bluuebunny/crossref_metadata_2025 huggingface dataset:
Population-scale proteome variation in human induced pluripotent stem cells
Authors: Mirauta Bogdan A , Seaton Daniel D , Bensaddek Dalila , Brenes Alejandro , Bonder Marc J , Kilpinen Helena ,   HipSci Consortium, Stegle Oliver , Lamond Angus I
Published: October 2018

Realising the potential of human induced pluripotent stem cell (iPSC) technology for drug discovery, disease modelling and cell therapy requires an understanding of variability across iPSC lines. While previous studies have characterized iPS cell lines genetically and transcriptionally, little is known about the variability of the iPSC proteome. Here, we present the first comprehensive proteomic iPSC dataset, analysing 202 iPSC lines derived from 151 donors. We characterise the major genetic determinants affecting proteome and transcriptome variation across iPSC lines and identify key regulatory mechanisms affecting variation in protein abundance. Our data identified >700 human iPSC protein quantitative trait loci (pQTLs). We mapped trans regulatory effects, identifying an important role for protein-protein interactions. We discovered that pQTLs show increased enrichment in disease-linked GWAS variants, compared with RNA-based eQTLs.
AMON: Annotation of metabolite origins via networks to better integrate microbiome and metabolome data
Authors: Shaffer M. , Quinn K. , Doenges K. , Zhang X. , Bokatzian S. , Reisdorph N. , Lozupone CA.
Published: October 2018

Motivation

Untargeted metabolomics of host-associated samples has yielded insights into mechanisms by which microbes modulate health. However, data interpretation is challenged by the complexity of origins of the small molecules measured, which can come from the host, microbes that live with the host, or from other exposures such as diet or the environment.

Results

We address this challenge through development of AMON: Annotation of Metabolite Origins via Networks. AMON is an open-source bioinformatics application that can be used to determine the degree to which annotated compounds in the metabolome may have been produced by bacteria present, the host, either (i.e. both the bacteria and host are capable of production), or neither (i.e. neither the human or the fecal microbiome are predicted to be capable of producing the observed metabolite).

Availability and Implementation

This software is available at https://github.com/lozuponelab/AMON as well as via pip.

Contact

catherine.lozupone@ucdenver.edu
Vitamin D3 regulates estrogen’s action and affects mammary epithelial organization in 3D cultures
Authors: Hasan Nafis , Sonnenschein Carlos , Soto Ana M.
Published: October 2018

Vitamin D3 (vitD3) and its active metabolite, calcitriol (1,25-(OH)2D3), affect multiple tissue types by interacting with the vitamin D receptor (VDR). Although vitD3 deficiency has been correlated with increased incidence of breast cancer and less favorable outcomes across ethnic groups and latitudes, randomized human clinical trials have yet to provide conclusive evidence on the efficacy of vitD3 in treating and/or preventing breast cancer. When considering that carcinogenesis is “development gone awry”, it becomes imperative to understand the role of vitD3 during breast development. Mammary gland development in VDR KO mice is altered by increased ductal elongation and lateral branching during puberty, precocious and increased alveologenesis at pregnancy and delayed post-lactational involution. These developmental processes are largely influenced by mammotropic hormones, i.e., ductal elongation by estrogen, branching by progesterone and alveologenesis by prolactin. However, research on vitD3’s effects on mammary gland morphogenesis focused on cell proliferation and apoptosis in 2D culture models and utilized supra-physiological doses of vitD3, conditions that spare the microenvironment in which morphogenesis takes place. Here, using two 3D culture models, we investigated the role of vitD3 in mammary epithelial morphogenesis. We found that vitD3 interferes with estrogen’s actions on T47D human breast cancer cells in 3D differently at different doses, and recapitulates what is observedin vivo. Also, vitD3 can act autonomously and affect the organization of MCF10A cells in 3D collagen matrix by influencing collagen fiber organization. Thus, we uncovered how vitD3 modulates mammary tissue organization independent of its already known effects on cell proliferation.
NetGO: Improving Large-scale Protein Function Prediction with Massive Network Information
Authors: You Ronghui , Yao Shuwei , Huang Xiaodi , Sun Fengzhu , Mamitsuka Hiroshi , Zhu Shanfeng
Published: October 2018

Automated function prediction (AFP) of proteins is of great significance in biology. In essence, AFP is a large-scale multi-label classification over pairs of proteins and GO terms. Existing AFP approaches, however, have their limitations on both sides of proteins and GO terms. Using various sequence information and the robust learning to rank (LTR) framework, we have developed GOLabeler, a state-of-the-art approach of CAFA3, which overcomes the limitation of the GO term side, such as imbalanced GO terms. Unfortunately, for the protein side issue, available abundant protein information, except for sequences, have not been effectively used for large-scale AFP in CAFA. We propose NetGO that is able to improve large-scale AFP with massive network information. The novelties of NetGO have threefold in using network information: 1) the powerful LTR framework of NetGO efficiently and effectively integrates both sequence and network information, which can easily make large-scale AFP; 2) NetGO can use whole and massive network information of all species (>2000) in STRING (other than only high confidence links and/or some specific species); and 3) NetGO can still use network information to annotate a protein by homology transfer even if it is not covered in STRING. Under numerous experimental settings, we examined the performance of NetGO, such as general performance comparison, species-specific prediction, and prediction on difficult proteins, by using training and test data separated by time-delayed settings of CAFA. Experimental results have clearly demonstrated that NetGO outperforms GOLabeler, DeepGO, and other compared baseline methods significantly. In addition, several interesting findings from our experiments on NetGO would be useful for future AFP research.
In vivo phosphoproteomics reveals pathogenic signaling changes in diabetic islets
Authors: Sacco Francesca , Seelig Anett , Humphrey Sean J. , Krahmer Natalie , Volta Francesco , Reggio Alessio , Gerdes Jantje , Mann Matthias
Published: October 2018

