bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prediction and Characterization of Disorder-Order Transition Regions in Proteins by Deep Learning
Authors: Yan Ziang , Omori Satoshi , Yamada Kazunori D , Nishi Hafumi , Kinoshita Kengo 
Published: June 2021

AbstractThe biological functions of proteins are traditionally thought to depend on well-defined three-dimensional structures, but many experimental studies have shown that disordered regions lacking fixed three-dimensional structures also have crucial biological roles. In some of these regions, disorder–order transitions are also involved in various biological processes, such as protein-protein interaction and ligand binding. Therefore, it is crucial to study disordered regions and structural transitions for further understanding of protein functions and folding. Owing to the costs and time requirements of experimental identification of natively disordered or transitional regions, the development of effective computational methods is a key research goal. In this study, we used overall residue dependencies and deep representation learning for prediction and reused the obtained disordered regions for the prediction of disorder–order transitions. Two similar and related prediction tasks were combined. Firstly, we developed a novel deep learning method, Res-BiLstm, for residue-wise disordered region prediction. Our method outperformed other predictors with respect to almost all criteria, as evaluated using an independent test set. For disorder-order transition prediction, we proposed a transfer learning method, Res-BiLstm-NN, with an acceptable but unbalanced performance, yielding reasonable results. To grasp underlining biophysical principles of disorder-order transitions, we performed qualitative analyses on the obtained results and discovered that most transitions have strong disordered or ordered preferences, and more transitions are consistent with the ordered state than the disordered state, different from conventional wisdom. To the best of our knowledge, this is the first sizable-scale study of transition prediction.Availabilityhttps://github.com/Yanzziang/Transition_Disorder_PredictionContactkengo@ecei.tohoku.ac.jp
Distributions of extinction times from fossil ages and tree topologies: the example of mid-Permian synapsid extinctions
Authors: Didier Gilles , Laurin Michel 
Published: June 2021

AbstractGiven a phylogenetic tree that includes only extinct, or a mix of extinct and extant taxa, where at least some fossil data are available, we present a method to compute the distribution of the extinction time of a given set of taxa under the Fossilized-Birth-Death model.Our approach differs from the previous ones in that it takes into account (i) the possibility that the taxa or the clade considered may diversify before going extinct and (ii) the whole phylogenetic tree to estimate extinction times, whilst previous methods do not consider the diversification process and deal with each branch independently. Because of this, our method can estimate extinction times of lineages represented by a single fossil, provided that they belong to a clade that includes other fossil occurrences.We assess and compare our new approach with a standard previous one using simulated data. Results show that our method provides more accurate confidence intervals.This new approach is applied to the study of the extinction time of three Permo-Carboniferous synapsid taxa (Ophiacodontidae, Edaphosauridae, and Sphenacodontidae) that are thought to have disappeared toward the end of the Cisuralian (early Permian), or possibly shortly thereafter. The timing of extinctions of these three taxa and of their component lineages supports the idea that the biological crisis in the late Kungurian/early Roadian consisted of a progressive decline in biodiversity throughout the Kungurian.
Control of SARS-CoV-2 infection after Spike DNA or Spike DNA+Protein co-immunization in rhesus macaques
Authors: Rosati Margherita , Agarwal Mahesh , Hu Xintao , Devasundaram Santhi , Stellas Dimitris , Chowdhury Bhabadeb , Bear Jenifer , Burns Robert , Donohue Duncan , Pessaint Laurent , Andersen Hanne , Lewis Mark G. , Terpos Evangelos , Dimopoulos Meletios Athanasios , Wlodawer Alexander , Mullins James I. , Venzon David. J. , Pavlakis George N. , Felber Barbara K 
Published: June 2021

AbstractThe speed of development, versatility and efficacy of mRNA-based vaccines have been amply demonstrated in the case of SARS-CoV-2. DNA vaccines represent an important alternative since they induce both humoral and cellular immune responses in animal models and in human trials. We tested the immunogenicity and protective efficacy of DNA-based vaccine regimens expressing different prefusion-stabilized SARS-CoV-2 Spike antigens upon intramuscular injection followed by electroporation in rhesus macaques. Different Spike DNA vaccine regimens induced antibodies that potently neutralized SARS-CoV-2 in vitro and elicited robust T cell responses. The DNA-only vaccine regimens were compared to a regimen that included co- immunization of Spike DNA and protein in the same anatomical site, the latter of which showed significant higher antibody responses. All vaccine regimens led to control of SARS-CoV-2 intranasal/intratracheal challenge and absence of virus dissemination to the lower respiratory tract. Vaccine-induced binding and neutralizing antibody titers and antibody-dependent cellular phagocytosis inversely correlated with transient virus levels in the nasal mucosa. Importantly, the Spike DNA+Protein co-immunization regimen induced the highest binding and neutralizing antibodies and showed the strongest control against SARS-CoV-2 challenge in rhesus macaques.Author summaryAnti-Spike neutralizing antibodies provide strong protection against SARS-CoV-2 infection in animal models, and correlate with protection in humans, supporting the notion that induction of strong humoral immunity is key to protection. We show induction of robust antibody and T cell responses by different Spike DNA-based vaccine regimens able to effectively mediate protection and to control SARS-CoV-2 infection in the rhesus macaque model. This study provides the opportunity to compare vaccines able to induce different humoral and cellular immune responses in an effort to develop durable immunity against the SARS-CoV-2. A vaccine regimen comprising simultaneous co-immunization of DNA and Protein at the same anatomical site showed best neutralizing abilities and was more effective than DNA alone in inducing protective immune responses and controlling SARS-CoV-2 infection. Thus, an expansion of the DNA vaccine regimen to include co-immunization with Spike protein may be of advantage also for SARS-CoV-2.
Target Dependent Coordinated Biogenesis Ensures Cascaded Expression of miRNAs in Activated Murine Macrophage
Authors: Chatterjee Susanta , Mukherjee Ishita , Bose Mainak , Bhattacharjee Shreya , Chakrabarti Saikat , Bhattacharyya Suvendra N. 
Published: June 2021

