bluuebunny/crossref_metadata_2025_split huggingface dataset:
Aurora kinase A is essential for meiosis in mouse oocytes
Authors: Blengini Cecilia S. , Ibrahimian Patricia , Vaskovicova Michaela , Drutovic David , Solc Petr , Schindler Karen 
Published: January 2021

AbstractThe Aurora protein kinases are well-established regulators of spindle building and chromosome segregation in mitotic and meiotic cells. In mouse oocytes, there is significant Aurora kinase A (AURKA) compensatory abilities when the other Aurora kinase homologs are deleted. Whether the other homologs, AURKB or AURKC can compensate for loss of AURKA is not known. Using a conditional mouse oocyte knockout model, we demonstrate that this compensation is not reciprocal because female oocyte-specific knockout mice are sterile and their oocytes fail to complete meiosis I. In determining the AURKA-specific functions, we demonstrate that its first meiotic requirement is to activate Polo-like kinase 1 at microtubule organizing centers (MTOCs; meiotic spindle poles). This activation induces fragmentation of the MTOCs, a step essential for building a bipolar spindle. The next step that requires AURKA is building the liquid-like spindle domain that involves TACC3. Finally, we find that AURKA is also required for anaphase I onset to trigger cohesin cleavage in an APC/C independent manner. We conclude that AURKA has multiple functions essential to completing MI that are distinct from AURKB and AURKC.Author SummaryFemale gametes, oocytes, are uniquely prone to chromosome segregation errors in meiosis I that are associated with early miscarriages. The Aurora protein kinases are essential to control chromosome segregation in all cell types. During mitosis, Aurora kinase A (AURKA) regulates the building of the spindle, the machinery responsible for pulling chromosomes apart. Here, we use a genetic approach to demonstrate that AURKA is essential for meiosis I in mouse oocytes. AURKA is required at multiple steps in meiosis I, first to trigger fragmentation of protein structures that make up the two ends of the meiotic spindle, later to regulate building of a specialized phase-separated spindle domain, and finally to trigger efficient cleavage of cohesin, the molecular glue that holds chromosomes together until anaphase onset. These findings are the first demonstration of distinct Aurora kinase function that cannot be compensated for by the other two homologs. Therefore, this mouse model is excellent tool for pinpointing specific Aurora kinase functions and identifying AURKA target proteins critical for chromosome segregation in meiosis I.
Transposable element landscape changes are buffered by RNA silencing in agingDrosophila
Authors: Yang Nachen , Srivastav Satyam P. , Rahman Reazur , Ma Qicheng , Dayama Gargi , Chinen Madoka , Lei Elissa P. , Rosbash Michael , Lau Nelson C. 
Published: January 2021

ABSTRACTGenetic mechanisms that repress transposable elements (TEs) in young animals decline during aging, as reflected by increased TE expression in aged animals. Does increased TE expression during aging lead to more genomic TE copies in older animals? To answer this question, we quantified TE Landscapes (TLs) via whole genome sequencing of young and agedDrosophilastrains of wild-type and mutant backgrounds. We quantified TLs in whole flies and dissected brains and validated the feasibility of our approach in detecting new TE insertions in agingDrosophilagenomes when natural defenses like RNA interference (RNAi) pathways are compromised. By also incorporating droplet digital PCR to validate genomic TE loads, we confirm TL changes can occur in a single lifespan ofDrosophilawhen TEs are not suppressed. We also describe improved sequencing methods to quantify extra-chromosomal DNA circles (eccDNAs) inDrosophilaas an additional source of TE copies that accumulate during aging. Lastly, to combat the natural progression of aging-associated TE expression, we show that knocking downPAF1, a conserved transcription elongation factor that antagonizes RNAi pathways, may bolster suppression of TEs during aging and extend lifespan. Our study suggests that RNAi mechanisms generally mitigate genomic TL expansion despite the increase in TE transcripts during aging.
A 12 kb multi-allelic copy number variation encompassing a GC gene enhancer is associated with mastitis resistance in dairy cattle
Authors: Lee Young-Lim , Takeda Haruko , Moreira Gabriel Costa Monteiro , Karim Latifa , Mullaart Erik , Coppieters Wouter ,   The GplusE consortium, Appeltant Ruth , Veerkamp Roel F. , Groenen Martien A. M. , Georges Michel , Bosse Mirte , Druet Tom , Bouwman Aniek C. , Charlier Carole 
Published: January 2021