Progressive decline of pancreatic beta cells function is key to the pathogenesis of type 2 diabetes. Protein phosphorylation is the central mechanism controlling glucose-stimulated insulin secretion in beta cells. However, if and how signaling networks are remodeled in diabetic isletsin vivoremain unknowns. Here we applied high-sensitivity mass spectrometry-based proteomics and quantified the levels of about 6,500 proteins and 13,000 phosphopeptides in islets of obese diabetic mice and matched controls. This highlighted drastic remodeling of key kinase hubs and signaling pathways. We integrated our phosphoproteomic dataset with a literature-derived signaling network, which revealed a crucial and conserved role of GSK3 kinase in the control of the beta cells-specific transcription factor PDX1 and insulin secretion, which we functionally verified. Our resource will enable the community to investigate potential mechanisms and drug targets in type 2 diabetes.
Phylogenetically based establishment of a dengue virus panel, representing all available genotypes, as a tool in dengue drug discovery
Authors: Touret Franck , Baronti Cécile , Goethals Olivia , Van Loock Marnix , de Lamballerie Xavier , Querat Gilles
Published: October 2018

Dengue fever is the most widespread of the human arbovirus diseases, with approximately one third of the world’s population at risk of infection. Dengue viruses are members of the genus Flavivirus (family Flaviviridae) and, antigenically, they separate as four closely related serotypes (1-4) that share 60 to 75 % amino acid homology. This genetic diversity complicates the process of antiviral drug discovery. Thus, currently no approved dengue-specific therapeutic treatments are available. With the aim of providing an efficient tool for dengue virus drug discovery, a collection of nineteen dengue viruses, representing the genotypic diversity within the four serotypes, was developed. After phylogenetic analysis of the full-length genomes, we selected relevant strains from the EVAg collection at Aix-Marseille University and completed the virus collection, using a reverse genetic system based on the infectious sub-genomic amplicons technique. Finally, we evaluated this dengue virus collection against three published dengue inhibitory compounds. NITD008, which targets the highly conserved active site of the viral NS5 polymerase enzyme, exhibited similar antiviral potencies against each of the different dengue genotypes in the panel. Compounds targeting less conserved protein subdomains, such as the capsid inhibitor ST-148, or SDM25N, a ∂ opioid receptor antagonist which indirectly targets NS4B, exhibited larger differences in potency against the various genotypes of dengue viruses. These results illustrate the importance of a phylogenetically based dengue virus reference panel for dengue antiviral research. The collection developed in this study, which includes such representative dengue viruses, has been made available to the scientific community through the European Virus Archive to evaluate novel DENV antiviral candidates.
Expanding the bioluminescence reporter toolkit for plant chronobiology with NanoLUC
Authors: Urquiza-García Uriel , Millar Andrew J.
Published: October 2018

Bioluminescence has been an important tool for gathering circadian data with the main reporter gene exploited firefly luciferase (LUC). In some circumstances the rapid inactivation of LUC could be disadvantageous, e.g. reporting total protein levels through reporter translational fusions. In the latter scenario the commercially available Nano luciferase (NanoLUC) might offer and advantage, however no data in plant has been provided so far. We tested NanoLUC under different research scenarios were LUC has been used, for example enzyme purification, expression in transient plant systems and in stable transgenic lines. We show that NanoLUC is active in these experimental scenarios. We also created a set of NanoLUC variants for example MBP-NanoLUC-3xFlag-10xHis version of NanoLUC can be easily purified and stable for several days (half-life 37.2 at 4°C) and can be used for generating calibration curves for quantifying protein as the signal is linear over a large dynamic range. In addition, we show that NanoLUC can report in-planta protein levels on circadian time scale thanks to the stability of furimazine. Therefore, opening the possibility of using NanoLUC for reporting protein dynamics in seedlings. With this new technology, we explored the dynamics of protein BROTHER OF LUX ARRHYTHMO (BOA), which has been suggested in mathematical models to be a rhythmic protein from RNA data. Using an automatic plate-reader, we were able to track BOAp:BOA-NL for an extended period of time by just adding a mix of furimazine with Triton X-100, as it is done with LUC-reporter lines. In our experimental context BOA protein does not present strong oscillatory dynamics similar to what has been reported for Phytocrhome B for which rhythmic accumulation of transcript can be observed while total protein levels remain constant under diurnal conditions. Our results support the use NanoLUC for studying the dynamics of plant proteins for extended period of time under different circumstances.
Anticipatory neural activity improves the decoding accuracy for dynamic head-direction signals
Authors: Zirkelbach Johannes , Stemmler Martin , Herz Andreas V.M.
Published: October 2018

