreatic islet transcription using RNA-Seq and genotyping data from 420 islet donors. We find: (a) eQTLs have a variable replication rate across the 44 GTEx tissues (<73%), indicating that our study captured islet-specific cis-eQTL signals; (b) islet eQTL signals show marked overlap with islet epigenome annotation, though eQTL effect size is reduced in the stretch enhancers most strongly implicated in GWAS signal location; (c) selective enrichment of islet eQTL overlap with the subset of T2D variants implicated in islet dysfunction; and (d) colocalization between islet eQTLs and variants influencing T2D or related glycemic traits, delivering candidate effector transcripts at 23 loci, including DGKB and TCF7L2. Our findings illustrate the advantages of performing functional and regulatory studies in tissues of greatest disease-relevance while expanding our mechanistic insights into complex traits association loci activity with an expanded list of putative transcripts implicated in T2D development.
Viral and bacterial infection elicit distinct changes in plasma lipids in febrile children
Authors: Wang Xinzhu , Nijman Ruud , Camuzeaux Stephane , Sands Caroline , Jackson Heather , Kaforou Myrsini , Emonts Marieke , Herberg Jethro , Maconochie Ian , Carrol Enitan D , Paulus Stephane C , Zenz Werner , Van der Flier Michiel , de Groot Ronald , Martinon-Torres Federico , Schlapbach Luregn J , Pollard Andrew J , Fink Colin , Kuijpers Taco T , Anderson Suzanne , Lewis Matthew , Levin Michael , McClure Myra ,   on behalf of EUCLIDS consortium
Published: May 2019

Fever is the most common reason that children present to Emergency Departments in the UK. Clinical signs and symptoms suggestive of bacterial infection are often non-specific, and there is no definitive test for the accurate diagnosis of infection. As a result, many children are prescribed antibiotics often unnecessarily, while others with life-threatening bacterial infections can remain untreated. The ‘omics’ approaches to identifying biomarkers from the host-response to bacterial infection are promising. In this study, lipidomic analysis was carried out with plasma samples obtained from febrile children with confirmed bacterial infection (n=20) and confirmed viral infection (n=20). We show for the first time that bacterial and viral infection elicit distinct changes in the host lipidome. Glycerophosphoinositol, sphingomyelin, lysophosphotidylcholine and cholesterol sulfate were increased in the confirmed virus infected group, while fatty acids, glycerophosphocholine, glycerophosphoserine, lactosylceramide and bilirubin were increased in cases with confirmed bacterial infection. A combination of three lipids achieved the area under the receiver operating characteristic (ROC) curve of 0.918 (95% CI 0.835 to 1). This pilot study demonstrates the potential of metabolic biomarkers to assist clinicians in distinguishing bacterial from viral infection in febrile children, to facilitate effective clinical management and to the limit inappropriate use of antibiotics.
Probing mechanisms of transcription elongation through cell-to-cell variability of RNA polymerase
Authors: Ali Md. Zulfikar , Choubey Sandeep , Das Dipjyoti , Brewster Robert C.
Published: May 2019

The process of transcription initiation and elongation are primary points of control in the regulation of gene expression. While biochemical studies have uncovered the mechanisms involved in controlling transcription at each step, how these mechanisms manifestin vivoat the level of individual genes is still unclear. Recent experimental advances have enabled single-cell measurements of RNAP molecules engaged in the process of transcribing a gene of interest. In this manuscript, we use Gillespie simulations to show that measurements of cell-to-cell variability of RNAP numbers and inter-polymerase distances can reveal the prevailing mode of regulation of a given gene. Mechanisms of regulation at each step, from initiation to elongation dynamics, produce qualitatively distinct signatures which can further be used to discern between them. Intriguingly, depending on the initiation kinetics, stochastic elongation can either enhance or suppress cell-to-cell variability at the RNAP level. To demonstrate the value of this framework, we analyze RNAP number distribution data for ribosomal genes in S. cerevisiae from three previously published studies and show that this approach provides crucial mechanistic insights into the transcriptional regulation of these genes.

Author Summary

The process of transcription comprises many distinct steps and understanding the regulation of each of these steps provides insight into how the levels of gene expression are controlled in the cell. In this manuscript, we use stochastic simulations to explore how regulation at the level of elongation and initiation together influences the distribution of actively transcribing RNAP on a gene. We find that each of these steps of regulation leaves a distinct imprint on the gene-to-gene variability of number of actively transcribing RNAP on the gene and their inter-RNAP distances. Using these results, we analyze recent experimental data of transcribing RNAP distributions and find that the perturbations in these studies primarily impact the transcription initiation dynamics of the genes.