AbstractClinical mastitis (CM) is an inflammatory disease occurring in the mammary glands of lactating cows. CM is under genetic control, and a prominent CM resistance QTL located on chromosome 6 was reported in various dairy cattle breeds. Nevertheless, the biological mechanism underpinning this QTL has been lacking. Herein, we mapped, fine-mapped, and discovered the putative causal variant underlying this CM resistance QTL in the Dutch dairy cattle population. We identified a~12 kb multi-allelic copy number variant (CNV), that is in perfect linkage disequilibrium with a GWAS lead SNP, as a promising candidate variant. By implementing a genome-wide association study (GWAS) and through expression QTL mapping, we showed that the group-specific component gene (GC), a gene encoding a vitamin D binding protein, is an excellent candidate causal gene for the QTL. The multiplicated alleles are associated with increasedGCexpression and low CM resistance. Ample evidence from functional genomics data supports the presence of an enhancer within this CNV, which would exertcis-regulatory effect onGC. We observed that strong positive selection swept the region near the CNV, and haplotypes associated with the multiplicated allele were strongly selected for. Moreover, the multiplicated allele showed pleiotropic effects for increased milk yield and reduced fertility, hinting that a shared underlying biology for these effects may revolve around the vitamin D pathway. These findings together suggest a putative causal variant of a CM resistance QTL, where acis-regulatory element located within a CNV can alter gene expression and affect multiple economically important traits.Author summaryClinical mastitis (CM) is an inflammatory disease that negatively influences dairy production and compromises animal welfare. Although one major genetic locus for CM resistance was mapped on bovine chromosome 6, a mechanistic description of this association has been lacking. Herein, we report a 12-kb multiallelic copy number variant (CNV), encompassing a strong enhancer for group-specific component gene (GC), as a likely causal variant for this locus. This CNV is associated with highGCexpression and low CM resistance. We speculate that upregulation ofGCleads to a large amount of vitamin D binding protein, which in turn, reduces biologically available vitamin D, resulting in vitamin D deficiency and low CM resistance. Despite the negative effect on CM resistance, the CNV contributes to increased milk production, hinting at balancing selection. Our results highlight how multiplication of a regulatory element can shape economically important traits in dairy cattle, both in favourable and unfavourable directions.
DeepHBV: A deep learning model to predict hepatitis B virus (HBV) integration sites
Authors: Wu Canbiao , Guo Xiaofang , Li Mengyuan , Fu Xiayu , Hou Zeliang , Zhai Manman , Shen Jingxian , Qiu Xiaofan , Cui Zifeng , Xie Hongxian , Qin Pengmin , Weng Xuchu , Hu Zheng , Liang Jiuxing 
Published: January 2021

AbstractHepatitis B virus (HBV) is one of the main causes for viral hepatitis and liver cancer. Previous studies showed HBV can integrate into host genome and further promote malignant transformation. In this study, we developed an attention-based deep learning model DeepHBV to predict HBV integration sites by learning local genomic features automatically. We trained and tested DeepHBV using the HBV integration sites data from dsVIS database. Initially, DeepHBV showed AUROC of 0.6363 and AUPR of 0.5471 on the dataset. Adding repeat peaks and TCGA Pan Cancer peaks can significantly improve the model performance, with an AUROC of 0.8378 and 0.9430 and an AUPR of 0.7535 and 0.9310, respectively. On independent validation dataset of HBV integration sites from VISDB, DeepHBV with HBV integration sequences plus TCGA Pan Cancer (AUROC of 0.7603 and AUPR of 0.6189) performed better than HBV integration sequences plus repeat peaks (AUROC of 0.6657 and AUPR of 0.5737). Next, we found the transcriptional factor binding sites (TFBS) were significantly enriched near genomic positions that were paid attention to by convolution neural network. The binding sites of AR-halfsite, Arnt, Atf1, bHLHE40, bHLHE41, BMAL1, CLOCK, c-Myc, COUP-TFII, E2A, EBF1, Erra and Foxo3 were highlighted by DeepHBV attention mechanism in both dsVIS dataset and VISDB dataset, revealing the HBV integration preference. In summary, DeepHBV is a robust and explainable deep learning model not only for the prediction of HBV integration sites but also for further mechanism study of HBV induced cancer.Author summaryHepatitis B virus (HBV) is one of the main causes for viral hepatitis and liver cancer. Previous studies showed HBV can integrate into host genome and further promote malignant transformation. In this study, we developed an attention-based deep learning model DeepHBV to predict HBV integration sites by learning local genomic features automatically. The performance of DeepHBV model significantly improves after adding genomic features, with an AUROC of 0.9430 and an AUPR of 0.9310. Furthermore, we enriched the transcriptional factor binding sites of proteins by convolution neural network. In summary, DeepHBV is a robust and explainable deep learning model not only for the prediction of HBV integration sites but also for the further study of HBV integration mechanism.
Distinguishing gene flow between malaria parasite populations
Authors: Brown Tyler S. , Taylor Aimee R. , Arogbokun Olufunmilayo , Buckee Caroline O. , Chang Hsiao-Han 
Published: January 2021