Insects and vertebrates harbor specific neurons that encode the animal’s head direction (HD) and provide an internal compass for spatial navigation. Each HD cell fires most strongly in one preferred direction. As the animal turns its head, however, HD cells in rat anterodorsal thalamic nucleus (ADN) and other brain areas fire already before their preferred direction is reached, as if the neurons anticipated the future head direction. This phenomenon has been explained at a mechanistic level but a functional interpretation is still missing. To close this gap, we use a computational approach based on the animal’s movement statistics and a simple model for the behavior of the ADN head-direction network. Network activity is read out using population vectors in a biologically plausible manner, so that only past spikes are taken into account. We find that anticipatory firing improves the representation of the present HD by reducing the motion-induced temporal bias inherent in causal decoding. The amount of anticipation observed in ADN enhances the precision of the HD compass read-out by up to 40%. In addition, our framework predicts that neural integration times not only reflect biophysical constraints, but also the statistics of natural stimuli; anticipatory tuning should be found whenever neurons encode sensory signals that change gradually in time.

Significance statement

Across different brain regions, populations of noisy neurons encode dynamically changing stimuli. Decoding a time-varying stimulus from the population response involves a trade-off: For short read-out times, stimulus estimates are unreliable as the number of stochastic spikes will be small; for long read-out times, estimates are biased because they lag behind the true stimulus. We show that optimal decoding relies not only on finding the right read-out time window, but requires neurons to anticipate future stimulus values. We apply this framework to the rodent head-direction system and show that the experimentally observed anticipation of future head directions can be explained at a quantitative level from the neuronal tuning properties, the network size, and the animal’s head-movement statistics.
Single step, high efficiency CRISPR-Cas9 genome editing in primary human disease-derived fibroblasts
Authors: Martufi Matteo , Good Robert B. , Rapiteanu Radu , Schmidt Tobias , Patili Eleni , Tvermosegaard Ketil , Nanthakumar Carmel B. , Betts Joanna , Blanchard Andy D. , Maratou Klio
Published: October 2018

Genome editing is a tool that has many applications including the validation of potential drug targets. However, performing genome editing in low passage, primary human cells with the greatest physiological relevance, is notoriously difficult. High editing efficiency is desired because it enables gene knock outs (KO) to be generated in bulk cellular populations and circumvents the problem of having to generate clonal cell isolates. Here, we describe a single step workflow enabling >90% KO generation in primary human lung fibroblasts via CRISPR ribonucleoprotein delivery, in the absence of antibiotic selection or clonal expansion. As proof of concept, we performed a disease relevant phenotypic assay measuring collagen deposition in response to TGFβ and demonstrated SMAD3 but not SMAD2 dependent deposition of type I collagen following knockout of each using our single step methodology. The optimization of this workflow can readily be transferred to other primary cell types.
The River Runs Through It: the Athabasca River Delivers Mercury to Aquatic Birds Breeding Far Downstream
Authors: Hebert Craig E.
Published: October 2018

This study examined factors contributing to temporal variability (2009-2017) in total mercury (THg) concentrations in aquatic bird eggs collected in the Peace-Athabasca Delta and Lake Athabasca in northern Alberta. Factors examined included annual changes in oil sands production, bird diets, forest fires, and flow of the Athabasca River. Surface mining activities associated with Alberta’s Athabasca oil sands are centered north of Fort McMurray, Alberta, adjacent to the northward-flowing Athabasca River. Previous studies have found that oil sands industrial operations release mercury into the local (within ~50 km) environment. However, temporal trends in egg THg levels did not track trends in synthetic oil production from the oil sands. Intraspecific fluctuations in bird diet also could not explain annual variability in egg THg levels. Annual extent of forest fires in Alberta was only related to egg THg concentrations in California Gulls from Lake Athabasca; annual levels in other species showed no relationship with fire extent. The inclusion of more terrestrial foods in gull diets may have contributed to this difference. For the majority of species, annual fluctuations in maximal flow of the Athabasca River were important in influencing annual egg THg levels. Eggs collected following years of high flow had higher THg concentrations with distinct stable Hg isotope compositions. Riverine processes associated with suspended sediment were likely critical in regulating Hg availability to nesting birds. This study highlights the importance of the Athabasca River as a conduit for Hg transport to ecologically-sensitive downstream ecosystems such as the Peace-Athabasca Delta and Wood Buffalo National Park (a UNESCO World Heritage Site). Human activities that increase atmospheric Hg deposition to the Athabasca River watershed, or that enhance Hg releases to the river through erosion of Hg-bearing soils, will likely increase the availability of Hg to organisms inhabiting downstream areas.
Presynaptic NMDA receptors cooperate with local action potentials to implement activity-dependent GABA release from the reciprocal olfactory bulb granule cell spine
Authors: Lage-Rupprecht Vanessa , Zhou Li , Bianchini Gaia , Aghvami S. Sara , Mueller Max , Rózsa Balázs , Sassoé-Pognetto Marco , Egger Veronica
Published: October 2018

