bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intact RNA structurome reveals mRNA structure-mediated regulation of miRNA cleavagein vivo
Authors: Yang Minglei , Woolfenden Hugh C. , Zhang Yueying , Fang Xiaofeng , Liu Qi , Vigh Maria Louisa , Cheema Jitender , Yang Xiaofei , Norris Matthew , Yu Sha , Carbonell Alberto , Brodersen Peter , Wang Jiawei , Ding Yiliang 
Published: December 2019

ABSTRACTMicroRNA (miRNA)-mediated cleavage is involved in numerous essential cellular pathways. miRNAs recognize target RNAs via sequence complementarity. In addition to complementarity,in vitroandin silicostudies have suggested that RNA structure may influence the accessibility of mRNAs to miRNA-Induced Silencing Complexes (miRISCs), thereby affecting RNA silencing. However, the regulatory mechanism of mRNA structure in miRNA cleavage remains elusive. Here, we investigated the role ofin vivoRNA secondary structure in miRNA cleavage by developing the new CAP-STRUCTURE-seq method to capture the intact mRNA structurome inArabidopsis thaliana. This approach revealed that miRNA target sites were not structurally accessible for miRISC binding prior to cleavagein vivo. Instead, the unfolding of the target site structure is the primary determinant for miRISC activityin vivo. Notably, we found that the single-strandedness of the two nucleotides immediately downstream of the target site, named Target Adjacent structure Motif (TAM), can promote miRNA cleavage but not miRNA binding, thus decoupling target site binding from cleavage. Our findings demonstrate that mRNA structurein vivocan regulate miRNA cleavage, providing evidence of mRNA structure-dependent regulation of biological processes.
Prioritization of enhancer mutations by combining allele-specific chromatin accessibility with deep learning
Authors: Atak Zeynep Kalender , Taskiran Ibrahim Ihsan , Flerin Christopher , Mauduit David , Minnoye Liesbeth , Hulsemans Gert , Christiaens Valerie , Ghanem Ghanem-Elias , Wouters Jasper , Aerts Stein 
Published: December 2019

Brief AbstractPrioritization of non-coding genome variation benefits from explainable AI to predict and interpret the impact of a mutation on gene regulation. Here we apply a specialized deep learning model to phased melanoma genomes and identify functional enhancer mutations with allelic imbalance of chromatin accessibility and gene expression.
Parental effects via glyphosate-based herbicides in a bird model?
Authors: Ruuskanen Suvi , Rainio Miia , Uusitalo Maiju , Saikkonen Kari , Helander Marjo 
Published: December 2019

AbstractControversial glyphosate-based herbicides (GBHs) are the most frequently used herbicides across the globe. In an increasing number of studies, researchers have identified GBH residues in soil, water, crops, and food products exposing non-target organisms to health risks; these organisms include wildlife, livestock, and humans. However, GBH-related parental effects are poorly understood. In the case of birds, GBHs may be transferred directly from mother to developing offspring (i.e. direct effects) via eggs, or they may indirectly influence offspring performance by altered maternal condition or resource allocation to eggs, for example. We experimentally exposed a parental generation of Japanese quails (Coturnix japonica) to GBHs or respective controls, recorded egg quality and glyphosate residues in eggs, and studied embryonic development and oxidative biomarkers. Glyphosate accumulated in eggs (ca 0.76 kg/mg). Embryonic development tended to be lower in eggs of GBH-exposed parents compared to control parents. Embryonic brain tissue from GBH-exposed parents tended to express more lipid damage. Given that we detected no differences in egg quality (egg, yolk, or shell mass, or egg hormone concentration) across the treatment groups, our results suggest these are likely direct effects of GBHs on offspring rather than indirect effects via altered maternal allocation of resources or hormonal signals.CapsuleExperimental, long-term parental exposure to GBHs tends to hinder offspring embryonic development and increase embryonic oxidative damage to lipids in a bird model.
Towards a digital diatom: image processing and deep learning analysis ofBacillaria paradoxadynamic morphology
Authors: Alicea Bradly , Gordon Richard , Harbich Thomas , Singh Ujjwal , Singh Asmit , Varma Vinay 
Published: December 2019