AbstractMeasuring gene flow between malaria parasite populations in different geographic locations can provide strategic information for malaria control interventions. Multiple important questions pertaining to the design of such studies remain unanswered, limiting efforts to operationalize genomic surveillance tools for routine public health use. This report evaluates numerically the ability to distinguish different levels of gene flow between malaria populations, using different amounts of real and simulated data, where data are simulated using parameters that approximate different epidemiological conditions. Specifically, usingPlasmodium falciparumwhole genome sequence data and sequence data simulated for a metapopulation with different migration rates and effective population sizes, we compare two estimators of gene flow, explore the number of genetic markers and number of individuals required to reliably rank highly connected locations, and describe how these thresholds change given different effective population sizes and migration rates. Our results have implications for the design and implementation of malaria genomic surveillance efforts.
Choosing optimal trigger points forex situ, in totoconservation of single population threatened species
Authors: Brown Kaitlyn , Tambyah Tamara , Fenwick Jack , Burke Aidan , Grant Patrick , Hegarty-Cremer Solene , Muller Joshua , Bode Michael 
Published: January 2021

ABSTRACTMany endangered species exist in only a single population, and almost all species that go extinct will do so from their last remaining population. Understanding how to best conserve these single population threatened species (SPTS) is therefore a distinct and important task for threatened species conservation science. As a last resort, managers of SPTS may consider taking the entire population into captivity –ex situ, in totoconservation. In the past, this choice has been taken to the great benefit of the SPTS, but it has also lead to catastrophe. Here, we develop a decision-support tool for planning when to trigger this difficult action. Our method considers the uncertain and ongoing decline of the SPTS, the possibility that drasticex situaction will fail, and the opportunities offered by delaying the decision. Specifically, these benefits are additional time for ongoingin situactions to succeed, and opportunities for the managers to learn about the system. To illustrate its utility, we apply the decision tool to four retrospective case-studies of declining SPTS. As well as offering support to this particular decision, our tool illustrates why trigger points for difficult conservation decisions should be formulated in advance, but must also be adaptive. A trigger-point for theex situ, in totoconservation of a SPTS, for example, will not take the form of a simple threshold abundance.
Microtubule-associated ROP interactors both delimit and transduce ROP signaling and regulate microtubule dynamics
Authors: Feiguelman Gil , Cui Xiankui , Sternberg Hasana , Fu Ying , Yalovsky Shaul 
Published: January 2021

AbstractEvidence suggests that ICR proteins function as adaptors that mediate ROP signaling. Here, we studied the functions of ICR2 and its homologs ICR5 and ICR3. We showed that ICR2 is a microtubule-associated protein that regulates microtubule dynamics. ICR2 can retrieve activated ROPs from the plasma membrane, and it is recruited to a subset of ROP domains. Secondary cell wall pits in the metaxylem oficr2andicr5 Arabidopsissingle mutants andicr2/icr5double andicr2/icr5/icr3triple mutants were denser and larger than those in wild-type Col-0 seedlings, implicating these three ICRs in restriction of ROP function. Theicr2but not theicr5mutants developed split root hairs further implicating ICR2 in restriction of ROP signaling. Taken together, our results show that ICR2, and likely also ICR5 and ICR3, have multiple functions as ROP effectors and as regulators of microtubule dynamics.
Computing the Riemannian curvature of image patch and single-cell RNA sequencing data manifolds using extrinsic differential geometry
Authors: Sritharan Duluxan , Wang Shu , Hormoz Sahand 
Published: January 2021

