bluuebunny/crossref_metadata_2025_split huggingface dataset:
Methylation of RNA Cap in SARS-CoV-2 captured by serial crystallography
Authors: Wilamowski M. , Sherrell D.A. , Minasov G. , Kim Y. , Shuvalova L. , Lavens A. , Chard R. , Maltseva N. , Jedrzejczak R. , Rosas-Lemus M. , Saint N. , Foster I.T. , Michalska K. , Satchell K.J.F. , Joachimiak A 
Published: August 2020

ABSTRACTThe genome of the SARS-CoV-2 coronavirus contains 29 proteins, of which 15 are nonstructural. Nsp10 and Nsp16 form a complex responsible for the capping of mRNA at the 5′ terminus. In the methylation reaction the S-adenosyl-L-methionine serves as the donor of the methyl group that is transferred to Cap-0 at the first transcribed nucleotide to create Cap-1. The presence of Cap-1 makes viral RNAs mimic the host transcripts and prevents their degradation. To investigate the 2′-O methyltransferase activity of SARS-CoV-2 Nsp10/16, we applied fixed-target serial synchrotron crystallography (SSX) which allows for physiological temperature data collection from thousands of crystals, significantly reducing the x-ray dose while maintaining a biologically relevant temperature. We determined crystal structures of Nsp10/16 that revealed the states before and after the methylation reaction, for the first time illustrating coronavirus Nsp10/16 complexes with them7GpppAm2′-OCap-1, where 2′OH of ribose is methylated. We compare these structures with structures of Nsp10/16 at 297 K and 100 K collected from a single crystal. This data provide important mechanistic insight and can be used to design small molecules that inhibit viral RNA maturation making SARS-CoV-2 sensitive to host innate response.
Secondary metabolites from food-derived yeasts inhibit virulence ofCandida albicans
Authors: Kunyeit Lohith , Kurrey Nawneet K , K A Anu-Appaiah , Rao Reeta P 
Published: August 2020

AbstractBeneficial microbes in the intestine are thought to control pathogen overgrowth by competing for limited nutrients. Our findings modify this prevailing paradigm of a passive, microbial antagonistic mode of action to an active, directed mechanism mediated by specific secondary metabolites. We describe two food-derived yeasts,Saccharomyces cerevisiaeandIssatchenkia occidentalis, that inhibit virulence traits ofCandida albicans, including hyphal morphogenesis, biofilms formation and adhesion to intestinal epithelial cells. These yeasts also protect the model hostCaenorhabditis elegansfromC. albicansinfection. We demonstrate that the protective activity is primarily retained in the secretome of the beneficial yeasts and the protection they provide as a physical barrier is minimal. Mutant analysis demonstrates that phenylethanol and tryptophol are necessary for protection and experiments with commercially procured compounds indicates that they are sufficient to inhibitC. albicansvirulence. We propose food-derived yeasts as an alternative or combination therapy to conventional antifungal therapy forC. albicansinfection.
Limb regeneration modulates reproductive attributes in ladybirds: A case study inPropylea dissectaandCoccinella septempunctata
Authors: Saxena Swati , Mishra Geetanjali , Omkar  
Published: August 2020

ABSTRACTRegeneration is the capability to regrow or repair the lost or injured body parts. In holometabolous insects, the adult development undergoes through larval and pupal stages. Literature revealed that the limb regeneration has various impact on different life traits of organisms. In the present study, we investigated limb regeneration of two different sized ladybirds affect their life attributes. Fourth instar larvae of small ladybirdPropylea dissectaand the large ladybirdCoccinella septempunctatawere taken from the laboratory stock and were given an ablation treatment,viz. forelegs of larvae were amputated at the base of the coxa. Amputated larvae were observed until the adult emergence. Emerged adults were grouped in different categories on the basis limb regenerationi.e. regenerated adults (incomplete regenerated in case ofP. dissecta), unregenerated, and normal (control) adults. These adults were kept in different mating treatments. The unregenerated adults of both the ladybirds took more time to commence mating with shorter copulation duration and reduced fecundity and percent egg viability. Thus, it can be concluded that regeneration ability modulates the life attributes of the ladybirds irrespective of their body size.
Rational Design of SARS-CoV-2 Spike Glycoproteins To Increase Immunogenicity By T Cell Epitope Engineering
Authors: Ong Edison , Huang Xiaoqiang , Pearce Robin , Zhang Yang , He Yongqun 
Published: August 2020