In the rodent olfactory bulb the smooth dendrites of the principal glutamatergic mitral cells (MCs) form reciprocal dendrodendritic synapses with large spines on GABAergic granule cells (GC), where unitary release of glutamate can trigger postsynaptic local activation of voltage-gated Na+-channels (Navs), i.e. a spine spike. Can such single MC input evoke reciprocal release? We find that unitary-like activation via two-photon uncaging of glutamate causes GC spines to release GABA both synchronously and asynchronously onto MC dendrites. This release indeed requires activation of Navs and high-voltage-activated Ca2+-channels (HVACCs), but also of NMDA receptors (NMDAR). Simulations show temporally overlapping HVACC- and NMDAR-mediated Ca2+-currents during the spine spike, and ultrastructural data prove NMDAR presence within the GABAergic presynapse. This cooperative action of presynaptic NMDARs allows to implement synapse-specific, activity-dependent lateral inhibition and thus could provide an efficient solution to combinatorial percept synthesis in a sensory system with many receptor channels.
Human iPSC-derived retinal pigment epithelium: a model system for identifying and functionally characterizing causal variants at AMD risk loci
Authors: Smith Erin N. , D’Antonio-Chronowska Agnieszka , Greenwald William W. , Borja Victor , Aguiar Lana R. , Pogue Robert , Matsui Hiroko , Borooah Shyamanga , D’Antonio Matteo , Ayyagari Radha , Frazer Kelly A.
Published: October 2018

We evaluate whether human induced pluripotent stem cell-derived retinal pigment epithelium (iPSC-RPE) cells can be used to prioritize and functionally characterize causal variants at age-related macular degeneration (AMD) risk loci. We generated iPSC-RPE from six subjects and show that they have morphological and molecular characteristics similar to native RPE. We generated RNA-seq, ATAC-seq, and H3K27ac ChIP-seq data and observe high similarity in gene expression and enriched transcription factor motif profiles between iPSC-RPE and human fetal-RPE. We performed fine-mapping of AMD risk loci by integrating molecular data from the iPSC-RPE, adult retina, and adult RPE, which identified rs943080 as the probable causal variant at VEGFA. We show that rs943080 is associated with altered chromatin accessibility of a distal ATAC-seq peak, decreased overall gene expression of VEGFA, and allele specific expression of a non-coding transcript. These results provide insight into the mechanism underlying the association of the VEGFA locus with AMD.
The microRNA, miR-18a, regulates NeuroD and photoreceptor differentiation in the retina of the zebrafish
Authors: Taylor Scott M. , Giuffre Emily , Moseley Patience , Hitchcock Peter F.
Published: October 2018

During embryonic retinal development, six types of retinal neurons are generated from a pool of multipotent progenitors in a strict spatiotemporal pattern. This pattern requires cell cycle exit (i.e. neurogenesis) and differentiation to be precisely regulated in a lineage-specific manner. In zebrafish, the bHLH transcription factor NeuroD governs photoreceptor genesis through Notch signaling but also governs photoreceptor differentiation though distinct mechanisms that are currently unknown. Also unknown are the mechanisms that regulate NeuroD and the spatiotemporal pattern of photoreceptor development. Members of the miR-17-92 microRNA cluster regulate CNS neurogenesis, and a member of this cluster, miR-18a, is predicted to target neuroD mRNA. The purpose of this study was to determine if miR-18a regulates NeuroD in the retina and if it plays a role in photoreceptor development. Quantitative RT-PCR showed that, of the three miR-18 family members (miR-18a, b and c), miR-18a expression most closely parallels neuroD expression. Morpholino oligonucleotides and CRISPR/Cas9 gene editing were used for miR-18a loss-of-function (LOF) and both approaches resulted in larvae with more mature photoreceptors at 70 hpf without affecting cell proliferation. Western blot showed that miR-18a LOF increases NeuroD protein levels and in vitro dual luciferase assay showed that miR-18a directly interacts with the 32UTR of neuroD. Finally, tgif1 mutants have increased miR-18a expression, less NeuroD protein and fewer mature photoreceptors, and the photoreceptor deficiency is rescued by miR-18a knockdown. Together these results show that, independent of neurogenesis, miR-18a regulates the timing of photoreceptor differentiation and indicate that this occurs through post-transcriptional regulation of NeuroD.
Dropout-Enabled Ensemble Learning for Multi-Scale Biomedical Data
Authors: Momeni Alexandre , Thibault Marc , Gevaert Olivier
Published: October 2018

Leveraging information from multiple scales is crucial to understanding complex diseases such as cancer where this could have a significant impact in improving diagnoses, patient management and treatment decisions. Recent advances in Convolutional Neural Networks (CNNs) have enabled major breakthroughs in biomedical image analysis, in particular for histopathology and radiology images. Our main contribution is a methodology to combine independent CNN models built for these two types of images in order to improve diagnostic accuracy. We train separate CNN models and combine them using a Dropout-Enabled meta-classifier. Our framework achieved second place in the MICCAI 2018 Computational Precision Medicine Challenge.
Functional clustering of dendritic activity during decision-making
Authors: Kerlin A , Mohar B , Flickinger D , MacLennan BJ , Davis C , Spruston N , Svoboda K
Published: October 2018

