bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enabling multiscale variation analysis with genome graphs
Authors: Letcher Brice , Hunt Martin , Iqbal Zamin 
Published: February 2021

AbstractBackgroundStandard approaches to characterising genetic variation revolve around mapping reads to a reference genome and describing variants in terms of differences from the reference; this is based on the assumption that these differences will be small and provides a simple coordinate system. However this fails, and the coordinates break down, when there are diverged haplotypes at a locus (e.g. one haplotype contains a multi-kilobase deletion, a second contains a few SNPs, and a third is highly diverged with hundreds of SNPs). To handle these, we need to model genetic variation that occurs at different length-scales (SNPs to large structural variants) and that occurs on alternate backgrounds. We refer to these together as multiscale variation.ResultsWe model the genome as a directed acyclic graph consisting of successive hierarchical subgraphs (“sites”) that naturally incorporate multiscale variation, and introduce an algorithm for genotyping, implemented in the softwaregramtools. This enables variant calling on different sequence backgrounds. In addition to producing regular VCF files, we introduce a JSON file format based on VCF, which records variant site relationships and alternate sequence backgrounds.We show two applications. First, we benchmark gramtools against existing state-of-the-art methods in joint-genotyping17 M. tuberculosissamples at long deletions and the overlapping small variants that segregate in a cohort of 1,017 genomes. Second, in 706 African and SE AsianP. falciparumgenomes, we analyse a dimorphic surface antigen gene which possesses variation on two diverged backgrounds which appeared to not recombine. This generates the first map of variation on both backgrounds, revealing patterns of recombination that were previously unknown.ConclusionsWe need new approaches to be able to jointly analyse SNP and structural variation in cohorts, and even more to handle variants on different genetic backgrounds. We have demonstrated that by modelling with a directed, acyclic and locally hierarchical genome graph, we can apply new algorithms to accurately genotype dense variation at multiple scales. We also propose a generalisation of VCF for accessing multiscale variation in genome graphs, which we hope will be of wide utility.
DNA damage and somatic mutations in mammalian cells after irradiation with a nail polish dryer
Authors: Zhivagui Maria , Hoda Areebah , Valenzuela Noelia , Yeh Yi-Yu , Dai Jason , He Yudou , Nandi Shuvro P. , Otlu Burcak , Van Houten Bennett , Alexandrov Ludmil B. 
Published: February 2021

ABSTRACTUltraviolet A light is commonly emitted by UV-nail polish dryers with recent reports suggesting that long-term use may increase the risk for developing skin cancer. However, no experimental evaluation has been conducted to reveal the effect of radiation emitted by UV-nail polish dryers on mammalian cells. Here, we show that irradiation by a UV-nail polish dryer causes high levels of reactive oxygen species, consistent with 8-oxo-7,8-dihydroguanine damage and mitochondrial dysfunction. Analysis of somatic mutations reveals a dose-dependent increase of C:G>A:T substitutions in irradiated samples with mutagenic patterns similar to mutational signatures attributed to reactive oxygen species. In summary, this study demonstrates that radiation emitted by UV-nail polish dryers can both damage DNA and permanently engrave mutations on the genomes of mammalian cells. These results have far-reaching implications in regard to public health and to preventing skin cancer due to consumer-based exposure to ultraviolet light from artificial sources.
Rapid divergence in independent aspects of the compatibility phenotype in the Spiroplasma/Drosophila interaction
Authors: Griffin Joanne S. , Gerth Michael , Hurst Gregory D. D. 
Published: February 2021