AbstractRecent years have witnessed a convergence of data and methods that allow us to approximate the shape, size, and functional attributes of biological organisms. This is not only limited to traditional model species: given the ability to culture and visualize a specific organism, we can capture both its structural and functional attributes. We present a quantitative model for the colonial diatomBacillaria paradoxa, an organism that presents a number of unique attributes in terms of form and function. To acquire a digital model ofB. paradoxa, we extract a series of quantitative parameters from microscopy videos from both primary and secondary sources. These data are then analyzed using a variety of techniques, including two rival deep learning approaches. We provide an overview of neural networks for non-specialists as well as present a series of analysis onBacillariaphenotype data. The application of deep learning networks allows for two analytical purposes. Application of the DeepLabv3 pre-trained model extracts phenotypic parameters describing the shape of cells constitutingBacillariacolonies. Application of a semantic model trained on nematode embryogenesis data (OpenDevoCell) provides a means to analyze masked images of potential intracellular features. We also advance the analysis ofBacillariacolony movement dynamics by using templating techniques and biomechanical analysis to better understand the movement of individual cells relative to an entire colony. The broader implications of these results are presented, with an eye towards future applications to both hypothesis-driven studies and theoretical advancements in understanding the dynamic morphology ofBacillaria.
Chromosome-level quality scaffolding of brown algal genomes using InstaGRAAL, a proximity ligation-based scaffolder
Authors: Baudry Lyam , Marbouty Martial , Marie-Nelly Hervé , Cormier Alexandre , Guiglielmoni Nadège , Avia Komlan , Mie Yann Loe , Godfroy Olivier , Sterck Lieven , Cock J. Mark , Zimmer Christophe , Coelho Susana M. , Koszul Romain 
Published: December 2019

ABSTRACTHi-C has become a popular technique in recent genome assembly projects. Hi-C exploits contact frequencies between pairs of loci to bridge and order contigs in draft genomes, resulting in chromosome-level assemblies. However, application of this approach is currently hampered by a lack of robust programs that are capable of effectively treating this type of data, particularly open source programs. We developed instaGRAAL, a complete overhaul of the GRAAL program, which has adapted the latter to allow efficient assembly of large genomes. Both GRAAL, and instaGRAAL use a Markov Chain Monte Carlo algorithm to perform Hi-C scaffolding, but instaGRAAL features a number of improvements including a modular polishing approach that optionally integrates independent data. To validate the program, we used it to generate chromosome-level assemblies for two brown algae, Desmarestia herbacea and the model Ectocarpus sp., and quantified improvements compared to the initial draft for the latter. Overall, instaGRAAL is a program able to generate, using default parameters with minimal human intervention, near-complete assemblies.
MRI tracking reveals selective accumulation of stem cell-derived magneto-extracellular vesicles in sites of injury
Authors: Han Zheng , Liu Senquan , Pei Yigang , Ding Zheng , Li Yuguo , Weiss Robert G. , van Zijl Peter C.M. , Bulte Jeff W.M. , Cheng Linzhao , Liu Guanshu 
Published: December 2019

AbstractHuman stem-cell-derived extracellular vesicles (EVs) are currently being investigated for cell-free therapy in regenerative medicine applications, but their biodistribution and tropic properties for homing to injured tissues are largely unknown. Here, we labeled EVs with magnetic nanoparticles to create magneto-EVs that can be tracked by magnetic resonance imaging (MRI). Superparamagnetic iron oxide (SPIO) nanoparticles were coated with polyhistidine tags, which enabled purification of labeled EVs by efficiently removing unencapsulated SPIO particles in the solution. The biodistribution of systemically injected human induced pluripotent stem cell (iPSC)-derived magneto-EV was assessed in three different animal models of kidney injury and myocardial ischemia. Magneto-EVs were found to selectively home to the injury sites and conferred substantial protection in a kidney injury model.In vivoMRI tracking of magnetically labeled EVs represents a new powerful method to assess and quantify their whole-body distribution, which may help optimize further development of EV-based cell-free therapy.
Inhibiting xCT/SLC7A11 induces ferroptosis of myofibroblastic hepatic stellate cells and protects against liver fibrosis
Authors: Du Kuo , Oh Seh Hoon , Sun Tianai , Yang Wen-Hsuan , Chi Jen-Tsan Ashley , Diehl Anna Mae 
Published: December 2019