The active properties of dendrites support local nonlinear operations, but previous imaging and electrophysiological measurements have produced conflicting views regarding the prevalence of local nonlinearities in vivo. We imaged calcium signals in pyramidal cell dendrites in the motor cortex of mice performing a tactile decision task. A custom microscope allowed us to image the soma and up to 300 μm of contiguous dendrite at 15 Hz, while resolving individual spines. New analysis methods were used to estimate the frequency and spatial scales of activity in dendritic branches and spines. The majority of dendritic calcium transients were coincident with global events. However, task-associated calcium signals in dendrites and spines were compartmentalized by dendritic branching and clustered within branches over approximately 10 μm. Diverse behavior-related signals were intermingled and distributed throughout the dendritic arbor, potentially supporting a large computational repertoire and learning capacity in individual neurons.
Cross-Sectional and Longitudinal Brain Scans Reveal Accelerated Brain Aging in Multiple Sclerosis
Authors: Høgestøl Einar A. , Kaufmann Tobias , Nygaard Gro O. , Beyer Mona K. , Sowa Piotr , Nordvik Jan E. , Kolskår Knut , Richard Geneviève , Andreassen Ole A. , Harbo Hanne F. , Westlye Lars T.
Published: October 2018

Multiple sclerosis (MS) is an inflammatory disorder of the central nervous system. By combining longitudinal MRI-based brain morphometry and brain age estimation using machine learning, we tested the hypothesis that MS patients have higher brain age relative to chronological age than healthy controls (HC) and that longitudinal rate of brain aging in MS patients is associated with clinical course.

Seventy-six MS patients, 71 % females and mean age 34.8 years (range 21-49) at inclusion, were examined with brain MRI at three time points with a mean total follow up period of 4.4 years. A machine learning model was applied on an independent training set of 3208 HC, estimating individual brain age and calculating the difference between estimated brain age and chronological age, termed brain age gap (BAG). We also assessed the longitudinal change rate in BAG in MS individuals. We used additional cross-sectional MRI data from 235 HC for case-control comparison.

MS patients showed increased BAG (4.4 ±6.6 years) compared to HC (Cohen’s D = 0.69, p = 4.0 × 10−6). Longitudinal estimates of BAG in MS patients suggested an accelerated rate of brain aging corresponding to an annual increase of 0.41 (±1.23) years compared to chronological aging for the MS patients (p = 0.008).

On average, patients with MS have significantly higher BAG compared to HC and accelerated rate of brain aging compared to chronological aging. Brain age estimation represents a promising method for evaluation of brain changes in MS, with potential for predicting future outcome and guide treatment.
The impact of short- and long-range perception on population movements
Authors: Johnston S. T. , Painter K. J.
Published: October 2018

Navigation of cells and organisms is typically achieved by detecting and processing orienteering cues. Occasionally, a cue may be assessed over a much larger range than the individual’s body size, as in visual scanning for landmarks. In this paper we formulate models that account for orientation in response to short- or long-range cue evaluation. Starting from an underlying random walk movement model, where a generic cue is evaluated locally or nonlocally to determine a preferred direction, we state corresponding macroscopic partial differential equations to describe population movements. Under certain approximations, these models reduce to well-known local and nonlocal biological transport equations, including those of Keller-Segel type. We consider a case-study application: “hilltopping” in Lepidoptera and other insects, a phenomenon in which populations accumulate at summits to improve encounter/mating rates. Nonlocal responses are shown to efficiently filter out the natural noisiness (or roughness) of typical landscapes and allow the population to preferentially accumulate at a subset of hilltopping locations, in line with field studies. Moreover, according to the timescale of movement, optimal responses may occur for different perceptual ranges.
Gradient in cytoplasmic pressure in the germline cells controls overlying epithelial cell morphogenesis
Authors: Lamiré Laurie-Anne , Milani Pascale , Runel Gaël , Kiss Annamaria , Arias Leticia , Vergier Blandine , Das Pradeep , Cluet David , Boudaoud Arezki , Grammont Muriel
Published: October 2018

It is unknown how growth in one tissue impacts morphogenesis in a neighboring tissue. To address this, we used theDrosophilaovarian follicle, where a cluster of 15 nurse cells and a posteriorly located oocyte are surrounded by a layer of epithelial cells. It is known that as the nurse cells grow, the overlying epithelial cells flatten in a wave that begins in the anterior. Here, we demonstrate that an anterior to posterior gradient of decreasing cytoplasmic pressure is present across the nurse cells and that this gradient acts through TGFß to control both the triggering and the progression of the wave of epithelial cell flattening. Our data indicate that intrinsic nurse cell growth is important to control proper nurse cell pressure. Finally, we reveal that nurse cell pressure and subsequent TGFß activity in the StC combine to increase follicle elongation in the anterior, which is crucial for allowing nurse cell growth and pressure control. More generally, our results reveal that during development, inner cytoplasmic pressure in individual cells has an important role in shaping their neighbors.

Impact Statement

Cell shape change depends on extrinsic forces exerted by cytoplasmic pressure in neighbouring cells.
Intra-individual methylomics detects the impact of early-life adversity
Authors: Jiang Shan , Kamei Noriko , Bolton Jessica L. , Ma Xinyi , Stern Hal S. , Baram Tallie Z. , Mortazavi Ali
Published: October 2018