AbstractHeritable symbionts represent important components of host biology, both as antagonistic reproductive parasites and as beneficial protective partners. An important component of heritable microbes’ biology is their ability to establish in new host species, a process equivalent to a host shift for an infectiously transmitted parasite or pathogen. For a host shift to occur, the symbiont must be compatible with the host: it must not cause excess pathology, must have good vertical transmission, and possess a drive phenotype that enables spread. Classically, compatibility has been considered a declining function of genetic distance between novel and ancestral host species. Here we investigate the evolutionary lability of compatibility to heritable microbes by comparing the capacity for a symbiont to establish in two novel host species equally related to the ancestral host. Compatibility of the protectiveSpiroplasmafromD. hydeiwithD. simulansandD. melanogasterwas tested. TheSpiroplasmahad contrasting compatibility in these two host species. The transinfection showed pathology and low vertical transmission inD. melanogasterbut was asymptomatic and transmitted with high efficiency inD. simulans. These results were not affected by the presence/absence ofWolbachiain either of the two species. The pattern of protection was not congruent with that for pathology/transmission, with protection being weaker in theD. simulans, the host in whichSpiroplasmawas asymptomatic and transmitted well. Further work indicated pathological interactions occurred inD. sechelliaandD. yakuba, indicating thatD. simulanswas unusual in being able to carry the symbiont without damage. The differing compatibility of the symbiont with these closely related host species emphasises first the rapidity with which host-symbiont compatibility evolves despite compatibility itself not being subject to direct selection, and second the independence of the different components of compatibility (pathology, transmission, protection). This requirement to fit three different independently evolving aspects of compatibility, if commonly observed, is likely to be a major feature limiting the rate of host shifts. Moving forward, the variation between sibling species pairs observed above provides an opportunity to identify the mechanisms behind variable compatibility between closely related host species, which will drive hypotheses as to the evolutionary drivers of compatibility variation.
Exotic bifurcations in three connected populations with Allee effect
Authors: Röst Gergely , Sadeghimanesh AmirHosein 
Published: February 2021

AbstractWe consider three connected populations with strong Allee effect, and give a complete classification of the steady state structure of the system with respect to the Allee threshold and the dispersal rate, describing the bifurcations at each critical point where the number of steady states change. One may expect that by increasing the dispersal rate between the patches, the system would become more well-mixed hence simpler. However, we show that it is not always the case, and the number of steady states may (temporarily) increase by increasing the dispersal rate. Besides sequences of pitchfork and saddle-node bifurcations, we find triple-transcritical bifurcations and also a sun-ray shaped bifurcation where twelve steady states meet at a single point then disappear. The major tool of our investigations is a novel algorithm that decomposes the parameter space with respect to the number of steady states and find the bifurcation values using cylindrical algebraic decomposition with respect to the discriminant variety of the polynomial system.
Oxidant-Resistant LRRC8A/C Anion Channels Support Superoxide Production by Nox1
Authors: Choi Hyehun , Rohrbough Jeffrey , Nguyen Hong N. , Dikalova Anna , Lamb Fred S. 
Published: February 2021

ABSTRACTTumor necrosis factor-α (TNFα) activates NADPH Oxidase 1 (Nox1) in vascular smooth muscle cells (VSMCs), producing superoxide (O2•-) required for subsequent signaling. LRRC8 family proteins A-E comprise volume-regulated anion channels (VRACs). The required subunit LRRC8A physically associates with Nox1, and VRAC activity is required for Nox activity and the inflammatory response to TNFα. LRRC8 channel currents are modulated by oxidants, suggesting that oxidant sensitivity and proximity to Nox1 may play a physiologically relevant role. In VSMCs, LRRC8C knockdown (siRNA) recapitulated the effects of siLRRC8A, inhibiting TNFα-induced extracellular and endosomal O2•-production, receptor endocytosis, NF-κB activation, and proliferation. In contrast, siLRRC8D potentiated NF-κB activation. Nox1 co-immunoprecipitated with 8C and 8D, and co-localized with 8D at the plasma membrane and in vesicles. We compared VRAC currents mediated by homomeric and heteromeric 8C and 8D channels expressed in HEK293 cells. The oxidant chloramine T (ChlorT, 1 mM) weakly inhibited LRRC8C, but potently inhibited 8D currents. ChlorT exposure also greatly reduced subsequent current block by DCPIB, implicating external sites of oxidation. Substitution of the extracellular loop domains (EL1, EL2) of 8D onto 8C conferred significantly stronger ChlorT-dependent inhibition. 8A/C channel activity is thus more effectively maintained in the oxidized microenvironment expected to result from Nox1 activation at the plasma membrane. Increased ratios of 8D:8C expression may potentially depress inflammatory responses to TNFα. LRRC8A/C channel downregulation represents a novel strategy to reduce TNFα-induced inflammation.Key PointsLRRC8A-containing anion channels associate with Nox1 and regulate superoxide production and TNFα signaling. Here we show that .LRRC8C and 8D also co-immunoprecipitate with Nox1 in vascular smooth muscle cells.LRRC8C knockdown inhibited TNFα-induced O2•-production, receptor endocytosis, NF-κB activation, and proliferation while LRRC8D knockdown enhanced NF-κB activation. Significant changes in LRRC8 isoform expression in human atherosclerosis and psoriasis suggest compensation for increased inflammation.The oxidant chloramine-T (ChlorT, 1 mM) weakly (∼25%) inhibited 8C currents but potently (∼80%) inhibited 8D currents. Substitution of the two extracellular loop (EL) domains of 8D onto 8C conferred significantly stronger ChlorT-dependent inhibition.ChlorT also impaired current block by DCPIB, which occurs through interaction with EL1, further implicating external sites of oxidation.8A/C channels most effectively maintain activity in an oxidized microenvironment, as is expected to result from Nox1 activity at the plasma membrane.
Reciprocalspaceship: A Python Library for Crystallographic Data Analysis
Authors: Greisman Jack B. , Dalton Kevin M. , Hekstra Doeke R. 
Published: February 2021