AbstractThe current COVID-19 pandemic caused by SARS-CoV-2 has resulted in millions of confirmed cases and thousands of deaths globally. Extensive efforts and progress have been made to develop effective and safe vaccines against COVID-19. A primary target of these vaccines is the SARS-CoV-2 spike (S) protein, and many studies utilized structural vaccinology techniques to either stabilize the protein or fix the receptor-binding domain at certain states. In this study, we extended an evolutionary protein design algorithm, EvoDesign, to create thousands of stable S protein variants without perturbing the surface conformation and B cell epitopes of the S protein. We then evaluated the mutated S protein candidates based on predicted MHC-II T cell promiscuous epitopes as well as the epitopes’ similarity to human peptides. The presented strategy aims to improve the S protein’s immunogenicity and antigenicity by inducing stronger CD4 T cell response while maintaining the protein’s native structure and function. The top EvoDesign S protein candidate (Design-10705) recovered 31 out of 32 MHC-II T cell promiscuous epitopes in the native S protein, in which two epitopes were present in all seven human coronaviruses. This newly designed S protein also introduced nine new MHC-II T cell promiscuous epitopes and showed high structural similarity to its native conformation. The proposed structural vaccinology method provides an avenue to rationally design the antigen’s structure with increased immunogenicity, which could be applied to the rational design of new COVID-19 vaccine candidates.
Optimizing checkpoint strategies based on first principles predicts experimental DNA damage checkpoint override times
Authors: Sadeghi Ahmad , Dervey Roxane , Gligorovski Vojislav , Rahi Sahand Jamal 
Published: August 2020

AbstractWhy biological quality-control systems fail is often mysterious. Specifically, checkpoints such as the DNA damage checkpoint or the spindle assembly checkpoint are overriden after prolonged arrests allowing cells to continue dividing despite the continued presence of errors.1–4Although critical for biological systems, checkpoint override is poorly understood quantitatively by experiment or theory. Override may represent a trade-off between risk and speed, a fundamental principle explaining biological phenomena.5,6Here, we derive the first, general theory of optimal checkpoint strategies, balancing risk and opportunities for growth. We demonstrate that the mathematical problem of finding the optimal strategy maps onto the question of calculating the optimal absorbing boundary for a random walk, which we show can be solved efficiently recursively. The theory predicts the optimal override strategy without any free parameters based on two inputs, the statistics i) of error correction and ii) of survival. We apply the theory to the prominent example of the DNA damage checkpoint in budding yeast (Saccharomyces cerevisiae) experimentally. Using a novel fluorescent construct which allowed cells with DNA breaks to be isolated by flow cytometry, we quantified i) the probability distribution function of repair for a double-strand DNA break (DSB), including for the critically important, rare events deep in the tail of the distribution, as well as ii) the survival probability if the checkpoint was overridden. Based on these two measurements, the optimal checkpoint theory predicted remarkably accurately the DNA damage checkpoint override times as a function of DSB numbers, which we measured precisely at the single-cell level. Our multi-DSB results refine well-known bulk culture measurements7and show that override is a more general phenomenon than previously thought. Further, we show for the first time that override is an advantageous strategy in cells with wild-type DNA repair genes. The universal nature of the balance between risk and self-replication opportunity is in principle relevant to many other systems, including other checkpoints, developmental decisions8, or reprogramming of cancer cells9, suggesting potential further applications of the theory.
Differential methylation as a mediator of COVID-19 susceptibility
Authors: Steyaert Sandra , Trooskens Geert , Delanghe Joris R. , Van Criekinge Wim 
Published: August 2020