Genetic and environmental factors interact during sensitive periods early in life to influence mental health and disease via epigenetic processes such as DNA methylation. However, it is not known if DNA methylation changes outside the brain provide an ‘epigenetic signature’ of early-life experiences. Here, we employed a novel intra-individual approach by testing DNA methylation from buccal cells of individual rats before and immediately after exposure to one week of typical or adverse life experience. We find that whereas inter-individual changes in DNA methylation reflect the effect of age, DNA methylation changes within paired DNA samples from the same individual reflect the impact of diverse neonatal experiences. Genes coding for critical cellular–metabolic enzymes, ion channels and receptors were more methylated in pups exposed to the adverse environment, predictive of their repression. In contrast, the adverse experience was associated with less methylation on genes involved in pathways of death and inflammation as well as cell-fate related transcription factors, indicating their potential upregulation. Thus, intra-individual methylome signatures indicate large-scale transcription-driven alterations of cellular fate, growth and function.
Genomic signatures of extensive inbreeding in Isle Royale wolves, a population on the threshold of extinction
Authors: Robinson Jacqueline A. , Räikkönen Jannikke , Vucetich Leah M. , Vucetich John A. , Peterson Rolf O. , Lohmueller Kirk E. , Wayne Robert K.
Published: October 2018

The observation that small, isolated populations often suffer reduced fitness as a result of inbreeding depression has guided conservation theory and practice for decades. However, investigating the genome-wide dynamics associated with inbreeding depression in natural populations is only now feasible with relatively inexpensive sequencing technology and annotated reference genomes. To characterize the genome-wide effects of intense inbreeding and isolation, we sequenced complete genomes from an iconic inbred population, the gray wolves (Canis lupus) of Isle Royale. Through comparison with other wolf genomes from a variety of demographic histories, we found that Isle Royale wolf genomes contain extensive runs of homozygosity, but neither the overall level of heterozygosity nor the number of deleterious variants per genome were reliable predictors of inbreeding depression. These findings are consistent with the hypothesis that severe inbreeding depression results from increased homozygosity of strongly deleterious recessive mutations, which are more prevalent in historically large source populations. Our results have particular relevance in light of the recently proposed reintroduction of wolves to Isle Royale, as well as broader implications for management of genetic variation in the fragmented landscape of the modern world.
Molecular phylogeny and diversification timing of the Nemouridae family (Insecta, Plecoptera) in the Japanese Archipelago
Authors: Gamboa Maribet , Muranyi David , Kanmori Shota , Watanabe Kozo
Published: October 2018

The generation of the high species diversity of insects in Japan was profoundly influenced by the formation of the Japanese Archipelago. We explored the species diversification and biogeographical history of the Nemouridae family in the Japanese Archipelago using mitochondrial DNA and nuclear DNA markers. We collected 49 species among four genera:Indonemoura,Protonemura,AmphinemuraandNemourain Japan, China, South Korea and North America. We estimated their divergence times—based on three molecular clock node calibrations—using Bayesian phylogeography approaches. Our results suggested that Japanese Archipelago formation events resulted in diversification events in the middle of the Cretaceous (<120 Ma), speciation in the Paleogene (<50 Ma) and intra-species diversification segregated into eastern and western Japan of the Fossa Magna region at late Neogene (20 Ma). TheIndonemourasamples were genetically separated into two clades—that of Mainland China and that of Japan. The Japanese clade clustered with the Nemouridae species from North America, suggesting the possibility of a colonisation event prior to the formation of the Japanese Archipelago. We believe that our results enhanced the understanding both of the origin of the species and of local species distribution in the Japanese Archipelago.
Minimal phenotyping yields GWAS hits of reduced specificity for major depression
Authors: Cai Na , Revez Joana A. , Adams Mark J , Andlauer Till F. M. , Breen Gerome , Byrne Edna M. , Clarke Toni-Kim , Forstner Andreas J. , Grabe Hans J. , Hamilton Steven P. , Levinson Douglas F. , Lewis Cathryn M. , Lewis Glyn , Martin Nicholas G. , Milaneschi Yuri , Mors Ole , Müller-Myhsok Bertram , Pennix Brenda W. J. H. , Perlis Roy H. , Pistis Giorgio , Potash James B. , Preisig Martin , Shi Jianxin , Smoller Jordan W. , Streit Fabien , Tiemeier Henning , Uher Rudolf , Van der Auwera Sandra , Viktorin Alexander , Weissman Myrna M. ,   MDD Working Group of the Psychiatric Genomics Consortium, Kendler Kenneth S. , Flint Jonathan
Published: October 2018

Minimal phenotyping refers to the reliance on the use of a small number of self-report items for disease case identification. This strategy has been applied to genome-wide association studies (GWAS) of major depressive disorder (MDD). Here we report that the genotype derived heritability (h2SNP) of depression defined by minimal phenotyping (14%, SE = 0.8%) is lower than strictly defined MDD (26%, SE = 2.2%). This cannot be explained by differences in prevalence between definitions or including cases of lower liability to MDD in minimal phenotyping definitions of depression, but can be explained by misdiagnosis of those without depression or with related conditions as cases of depression. Depression defined by minimal phenotyping is as genetically correlated with strictly defined MDD (rG = 0.81, SE = 0.03) as it is with the personality trait neuroticism (rG = 0.84, SE = 0.05), a trait not defined by the cardinal symptoms of depression. While they both show similar shared genetic liability with neuroticism, a greater proportion of the genome contributes to the minimal phenotyping definitions of depression (80.2%, SE = 0.6%) than to strictly defined MDD (65.8%, SE = 0.6%). We find that GWAS loci identified in minimal phenotyping definitions of depression are not specific to MDD: they also predispose to other psychiatric conditions. Finally, while highly predictive polygenic risk scores can be generated from minimal phenotyping definitions of MDD, the predictive power can be explained entirely by the sample size used to generate the polygenic risk score, rather than specificity for MDD. Our results reveal that genetic analysis of minimal phenotyping definitions of depression identifies non-specific genetic factors shared between MDD and other psychiatric conditions. Reliance on results from minimal phenotyping for MDD may thus bias views of the genetic architecture of MDD and may impede our ability to identify pathways specific to MDD.
Decreased kinesin-1 mitigates NMDA-induced exicitotoxicity and ischemia-evoked neurodegeneration
Authors: Lin Raozhou , Duan Zhigang , Sun Haitao , Fung Man-Lung , Chen Hansen , Wang Jing , Lau Chi-Fai , Yang Di , Liu Yu , Ni Yanxiang , Wang Zai , Cui Ju , Wu Wutian , Yung Wing-Ho , Chan Ying-Shing , Lo Amy C. Y. , Xia Jun , Shen Jiangang , Huang Jian-Dong
Published: October 2018