AbstractX-ray crystallography is an invaluable technique for studying the atomic structure of macromolecules. Much of crystallography’s success is due to the software packages developed to enable the automated processing of diffraction data. However, the analysis of unconventional diffraction experiments can still pose significant challenges—many existing programs are closed-source, sparsely documented, or are challenging to integrate with modern libraries for scientific computing and machine learning. Here we describereciprocalspaceship, a Python library for exploring reciprocal space. It provides a tabular representation for reflection data from diffraction experiments that extends the widely-used pandas library with built-in methods for handling space group, unit cell, and symmetry-based operations. As we illustrate, this library facilitates new modes of exploratory data analysis while supporting the prototyping, development, and release of new methods.
Understanding of the 2-oxoglutarate dehydrogenase and 2-oxoadipate dehydrogenase assembly with the E2o core relevant to a hybrid complex formation
Authors: Zhang Xu , Nemeria Natalia S. , Jordan Frank 
Published: February 2021

AbstractThe 2-oxoglutarate (OG) dehydrogenase complex (OGDHc) is a key enzyme in the tricarboxylic acid cycle (TCA) and comprises multiple copies of three components: 2-oxoglutarate dehydrogenase (hE1o), dihydrolipoamide succinyltransferase (hE2o), and dihydrolipoamide dehydrogenase (hE3). The OGDHc is one of the major regulators of mitochondrial metabolism through NADH and reactive oxygen species levels and impacts cell metabolic and cell signaling pathways through the coupling of OG metabolism to gene transcription, related to tumor cell proliferation and aging. The reduced OGDHc activity is linked to a number of neurodegenerative diseases. Evidence was obtained for the formation of a hybrid 2-oxo acid dehydrogenase complex between the OGDHc and its homologue 2-oxoadipate (OA) dehydrogenase (hE1a) in the L-lysine metabolic pathway, suggesting a potential cross-talk between the two distinct metabolic pathways. These findings raised fundamental questions about assembly of hE1a and hE1o to the hE2o core. Due to the lack of an atomic structure of the OGDHc from any sources, and of knowledge about exact distribution of components around the E2 core, hydrogen/deuterium exchange (HDX-MS) and chemical cross-linking mass spectrometry (CL-MS) have been carried out in binary hE1o-hE2o, hE1a-hE2o, hE1o-hE3 and hE2o-hE3 sub-complexes followed by structural modeling. Here we report findings that revealed some similarities in the assembly of hE1o and hE1a to the hE2o core. At the same time, three regions of the hE2o core comprising residues 191-208, 273-288, and 370-386 revealed a different binding mode to hE1o and hE1a, suggesting that hE2o can differentiate between these two proteins that may have physiological consequences.
Pelagic larval polyclads that practice macrophagous carnivory
Authors: von Dassow George , Mendes Cecili 
Published: February 2021