AbstractThe COVID-19 outbreak shows a huge variation in prevalence and mortality on geographical level but also within populations1. TheACE2gene, identified as the SARS-CoV2 receptor, has been shown to facilitate the viral invasion and people with higherACE2expression generally are more severely affected2, 3. As there is a lot of variability inACE2expression between individuals we hypothesized that differential DNA methylation profiles could be (one of) the confounding factors explaining this variability. Here we show that epigenetic profiling of host tissue, especially in theACE2promoter region and its homologueACE1, may be important risk factors for COVID-19. Our results propose that variable methylation can explain (part of) the differential susceptibility, symptom severity and death rate for COVID-19. Our findings are a promising starting point to further evaluate the potential ofACE1/2methylation and other candidates as a predictor for clinical outcome upon SARS-CoV2 infection.
A neural signature of choice under sensory conflict inDrosophila
Authors: Sareen Preeti , McCurdy Li Yan , Nitabach Michael N. 
Published: August 2020

SummaryFeeding decisions are fundamental to survival, and decision making is often disrupted in disease, yet the neuronal and molecular mechanisms of adaptive decision making are not well understood. Here we show that neural activity in a small population of neurons projecting to the fan-shaped body higher-order central brain region ofDrosophilarepresents final food choice during sensory conflict. We found that hungry flies made tradeoffs between appetitive and aversive values of food in a decision making task to choose bittersweet food with high sucrose concentration, but adulterated with bitter quinine, over sweet-only food with less sucrose. Using cell-specific optogenetics and receptor RNAi knockdown during the decision task, we identified an upstream neuropeptidergic and dopaminergic network that relays internal state and other decision-relevant information, such as valence and previous experience, to a specific subset of fan-shaped body neurons. Importantly, calcium imaging revealed that these neurons were strongly inhibited by the taste of the rejected food choice, suggesting that they encode final behavioral food choice. Our findings reveal that fan-shaped body taste responses to food choices are determined not only by taste quality, but also by previous experience (including choice outcome) and hunger state, which are integrated in the fan-shaped body to encode the decision before relay to downstream motor circuits for behavioral implementation. Our results uncover a novel role for the fan-shaped body in choice encoding, and reveal a neural substrate for sensory and internal state integration for decision making in a genetically tractable model organism to enable mechanistic dissection at circuit, cellular, and molecular levels.
The Planarian Anatomy Ontology: A resource to connect data within and across experimental platforms
Authors: Nowotarski Stephanie H. , Davies Erin L. , Robb Sofia M. C. , Ross Eric J. , Matentzoglu Nicolas , Doddihal Viraj , Mir Mol , McClain Melainia , Alvarado Alejandro Sánchez 
Published: August 2020

AbstractAs the planarianSchmidtea mediterranea(Smed) gains popularity as a research organism, the need for standard anatomical nomenclature is increasingly apparent. A controlled vocabulary streamlines data annotation, improves data organization, and enhances cross-platform and cross-species searchability. We created the Planarian Anatomy Ontology (PLANA), an extendable framework of definedSmedanatomical terms organized using relationships. The most current version contains over 800 terms that describeSmedanatomy from subcellular to system-level across all life cycle stages, in intact animals, and regenerating body fragments. Terms from other anatomy ontologies were imported into PLANA to promote ontology interoperability and comparative anatomy studies. To demonstrate the utility of PLANA for data curation, we created web-based resources for planarian embryogenesis, including a staging series and molecular fate mapping atlas, as well as a searchable Planarian Anatomy Gene Expression database, which integrates a variety of published gene expression data and allows retrieval of information of all published sequences associated with specific planarian anatomical regions. Finally, we report methods for continued curation of PLANA, providing a path for expansion and evolution of this community resource.Summary StatementWe report construction of an anatomy ontology for an emerging research organism and show its use to curate and mine data across multiple experimental platforms.
Comparison of methods for milk pre-processing, exosome isolation, and RNA extraction in bovine and human milk
Authors: Wijenayake Sanoji , Eisha Shafinaz , Tawhidi Zoya , Pitino Michael A. , Steele Michael A. , Fleming Alison S. , McGowan Patrick O. 
Published: August 2020