N-methyl-D-aspartate receptor (NMDAR) is highly compartmentalized in neurons and the dysfunction has been implicated in various neuropsychiatric and neurodegenerative disorders. Recent failure to exploit NMDAR antagonization as a potential therapeutic target has driven the need to identify molecular mechanisms that regulate NMDAR compartmentalization. Here, we report that neural activity-dependent reduction of Kif5b, the heavy chain of kinesin-1, protected neurons against NMDA-induced excitotoxicity and ischemia-provoked neurodegeneration. Direct binding of Kinesin-1 to the GluN2B cytoplasmic tails regulated levels of NMDAR at extrasynaptic sites and the subsequent influx of calcium mediated by extrasynaptic NMDAR via regulating the insertion of NMDARs into neuronal surface. Transient increase of Kif5b restored the surface levels of NMDAR and the decreased neuronal susceptibility to NMDA-induced excitotoxicity. Our findings reveal that kinesin-1 regulates extrasynaptic NMDAR targeting and signaling, and the reduction of kinesin-1 could be regulated by neural activity and could be exploited to postpone or halt neurodegeneration.
Aminoacyl tRNA Synthetases as Malarial Drug Targets: A Comparative Bioinformatics Study
Authors: Wavinya Nyamai Dorothy , Tastan Bishop Özlem
Published: October 2018

Treatment of parasitic diseases has been challenging due to the development of drug resistance by parasites, and thus there is need to identify new class of drugs and drug targets. Protein translation is important for survival of plasmodium and the pathway is present in all the life cycle stages of the plasmodium parasite. Aminoacyl tRNA synthetases are primary enzymes in protein translation as they catalyse the first reaction where an amino acid is added to the cognate tRNA. Currently, there is limited research on comparative studies of aminoacyl tRNA synthetases as potential drug targets. The aim of this study is to understand differences between plasmodium and human aminoacyl tRNA synthetases through bioinformatics analysis.Plasmodium falciparum,P. fragile,P. vivax,P. ovale,P. knowlesi,P. bergei,P. malariaeand human aminoacyl tRNA synthetase sequences were retrieved from UniProt database and grouped into 20 families based on amino acid specificity. Despite functional and structural conservation, multiple sequence analysis, motif discovery, pairwise sequence identity calculations and molecular phylogenetic analysis showed striking differences between parasite and human proteins. Prediction of alternate binding sites revealed potential druggable sites in PfArgRS, PfMetRS and PfProRS at regions that were weakly conserved when compared to the human homologues. These differences provide a basis for further exploration of plasmodium aminoacyl tRNA synthetases as potential drug targets.
Phylogenomics of the major tropical plant family Annonaceae using targeted enrichment of nuclear genes
Authors: Couvreur Thomas L.P. , Helmstetter Andrew J. , Koenen Erik J.M. , Bethune Kevin , Brandão Rita D. , Little Stefan , Sauquet Hervé , Erkens Roy H.J.
Published: October 2018

Targeted enrichment and sequencing of hundreds of nuclear loci for phylogenetic reconstruction is becoming an important tool for plant systematics and evolution. Annonaceae is a major pantropical plant family with 109 genera and ca. 2450 species, occurring across all major and minor tropical forests of the world. Baits were designed by sequencing the transcriptomes of five species from two of the largest Annonaceae subfamilies. Orthologous loci were identified. The resulting baiting kit was used to reconstruct phylogenetic relationships at two different levels using concatenated and gene tree approaches: a family wide Annonaceae analysis sampling 65 genera and a species level analysis of tribe Piptostigmateae sampling 29 species with multiple individuals per species. DNA extraction was undertaken mainly on silicagel dried leaves, with two samples from herbarium dried leaves. Our kit targets 469 exons (364 653 bp of sequence data), successfully capturing sequences from across Annonaceae. Silicagel dried and herbarium DNA worked eaually well. We present for the first time a nuclear gene-based phylogenetic tree at the generic level based on 317 supercontigs. Results mainly confirm previous chloroplast based studies. However, several new relationships are found and discussed. We show significant differences in branch lengths between the two large subfamilies Annonoideae and Malmeoideae. A new tribe, Annickieae, is erected containing a single African genus Annickia. We also reconstructed a well resolved species-level phylogenetic tree of the Piptostigmteae tribe. Our baiting kit is useful for reconstructing well supported phylogenetic relationships within Annonaceae at different taxonomic levels. The nuclear genome is mainly concordant with plastome information with a few exceptions. Moreover, we find that substitution rate heterogeneity between the two subfamilies is also found within the nuclear compartment, and not just plastomes and ribosomal DNA as previously shown. Our results have implications for understanding the biogeography, molecular dating and evolution of Annonaceae.
The HexMaze: A previous knowledge and schema task for mice
Authors: Alonso Alejandra , Bokeria Levan , van der Meij Jacqueline , Samanta Anumita , Eichler Ronny , Spooner Patrick , Lobato Irene Navarro , Genzel Lisa
Published: October 2018