ABSTRACTWe report evidence that hatchling polyclads of several genera feed in the plankton on large prey. These ciliated swimmers, despite apparently lacking means to concentrate food or even detect it at a distance, subdue and consume fast-moving active-swimming plankters such as crustacean larvae and copepods, or molluskan veligers. We describe feeding events in captivity using videomicroscopy, and identify several wild-caught predatory pelagic polyclad larvae to genus or species level by DNA barcoding. Remarkably, one of these types is identified unambiguously with a species previously observed as Müller’s larvae, which live as conventional planktotrophs on an inferred diet of small phytoflagellates. Therefore we conclude first that while so-called “direct-developing” polyclad flatworms may hatch with juvenile-like morphology, at least some of these are functionally larvae. Second, that some species of polyclad have at least a triphasic life cycle, with a first larval stage living in the plankton on primary producers followed by a second larval stage living in the plankton by macrophagous carnivory, before presumably settling to the benthos for adult life.
Glutamatergic dysfunction precedes neuron loss in cerebral organoids withMAPTmutation
Authors: Bowles Kathryn R. , Silva M. Catarina , Whitney Kristen , Bertucci Taylor , Garza Jacob C. , Boles Nathan C. , Strang Kevin H. , Mahali Sidhartha , Marsh Jacob A. , Chen Cynthia , Pugh Derian A. , Liu Yiyuan , Berlind Joshua E. , Lai Jesse D. , Goderie Susan K. , Chowdhury Rebecca , Lotz Steven , Lane Keith , Onanuga Khadijah , Karch Celeste M. , Ichida Justin K. , Crary John F. , Haggarty Stephen J. , Goate Alison M. , Temple Sally 
Published: February 2021

SUMMARYFrontotemporal dementia (FTD) due toMAPTmutation causes pathological accumulation of tau and glutamatergic cortical neuronal death by unknown mechanisms. We used human induced pluripotent stem cell (iPSC)-derived cerebral organoids expressing tau-V337M and isogenic corrected controls to discover early alterations due to the mutation that precede neurodegeneration. At 2 months, mutant organoids show upregulated expression ofMAPT, and glutamatergic signaling pathways and regulators including the RNA-binding proteinELAVL4. Over the following 4 months, mutant organoids accumulate splicing changes, disruption of autophagy function and build-up of tau and P-tau S396. By 6 months, tau-V337M organoids show specific loss of glutamatergic neurons of layers affected in patients. Mutant neurons are susceptible to glutamate toxicity which was rescued pharmacologically by treatment with the PIKFYVE kinase inhibitor apilimod. Our results demonstrate a sequence of events that precede cell death, revealing molecular pathways associated with glutamate signaling as potential targets for therapeutic intervention in FTD.
A high-throughput radioactivity-based assay for screening SARS-CoV-2 nsp10-nsp16 complex
Authors: Yazdi Aliakbar Khalili , Li Fengling , Devkota Kanchan , Perveen Sumera , Ghiabi Pegah , Hajian Taraneh , Bolotokova Albina , Vedadi Masoud 
Published: February 2021

AbstractFrequent outbreaks of novel coronaviruses (CoVs), highlighted by the current SARS-CoV-2 pandemic, necessitate the development of therapeutics that could be easily and effectively administered world-wide. The conserved mRNA-capping process enables CoVs to evade their host immune system and is a target for antiviral development. Nonstructural protein (nsp) 16 in complex with nsp10 catalyzes the final step of coronaviral mRNA-capping through its 2’-O-methylation activity. Like other methyltransferases, SARS-CoV-2 nsp10-nsp16 complex is druggable. However, the availability of an optimized assay for high-throughput screening (HTS) is an unmet need. Here, we report the development of a radioactivity-based assay for methyltransferase activity of nsp10-nsp16 complex in a 384-well format, and kinetic characterization, and optimization of the assay for HTS (Z′-factor: 0.83). Considering the high conservation of nsp16 across known CoV species, the potential inhibitors targeting SARS-CoV-2 nsp10-nsp16 complex may also be effective against other emerging pathogenic CoVs.
RNA polymerase II clusters form in line with liquid phase wetting of chromatin
Authors: Pancholi Agnieszka , Klingberg Tim , Zhang Weichun , Prizak Roshan , Mamontova Irina , Noa Amra , Kobitski Andrei Yu , Nienhaus Gerd Ulrich , Zaburdaev Vasily , Hilbert Lennart 
Published: February 2021