AbstractMilk is a highly complex, heterogeneous biological fluid that contains bioactive, membrane-bound extracellular vesicles called exosomes. Characterization of milk-derived exosomes (MDEs) is challenging due to the lack of standardized methods that are currently being used for milk pre-processing, exosome isolation, and RNA extraction. In this study, we tested: 1) three pre-processing methods to remove cream, fat, and casein proteins from bovine milk to determine whether pre-processing of whole milk, prior to long-term storage, improves MDE isolations, 2) two commonly-used exosome isolation methods, and 3) four extraction protocols for obtaining high quality MDE RNA from bovine and human milk. MDEs were characterized via Transmission Electron Microscopy (TEM) and Nanoparticle Tracking Analysis (NTA). We also present an optimized method of TEM sample preparation and isolation of total soluble protein from MDEs. Our results indicated that: 1) pre-processing of bovine milk prior to storage does not affect the final exosome yield or the purity, 2) ExoQuick precipitation is better suited for MDE isolation than ultracentrifugation for bovine and human milk, and 3) TRIzol LS produced the highest RNA yield in bovine milk, whereas TRIzol LS, TRIzol+RNA Clean and Concentrator, and TRIzol LS+RNA Clean and Concentrator methods can be used for human milk.
Somite surface tension buffers imprecise segment lengths to ensure left-right symmetry
Authors: Naganathan Sundar R. , Popović Marko , Oates Andrew C. 
Published: August 2020

AbstractThe body axis of vertebrate embryos is periodically segmented into bilaterally symmetric pairs of somites. The anteroposterior (AP) length of somites, their position and left-right symmetry are thought to be molecularly determined prior to somite morphogenesis. Here we discover that in zebrafish embryos, initial somite AP lengths and positions are imprecise and consequently many somite pairs form left-right asymmetrically. Strikingly, these imprecisions are not left unchecked and we find that AP lengths adjust within an hour after somite formation, thereby increasing morphological symmetry. We find that AP length adjustments result entirely from changes in somite shape without change in somite volume, with changes in AP length being compensated by corresponding changes in mediolateral length. The AP adjustment mechanism is facilitated by somite surface tension, which we show by comparingin vivoexperiments andin vitrosingle-somite explant cultures with a mechanical model. Length adjustment is inhibited by perturbation of Integrin and Fibronectin, consistent with their involvement in surface tension. In contrast, the adjustment mechanism is unaffected by perturbations to the segmentation clock, thus revealing a distinct process that determines morphological segment lengths. We propose that tissue surface tension provides a general mechanism to adjust shapes and ensure precision and symmetry of tissues in developing embryos.
Implicit anticipation of probabilistic regularities: Larger CNV emerges for unpredictable events
Authors: Kóbor Andrea , Kardos Zsófia , Horváth Kata , Janacsek Karolina , Takács Ádám , Csépe Valéria , Nemeth Dezso 
Published: August 2020

AbstractAnticipation of upcoming events plays a crucial role in automatic behaviors. It is, however, still unclear whether the event-related brain potential (ERP) markers of anticipation could track the implicit acquisition of probabilistic regularities that can be considered as building blocks of automatic behaviors. Therefore, in a four-choice reaction time (RT) task performed by young adults (N= 36), the contingent negative variation (CNV) as an ERP marker of anticipation was measured from the onset of a cue stimulus until the presentation of a target stimulus. Due to the probability structure of the task, target stimuli were either predictable or unpredictable, but this was unknown to participants. The cue did not contain predictive information on the upcoming target. Results showed that the CNV amplitude during response preparation was larger before the unpredictable than before the predictable target stimuli. In addition, although RTs increased, the P3 amplitude decreased for the unpredictable as compared with the predictable target stimuli, possibly due to the stronger response preparation that preceded stimulus presentation. These results suggest that enhanced attentional resources are allocated to the implicit anticipation and processing of unpredictable events. This might originate from the formation of internal models on the probabilistic regularities of the stimulus stream, which primarily facilitates the processing of predictable events. Overall, we provide ERP evidence that supports the role of implicit anticipation and predictive processes in the acquisition of probabilistic regularities.
Logical modeling of dendritic cellsin vitrodifferentiation from human monocytes unravels novel transcriptional regulatory interactions
Authors: Nuñez-Reza Karen J. , Naldi Aurélien , Sanchéz-Jiménez Arantza , Leon-Apodaca Ana V. , Santana M. Angélica , Thomas-Chollier Morgane , Thieffry Denis , Medina-Rivera Alejandra 
Published: August 2020