AbstractBackground and AimsLiver fibrosis develops in the context of excessive oxidative stress, cell death and accumulation of myofibroblasts (MFs) derived from hepatic stellate cells (HSCs). Ferroptosis is a type of regulated cell death that can be caused by inhibiting the cystine/glutamate antiporter xCT. However, while xCT is induced in various liver diseases, its role in HSC activation and liver fibrosis is unknown. We hypothesized that xCT is required for HSCs to antagonize ferroptosis and remain myofibroblastic.MethodsxCT activity was disrupted by siRNA or pharmacological inhibitors in MF-HSC cell lines to determine its effect on redox homeostasis, growth, myofibroblastic activity and viability. xCT expression was then determined by RNA sequencing and RT-PCR during primary HSC activation, and its role in HSC trans-differentiation was assessed. For comparison, xCT expression and function were also determined in primary hepatocytes. Finally, the roles of xCT in HSC accumulation and liver fibrosis were assessed in mice treated acutely with CCl4.ResultsInhibiting xCT in MF-HSCs decreased intracellular glutathione (GSH), suppressed growth and fibrogenesis, and induced cell death. These effects were rescued by antioxidants, an iron chelator, and a canonical ferroptosis inhibitor, but not by inhibitors of apoptosis or necrosis. xCT was dramatically up-regulated during primary HSC activation, and inhibiting xCT suppressed myofibroblastic trans-differentiation and induced ferroptosis. In contrast, healthy hepatocytes were relatively insensitive to ferroptosis induced by xCT inhibition. In vivo, inhibiting xCT systemically reduced MF-HSC accumulation and liver fibrosis after a single dose of CCl4 without exacerbating liver injury or reducing hepatocyte regeneration.ConclusionCompared to healthy hepatocytes, MF-HSCs are exquisitely sensitive to ferroptosis induced by inhibiting xCT. In acutely injured livers, systemic inhibitors of xCT can inhibit fibrosis without worsening liver injury. Further research is needed to determine if this therapeutic window remains sufficiently robust to safely target MF-HSCs and inhibit fibrogenesis in chronically injured liver.
Phylogenomics supports a Cenozoic rediversification of the “living fossil” Isoetes
Authors: Wood Daniel , Besnard Guillaume , Beerling David J. , Osborne Colin P. , Christin Pascal-Antoine 
Published: December 2019

AbstractThe fossil record provides an invaluable insight into the temporal origins of extant lineages of organisms. However, establishing the relationships between fossils and extant lineages can be difficult in groups with low rates of morphological change over time. Molecular dating can potentially circumvent this issue by allowing distant fossils to act as calibration points, but rate variation across large evolutionary scales can bias such analyses. In this study, we apply multiple dating methods to genome-wide datasets to infer the origin of extant species of Isoetes, a group of mostly aquatic and semi-aquatic isoetalean lycopsids, which closely resemble fossil forms dating back to the Triassic. Rate variation observed in chloroplast genomes hampers accurate dating, but genome-wide nuclear markers place the origin of extant diversity within this group in the mid-Paleogene, 45-60 million years ago. Our genomic analyses coupled with a careful evaluation of the fossil record indicate that despite resembling forms from the Triassic, extant Isoetes species do not represent the remnants of an ancient and widespread group, but instead have spread around the globe in the relatively recent past.
Leptin signaling and the intervertebral disc: Sex dependent effects of leptin receptor deficiency and Western diet on the spine in a type 2 diabetes mouse model
Authors: Natelson Devorah M. , Lai Alon , Krishnamoorthy Divya , Hoy Rob C. , Iatridis James C. , Illien-Jünger Svenja 
Published: December 2019

AbstractType 2 diabetes and obesity are associated with back pain in juveniles and adults and are implicated in intervertebral disc (IVD) degeneration. Hypercaloric Western diets are associated with both obesity and type 2 diabetes. The objective of this study was to determine if obesity and type 2 diabetes result in spinal pathology in a sex-specific manner usingin vivodiabetic and dietary mouse models. Leptin is an appetite-regulating hormone, and its deficiency leads to polyphagia, resulting in obesity and diabetes. Leptin is also associated with IVD degeneration, and increased expression of its receptor was identified in degenerated IVDs. We used young, leptin receptor deficient (Db/Db) mice to mimic the effect of diet and diabetes on adolescents. Db/Db and Control mice were fed either Western or Control diets, and were sacrificed at 3 months of age. Db/Db mice were obese, while only female mice developed diabetes. Female Db/Db mice displayed altered IVD morphology, with increased intradiscal notochordal band area, suggesting delayed IVD cell proliferation and differentiation, rather than IVD degeneration. Motion segments from Db/Db mice exhibited increased failure risk with decreased torsional failure strength. Db/Db mice also had inferior bone quality, which was most prominent in females. We conclude that obesity and diabetes due to impaired leptin signaling contribute to pathological changes in vertebrae, as well as an immature IVD phenotype, particularly of females, suggesting a sex-dependent role of leptin in the spine.
Environmental unpredictability shapes glucocorticoid regulation across populations of tree swallows
Authors: Zimmer Cedric , Taff Conor C. , Ardia Daniel R. , Rose Alexandra P. , Aborn David A. , Johnson L. Scott , Vitousek Maren N. 
Published: December 2019