AbstractIt is essential for cells to control which genes are transcribed into RNA. In eukaryotes, two major control points are recruitment of RNA polymerase II (Pol II) into a paused state and subsequent pause release to begin transcript elongation. Pol II associates with macromolecular clusters during recruitment, but it remains unclear how Pol II recruitment and pause release might affect these clusters. Here, we show that clusters exhibit morphologies that are in line with wetting of chromatin by a liquid phase enriched in recruited Pol II. Applying instantaneous structured illumination microscopy and stimulated emission double depletion microscopy to pluripotent zebrafish embryos, we find recruited Pol II associated with large clusters, and elongating Pol II with dispersed clusters. A lattice kinetic Monte Carlo model representing recruited Pol II as a liquid phase reproduced the observed cluster morphologies. In this model, chromatin is a copolymer chain containing regions that attract or repel recruited Pol II, supporting droplet formation by wetting or droplet dispersal, respectively.
Multiple indole glucosinolates and myrosinases defend Arabidopsis againstTetranychus urticaeherbivory
Authors: Widemann Emilie , Bruinsma Kristie , Walshe-Roussel Brendan , Saha Repon Kumer , Letwin David , Zhurov Vladimir , Bernards Mark A. , Grbić Miodrag , Grbić Vojislava 
Published: February 2021

ABSTRACTArabidopsis defenses against herbivores are regulated by the jasmonate hormonal signaling pathway, which leads to the production of a plethora of defense compounds, including tryptophan-derived metabolites produced through CYP79B2/CYP79B3. Jasmonate signaling and CYP79B2/CYP79B3 limit Arabidopsis infestation by the generalist herbivore two-spotted spider mite,Tetranychus urticae. However, the phytochemicals responsible for Arabidopsis protection againstT. urticaeare unknown. Here, using Arabidopsis mutants that disrupt metabolic pathways downstream of CYP79B2/CYP79B3, and synthetic indole glucosinolates, we identified phytochemicals involved in the defense againstT. urticae. We show that Trp-derived metabolites depending on CYP71A12 and CYP71A13 are not affecting mite herbivory. Instead, the supplementation ofcyp79b2 cyp79b3mutant leaves with the 3-indolylmethyl glucosinolate and its derived metabolites demonstrated that the indole glucosinolate pathway is sufficient to assure CYP79B2/CYP79B3-mediated defenses againstT. urticae. We demonstrate that three indole glucosinolates can limitT. urticaeherbivory, but that they have to be processed by the myrosinases to hinderT. urticaeoviposition. Finally, the supplementation of the mutantmyc2 myc3 myc4with indole glucosinolates indicated that the transcription factors MYC2/MYC3/MYC4 induce additional indole glucosinolate-independent defenses that controlT. urticaeherbivory. Together, these results reveal the complexity of Arabidopsis defenses againstT. urticaethat rely on multiple indole glucosinolates, specific myrosinases, and additional MYC2/MYC3/MYC4-dependent defenses.One sentence summaryThree indole glucosinolates and the myrosinases TGG1/TGG2 help protectArabidopsis thalianaagainst the herbivory of the two-spotted spider miteTetranychus urticae.
Natural Selection is Unlikely to Explain Why Species Get a Thin Slice ofπ
Authors: Buffalo Vince 
Published: February 2021

AbstractNeutral theory predicts that genetic diversity increases with population size, yet observed levels of diversity across metazoans vary only two orders of magnitude while population sizes vary over several. This unexpectedly narrow range of diversity is known as Lewontin’s Paradox of Variation (1974). While some have suggested selection constrains diversity, tests of this hypothesis seem to fall short. Here, I revisit Lewontin’s Paradox to assess whether current models of linked selection are capable of reducing diversity to this extent. To quantify the discrepancy between pairwise diversity and census population sizes across species, I combine previously-published estimates of pairwise diversity from 172 metazoan taxa with estimates of census sizes. Using phylogenetic comparative methods, I show this relationship is significant accounting for phylogeny, but with high phylogenetic signal and evidence that some lineages experience shifts in the evolutionary rate of diversity deep in the past. Additionally, I find a negative relationship between recombination map length and census size, suggesting abundant species have less recombination and experience greater reductions in diversity due to linked selection. However, I show that even using strong selection parameter estimates, models of linked selection are unlikely to explain the observed relationship between diversity and census sizes across species.