New information is rarely learned in isolation, instead most of what we experience can be incorporated into or uses previous knowledge networks in some form. However, most rodent laboratory tasks assume the animal to be naïve with no previous experience influencing the results. Previous knowledge in form of a schema can facilitate knowledge acquisition and accelerate systems consolidation: memories become more rapidly hippocampal independent and instead rely more on the prefrontal cortex. Here, we developed a new spatial navigation task where food locations are learned in a large, gangway maze – the HexMaze. Analysing performance across sessions as well as on specific trials, we can show simple memory effects as well as multiple effects of previous knowledge accelerating both online learning and performance increases over offline periods. Importantly, we are the first to show that schema build-up is dependent on how much time passes, not how often the animal is trained.
Galvanic corrosion susceptibility between X53CrMnNiN219 and X45CrSi93 stainless steels in chloride solution using electrochemical measurements
Authors: Shahriyari Zahra , Gheisari Khalilollah
Published: October 2018

Purpose

In this study, corrosion behavior of X53CrMnNiN219 austenitic stainless steel (SS) and X45CrSi93 martensitic SS, as well as the galvanic corrosion produced by coupling of these dissimilar alloys, are evaluated in a 3.5 Wt.% NaCl solution at temperature 25°C ± 1°C.

Design/methodology/approach

The corrosion parameters were estimated through a series of electrochemical tests, including Tafel polarization, electrochemical impedance spectroscopy (EIS), and zero-resistance ammeter (ZRA) technique.

Findings

The results of polarization measurements indicate that the value of corrosion current in the galvanic pair is slightly higher than that of both the austenitic and martensitic SS during the initial time of immersion in the chloride solution, which is an indication of compatibility of members in the couple. The galvanic current density measured by ZRA technique shows negative values throughout the test; accordingly, the martensitic SS acts as anode of the pair and corrodes preferentially. Localization index values are limited to the mixed corrosion process, showing relative susceptibility of the martensitic alloy to the uniform and localized corrosion (pitting) due to chloride ions.

Originality/value

The originality is the evaluation of galvanic corrosion susceptibility of X53CrMnNiN219 and X45CrSi93 SSs in chloride solution by the various electrochemical methods consisting of Tafel polarization, EIS, and (ZRA) technique. To our knowledge, no work has been reported on this issue for these chemical compositions under this condition up to now.
Maximum lift/drag ratio improvement of TUAVs via small aerodynamic modifications
Authors: Oktay Tugrul , Uzun Metin , Kanat Ozturk Ozdemir
Published: October 2018

Purpose

The purpose of this study is to increase maximum lift/drag ratio (Emax) of tactical unmanned aerial vehicles (TUAVs) via applying novel small aerodynamic modifications.

Design methodology/approach

A TUAV is manufactured in Erciyes University, Faculty of Aeronautics and Astronautics, Model Aircraft Laboratory. It has both passive and active morphing capabilities. Its nosecone and tailcone shapes are redesigned to improve Emax. Moreover, active flow control is also built on its wing for improving Emax.

Findings

Using these novel small aerodynamic modifications, considerable improvement on Emax is obtained.

Research limitations/implications

Permission of Directorate General of Civil Aviation in Turkey is required for testing TUAVs in real-time applications.

Practical implications

Small aerodynamic modifications such as nosecone-tailcone shape modifications and building active flow control on wing are very beneficial for improving Emax of TUAVs.

Social implications

Small aerodynamic modifications satisfy confidence, high performance and easy utility demands of TUAV users.

Originality/value

The study will enable the creation of novel approaches to improve Emax value and therefore aerodynamic performance of TUAVs.
Evaluating the effectiveness of information retrieval systems using effort-based relevance judgment
Authors: Rajagopal Prabha , Ravana Sri Devi , Koh Yun Sing , Balakrishnan Vimala
Published: October 2018

Purpose

The effort in addition to relevance is a major factor for satisfaction and utility of the document to the actual user. The purpose of this paper is to propose a method in generating relevance judgments that incorporate effort without human judges’ involvement. Then the study determines the variation in system rankings due to low effort relevance judgment in evaluating retrieval systems at different depth of evaluation.

Design/methodology/approach

Effort-based relevance judgments are generated using a proposed boxplot approach for simple document features, HTML features and readability features. The boxplot approach is a simple yet repeatable approach in classifying documents’ effort while ensuring outlier scores do not skew the grading of the entire set of documents.

Findings

The retrieval systems evaluation using low effort relevance judgments has a stronger influence on shallow depth of evaluation compared to deeper depth. It is proved that difference in the system rankings is due to low effort documents and not the number of relevant documents.

Originality/value

Hence, it is crucial to evaluate retrieval systems at shallow depth using low effort relevance judgments.