AbstractResponding appropriately to challenges is an important contributor to fitness. Variation in the regulation of glucocorticoid hormones, which mediate the phenotypic response to challenges, can therefore influence the ability to persist in a given environment. We compared stress responsiveness in four populations of tree swallows (Tachycineta bicolor) along an environmental gradient to evaluate support for different selective pressures in driving the evolution of glucocorticoid regulation. In accordance with the environmental unpredictability hypothesis, stronger stress responses were seen in more unpredictable environments. Contrary to the reproductive value hypothesis, the stress response was not lower in populations engaging in more valuable reproductive attempts. Populations with stronger stress responses also had stronger negative feedback, which supports a “mitigating” rather than a “magnifying” effect of negative feedback on stress responses. These results suggest that combining a robust stress response with strong negative feedback may be important for persisting in unpredictable or rapidly changing environments.
TandemMapper and TandemQUAST: mapping long reads and assessing/improving assembly quality in extra-long tandem repeats
Authors: Mikheenko Alla , Bzikadze Andrey V. , Gurevich Alexey , Miga Karen H. , Pevzner Pavel A. 
Published: December 2019

AbstractExtra-long tandem repeats (ETRs) are widespread in eukaryotic genomes and play an important role in fundamental cellular processes, such as chromosome segregation. Although emerging long-read technologies have enabled ETR assemblies, the accuracy of such assemblies is difficult to evaluate since there is no standard tool for their quality assessment. Moreover, since the mapping of long error-prone reads to ETR remains an open problem, it is not clear how to polish draft ETR assemblies. To address these problems, we developed the tandemMapper tool for mapping reads to ETRs and the tandemQUAST tool for polishing ETR assemblies and their quality assessment. We demonstrate that tandemQUAST not only reveals errors in and evaluates ETR assemblies, but also improves them. To illustrate how tandemMapper and tandemQUAST work, we apply them to recently generated assemblies of human centromeres.
TrkB agonists prevent post-ischemic BDNF-TrkB mediated emergence of refractory neonatal seizures in CD-1 pups
Authors: Kipnis P.A. , Sullivan B.J. , Carter B.M. , Kadam S.D. 
Published: December 2019

AbstractRefractory neonatal seizures do not respond to first-line anti-seizure medications (ASMs) like phenobarbital (PB), a positive allosteric modulator for GABAA receptors, the most widely used ASM to treat neonatal seizures. GABAA receptor-mediated inhibition is dependent upon neuronal chloride regulation. The electroneutral cation-chloride transporter KCC2 mediates neuronal chloride extrusion; an age-dependent increase of KCC2 expression enables the shift of GABAergic signaling from depolarizing to hyperpolarizing. BDNF-TrkB activation following excitotoxic injury recruits downstream targets like PLCγ1, leading to KCC2 hypofunction. This study investigated the efficacy of partial and full TrkB agonists; LM22A-4 (LM), HIOC and Deoxygedunin (DG) respectively, on PB-refractory seizures, post-ischemic TrkB-pathway activation, and KCC2 membrane stability in a P7 CD-1 mouse model of refractory neonatal seizures. Anti-seizure efficacy was determined by quantifying seizure burdens with continuous video-EEG. LM rescued PB-refractory seizures in a sexually dimorphic manner. LM anti-seizure efficacy was associated with a significant reduction in the post-ischemic phosphorylation of TrkB at Y816, a site known to mediate post-ischemic KCC2 hypofunction via PLCγ1 activation. LM additionally rescued ischemia-induced pKCC2-S940 dephosphorylation preserving its membrane stability. HIOC and DG, two novel full TrkB agonists, also rescued PB-refractoriness and post-ischemic TrkB-PLCγ1 pathway activation. Additionally, chemogenetic inactivation of TrkB significantly reduced post-ischemic neonatal seizure burdens at P7. Developmental expression profiles of TrkB and KCC2 in naïve pups identified developmental differences that may underlie the sex-dependent variance in anti-seizure efficacy. These results support a novel role for the TrkB receptor in the emergence of age-dependent refractory neonatal seizures.
Evolutionary rescue and drug resistance on multicopy plasmids
Authors: Santer Mario , Uecker Hildegard 
Published: December 2019