AbstractMost high-dimensional datasets are thought to be inherently low-dimensional, that is, datapoints are constrained to lie on a low-dimensional manifold embedded in a high-dimensional ambient space. Here we study the viability of two approaches from differential geometry to estimate the Riemannian curvature of these low-dimensional manifolds. The intrinsic approach relates curvature to the Laplace-Beltrami operator using the heat-trace expansion, and is agnostic to how a manifold is embedded in a high-dimensional space. The extrinsic approach relates the ambient coordinates of a manifold’s embedding to its curvature using the Second Fundamental Form and the Gauss-Codazzi equation. Keeping in mind practical constraints of real-world datasets, like small sample sizes and measurement noise, we found that estimating curvature is only feasible for even simple, low-dimensional toy manifolds, when the extrinsic approach is used. To test the applicability of the extrinsic approach to real-world data, we computed the curvature of a well-studied manifold of image patches, and recapitulated its topological classification as a Klein bottle. Lastly, we applied the approach to study single-cell transcriptomic sequencing (scRNAseq) datasets of blood, gastrulation, and brain cells, revealing for the first time the intrinsic curvature of scRNAseq manifolds.
Cellular, molecular, and therapeutic characterization of pilocarpine-induced temporal lobe epilepsy
Authors: Henkel Nicholas D. , Smail Marissa A. , Wu Xiaojun , Enright Heather A. , Fischer Nicholas , Eby Hunter M. , Carney Paul R. , McCullumsmith Robert E. , Shukla Rammohan 
Published: January 2021

ABSTRACTWe probed a transcriptomic dataset of pilocarpine-induced TLE using various ontological, machine-learning, and systems-biology approaches. We showed that, underneath the complex and penetrant changes, moderate-to-subtle upregulated homeostatic and downregulated synaptic changes associated with the dentate gyrus and hippocampal subfields could not only predict TLE but various other forms of epilepsy. At the cellular level, pyramidal neurons and interneurons showed disparate changes, whereas the proportion of non-neuronal cells increased steadily. A probabilistic Bayesian network demonstrated an aberrant and oscillating physiological interaction between oligodendrocytes and interneurons in driving seizures. Validating the Bayesian inference, we showed that the cell types driving the seizures were associated with known antiepileptic and epileptic drugs. These findings provide predictive biomarkers of epilepsy, insights into the cellular connections and causal changes associated with TLE and a drug discovery method focusing on these events.
Local Shifts in Inflammatory and Resolving Lipid Mediators in Response to Tendon Overuse
Authors: Markworth James F. , Sugg Kristoffer B. , Sarver Dylan C. , Maddipati Krishna Rao , Brooks Susan V. 
Published: January 2021

AbstractTendon inflammation has been implicated in both adaptive connective tissue remodeling and overuse-induced tendinopathy. Lipid mediators control the initiation and resolution of inflammation, but their roles within tendon are largely unknown. Here we profiled local shifts in intratendinous lipid mediators via liquid chromatography-tandem mass spectrometry in response to synergist ablation-induced plantaris tendon overuse. Sixty-four individual lipid mediators were detected in homogenates of habitually loaded plantaris tendons from healthy ambulatory rats. This included many bioactive metabolites of the cyclooxygenase (COX), lipoxygenase (LOX), and epoxygenase (CYP) pathways. Synergist ablation induced a robust inflammatory response at day 3 post-surgery characterized by epitenon infiltration of polymorphonuclear leukocytes (PMNs) and macrophages (MΦ), heightened expression of inflammation-related genes, and increased intratendinous concentrations of the pro-inflammatory eicosanoids thromboxane B2(TXB2) and prostaglandin E2(PGE2). By day 7, MΦ became the predominant myeloid cell type in tendon and there were further delayed increases in other COX metabolites including PGD2, PGF2αand PGI2. Specialized pro-resolving mediators (SPMs) including protectin D1 (PD1) and resolvin D6 (RvD6), as well as related pathway markers of D-resolvins (17-HDoHE), E-resolvins (18-HEPE) and lipoxins (15-HETE) were also increased locally in response to tendon overuse, as were many anti-inflammatory fatty acid epoxides of the CYP pathway (e.g. EpETrEs). Nevertheless, intratendinous prostaglandins remained markedly increased even following 28 days of tendon overuse together with a lingering MΦ presence. These data reveal a delayed and prolonged local inflammatory response to tendon overuse characterized by an overwhelming predominance of pro-inflammatory eicosanoids and a relative lack of pro-resolving lipid mediators.
Structural and mechanistic insight into spectral tuning in flavin-binding fluorescent proteins
Authors: Röllen Katrin , Granzin Joachim , Remeeva Alina , Davari Mehdi D. , Gensch Thomas , Nazarenko Vera V. , Kovalev Kirill , Bogorodskiy Andrey , Borshchevskiy Valentin , Hemmer Stefanie , Schwaneberg Ulrich , Gordeliy Valentin , Jaeger Karl-Erich , Batra-Safferling Renu , Gushchin Ivan , Krauss Ulrich 
Published: January 2021