AbstractDendritic cells are the major specialized antigen-presenting cells, thereby connecting innate and adaptive immunity. Because of their role in establishing adaptive immunity, they have been used as targets for immunotherapy. Monocytes can differentiate into dendritic cellsin vitroin the presence of colony-stimulating factor 2 (CSF2) and interleukin 4 (IL4), activating four signalling pathways (MAPK, JAK/STAT, NFKB, and PI3K). However, the transcriptional regulation responsible for dendritic cell differentiation from monocytes (moDCs) remains unknown. By curating scientific literature on moDCs differentiation, we established a preliminary logical model that helped us identify missing information for the activation of genes responsible for this differentiation, including missing targets for key transcription factors (TFs). Using ChIP-seq and RNA-seq data from the Blueprint consortium, we defined active and inactive promoters, together with differentially expressed genes in monocytes, moDCs, and macrophages (which correspond to an alternative cell fate). We then used this functional genomic information to predict novel targets for the identified TFs. We established a second logical model integrating this information, which enabled us to recapitulate the main established facts regarding moDCs differentiation. Prospectively, the resulting model should be useful to develop novel immunotherapies based on moDCs regulatory network.
Evolution of dosage compensation does not depend on genomic background
Authors: Rovatsos Michail , Kratochvíl Lukáš 
Published: August 2020

AbstractOrganisms evolved various mechanisms to cope with the differences in the gene copy numbers between sexes caused by degeneration of Y and W sex chromosomes. Complete dosage compensation or at least expression balance between sexes was reported predominantly in XX/XY, but rarely in ZZ/ZW systems. However, this often-reported pattern is based on comparisons of lineages where sex chromosomes evolved from non-homologous genomic regions, potentially differing in sensitivity to differences in gene copy numbers. Here we document that two reptilian lineages (XX/XY iguanas and ZZ/ZW softshell turtles), which independently co-opted the same ancestral genomic region for the function of sex chromosomes, evolved different gene dose regulatory mechanisms. The independent co-option of the same genomic region for the role of sex chromosome as in the iguanas and the softshell turtles offers a great opportunity for testing evolutionary scenarios on the sex chromosome evolution under the explicit control for the genomic background and for gene identity. We showed that the parallel loss of functional genes from the Y chromosome of the green anole and the W chromosome of the Florida softshell turtle led to different dosage compensation mechanisms. Our approach controlling for genetic background thus does not support that the variability in the regulation of the gene dose differences is a consequence of ancestral autosomal gene content.
Alterations in bile acid metabolizing gut microbiota and specific bile acid genes as a precision medicine to subclassify NAFLD
Authors: Jiao Na , Loomba Rohit , Yang Zi-Huan , Wu Dingfeng , Fang Sa , Bettencourt Richele , Lan Ping , Zhu Ruixin , Zhu Lixin 
Published: August 2020

AbstractBackground & AimsMultiple mechanisms for the gut microbiome contributing to the pathogenesis of non-alcoholic fatty liver disease (NAFLD) have been implicated. Here, we aim to investigate the contribution and potential application for altered bile acid (BA) metabolizing microbe in NAFLD using whole metagenome sequencing (WMS) data.Methods86 well-characterized biopsy-proven NAFLD patients and 38 healthy controls were included in the discovery cohort. Assembly-based analysis was performed to identify BA-metabolizing microbes. Statistical tests, feature selection and microbial interaction analysis were integrated to identify microbial alterations and markers in NAFLD. An independent validation cohort was subjected to similar analyses.ResultsNAFLD microbiota exhibited decreased diversity and microbial interactions. We established a classifier model with 53 differential species exhibiting a robust diagnostic accuracy (AUC=0.97) for dectecting NAFLD. Next, 8 important differential pathway markers including secondary BA biosynthesis were identified. Specifically, increased abundance of 7α-HSDH, baiA and baiB were detected in NAFLD. Further, 10 of 50 BA-metabolizing metagenome-assembled genomes (MAG)s, fromBacteroides ovatusandEubacterium biforme, were dominant in NAFLD and interplayed as a synergetic ecological guild. Importantly, two subtypes of NAFLD patients were observed according to secondary BA metabolism potentials. Elevated capability for secondary BA biosynthesis was also observed in the validation cohort.ConclusionsWe identified novel bacterial BA-metabolizing genes and microbes that may contribute to NAFLD pathogenesis and serve as disease markers. Microbial differences in BA-metabolism and strain-specific differences among patients highlight the potential for precision medicine in NAFLD treatment.