AbstractBacteria often carry “extra DNA” in form of plasmids in addition to their chromosome. Many plasmids have a copy number greater than one such that the genes encoded on these plasmids are present in multiple copies per cell. This has evolutionary consequences by increasing the mutational target size, by prompting the (transitory) co-occurrence of mutant and wild-type alleles within the same cell, and by allowing for gene dosage effects. We develop and analyze a mathematical model for bacterial adaptation to harsh environmental change if adaptation is driven by beneficial alleles on multicopy plasmids. Successful adaptation depends on the availability of advantageous alleles and on their establishment probability. The establishment process involves the segregation of mutant and wild-type plasmids to the two daughter cells, allowing for the emergence of mutant-homozygous cells over the course of several generations. To model this process, we use the theory of multi-type branching processes, where a type is defined by the genetic composition of the cell. Both factors – the number of adaptive alleles and their establishment probability – depend on the plasmid copy number, and they often do so antagonistically. We find that in the interplay of various effects, a lower or higher copy number may maximize the probability of evolutionary rescue. The decisive factor is the dominance relationship between mutant and wild-type plasmids and potential gene dosage effects. Results from a simple model of antibiotic degradation indicate that the optimal plasmid copy number may depend on the specific environment encountered by the population.
Medicago truncatula Yellow Stripe1-Like3gene is involved in symbiotic nitrogen fixation
Authors: Castro-Rodríguez Rosario , Abreu Isidro , Reguera María , Novoa-Aponte Lorena , Mijovilovich Ana , Jiménez-Pastor Francisco J. , Abadía Javier , Wen Jiangqi , Mysore Kirankumar S. , Álvarez-Fernández Ana , Küpper Hendrik , Imperial Juan , González-Guerrero Manuel 
Published: December 2019

AbstractSymbiotic nitrogen fixation carried out in legume root nodules requires transition metals. These nutrients are delivered by the host plant to the endosymbiotic nitrogen-fixing bacteria living with the nodule cells, a process in which vascular transport is essential. As occurs in root-to-shoot transport, members of the Yellow Stripe-Like (YSL) family of metal transporters should also be required for root-to-nodule metal delivery. The genome of the model legumeMedicago truncatulaencodes for eight YSL proteins, four of them with a high degree of similarity toArabidopsis thalianaYSLs involved in long-distance metal trafficking. Among them, MtYSL3 is a plasma membrane protein expressed by vascular cells in roots and nodules, and by cortical nodule cells. Reducing expression levels of this gene had no major effect on plant physiology when assimilable nitrogen was provided in the nutrient solution. However, nodule functioning was severely impaired, with a significant reduction of nitrogen fixation capabilities. Further, iron and zinc accumulation and distribution changed. Iron was retained in the apical region of the nodule, while zinc became strongly accumulated in the nodule veins in theysl3mutant. These data suggest a role of MtYSL3 in vascular delivery of iron and zinc to symbiotic nitrogen fixation.HighlightMedicago truncatulaYSL3 transporter is required for optimal nitrogen fixation in root nodules, mediating iron and zinc distribution in these organs.
An RNA degradation complex required for silencing of Polycomb target genes
Authors: Zhou Haining , Shipkovenska Gergana , Kalocsay Marian , Zhang Jiuchun , Luo Zhenhua , Gygi Steven P. , Moazed Danesh 
Published: December 2019

AbstractPolycomb Repressive Complex (PRC) 1 and 2 are histone-modifying and chromatin-binding complexes that are required for silencing of developmental regulatory genes and genes that control cellular proliferation. Their gene silencing functions are thought to involve chromatin compaction and condensate formation but whether other mechanisms contribute to silencing is unknown. Here we show that the rixosome, a conserved RNA degradation complex with roles in ribosomal RNA processing and heterochromatic RNA degradation in fission yeast, associates with human PRC complexes, is recruited to promoters of Polycomb target genes in differentiated cell lines and embryonic stem cells, and is required for efficient silencing of Polycomb target genes. These findings reveal an unanticipated role for RNA degradation in Polycomb-mediated silencing.