AbstractDetermining the molecular origin of spectral tuning in photoactive biological systems is instrumental for understanding their function. Spectral-tuning efforts for flavin-binding fluorescent proteins (FbFPs), an emerging class of fluorescent reporters, are limited by their dependency on protein-bound flavins, whose structure and hence electronic properties, cannot be altered by mutation. To address those shortcomings, we here present the photophysical, computational and structural characterization of structurally uncharacterized blue-shifted FbFPs, carrying a previously described lysine substitution within their flavin-binding pocket. X-ray structures reveal displacement of the lysine away from the chromophore and opening up of the structure as cause for the blue shift. Site-saturation mutagenesis and high-throughput screening, yielded a red-shifted variant, in which the lysine side chain of the blue-shifted variant is stabilized in close distance to the flavin by a secondary mutation, mechanistically accounting for the red shift. Thus, a single secondary mutation in a blue-shifted variant is sufficient to generate a red-shifted FbFP. Using spectroscopy, X-ray crystallography and quantum mechanics molecular mechanics calculations, we provide a firm structural and functional understanding of spectral tuning in FbFPs. We also show that the identified blue- and red-shifted variants allow for two-color microscopy based on spectral separation. In summary, the generated blue- and red-shifted variants represent promising new tools that should find application in life sciences.
The Application of Countercurrent Chromatography for the study of Bacteriophages
Authors: Friedersdorff Jessica C A , Bright Colin , Rooke David , Creevey Christopher J , Kingston-Smith Alison H 
Published: January 2021

1.AbstractBacteriophages (phages) are viruses that target bacteria, with the ability to lyse and kill host bacterial cells. Due to this, they have been of some interest as a therapeutic since their discovery in the early 1900s, but with the recent increase in antibiotic resistance, phages have seen a resurgence in attention. Current methods of isolation and purification of phages can be long and tedious, with caesium chloride concentration gradients the gold standard for purifying a phage fraction. Isolation of novel phages requires centrifugation and ultrafiltration of mixed samples, such as water sources, effluent or faecal samples etc, to prepare phage filtrates for further testing. We propose countercurrent chromatography as a novel and alternative approach to use when studying phages, as a scalable and high-yield method for obtaining phage fractions. However, the full extent of the usefulness and resolution of separation with this technique has not been researched; it requires optimisation and ample testing before this can be revealed. Here we present an initial study to determine survivability of two phages, T4 and ϕX174, using only water as a mobile phase in a Spectrum Series 20 HPCCC. Both phages were found to remain active once eluted from the column. Phages do not fully elute from the column and sodium hydroxide is necessary to flush the column between runs to deactivate remaining phages.
A global cancer data integrator reveals principles of synthetic lethality, sex disparity and immunotherapy
Authors: Yogodzinski Christopher , Arab Abolfazl , Pritchard Justin R. , Goodarzi Hani , Gilbert Luke A. 
Published: January 2021

AbstractAdvances in cancer biology are increasingly dependent on integration of heterogeneous datasets. Large scale efforts have systematically mapped many aspects of cancer cell biology; however, it remains challenging for individual scientists to effectively integrate and understand this data. We have developed a new data retrieval and indexing framework that allows us to integrate publicly available data from different sources and to combine publicly available data with new or bespoke datasets. Beyond a database search, our approach empowered testable hypotheses of new synthetic lethal gene pairs, genes associated with sex disparity, and immunotherapy targets in cancer. Our approach is straightforward to implement, well documented and is continuously updated which should enable individual users to take full advantage of efforts to map cancer cell biology.