AbstractMicroRNAs (miRNAs) repress protein expression by binding to the 3’ UTR of the target mRNAs. By exploring the effect of target mRNA on biogenesis of cognate miRNAs, we have noted miRNA with higher number of binding sites (primary miRNA) coordinates the biogenesis and activity of another miRNA (secondary miRNA) having binding sites on the 3’ UTR of a common target mRNA. From the quantitative data obtained from macrophage cells, we detected miR-146a-5p as a “primary” miRNA that coordinates biogenesis of “secondary” miR-125b, miR-21 or miR-142-3p to target new sets of mRNAs to balance the immune response in activated macrophage cells. Interestingly, target dependent coordinated biogenesis of miRNAs, happening on the rough endoplasmic reticulum attached membrane, ensures a cumulative mode of action of primary and secondary miRNAs on the secondary target mRNAs where a cascaded effect of primary miRNA on its secondary targets has been detected. Extensive computational analysis for the presence of coordinated biogenesis pairs of miRNAs in mammalian cells has also allowed us to construct a coordinate biogenesis repository to determine context specific coordinated biogenesis relationships exists for specific pairs of miRNAs in mammalian cells.Graphical AbstractmiRNA with higher number of binding sites (primary miRNA) can coordinates the biogenesis and activity of another miRNA (secondary miRNA)Target dependent coordinated biogenesis of miRNAs ensures a cumulative mode of action of primary and secondary miRNAs on the secondary target mRNAs on rER attached polysomesmiR-146a-5p acts as a “primary” miRNA to coordinate biogenesis of “secondary” miR-125b, miR-21 or miR-142-3p in activated macrophage cellsCoordinate biogenesis balance the immune response in activated macrophage cells by ensuring propagation of primary miRNAs effect to diverse target mRNAs through secondary miRNAs.
Evolutionary analysis of gene ages across TADs associates chromatin topology with whole genome duplications
Authors: James Caelinn , Trevisan-Herraz Marco , Juan David , Rico Daniel 
Published: June 2021

SummaryTopologically associated domains (TADs) are interaction sub-networks of chromosomal regions in 3D genomes. TAD boundaries frequently coincide with genome breaks while boundary deletion is under negative selection, suggesting that TADs may facilitate genome rearrangements and evolution. We show that genes co-localise by evolutionary age in humans and mice, resulting in TADs having different proportions of younger and older genes. We observe a major transition in the age co-localisation patterns between the genes born during vertebrate whole genome duplications (WGDs) or before, and those born afterwards. We also find that genes recently duplicated in primates and rodents are more frequently essential when they are located in old-enriched TADs and interact with genes that last duplicated during the WGD. Therefore, the evolutionary relevance of recent genes may increase when located in TADs with established regulatory networks. Our data suggests that TADs could play a role in organising ancestral functions and evolutionary novelty.HighlightsTADs coincide with clusters of genes that are close in their evolutionary age.Whole genome duplications mark a transition in gene age co-localisation clusters.Gene age co-localisation patterns are associated with TAD insulation.Young essential genes share TADs and interact with old genes.
Cas9-targeted Nanopore sequencing rapidly elucidates the transposition preferences and DNA methylation profiles of mobile elements in plants
Authors: Merkulov Pavel , Gvaramiya Sofya , Komakhin Roman , Omarov Murad , Dudnikov Maxim , Kocheshkova Alina , Konstantinov Zakhar , Soloviev Alexander , Karlov Gennady , Divashuk Mikhail , Kirov Ilya 
Published: June 2021

AbstractTransposable element insertions (TEIs) are an important source of genomic innovation by contributing to plant adaptation, speciation, and the production of new varieties. The often large, complex plant genomes make identifying TEIs from short reads difficult and expensive. Moreover, rare somatic insertions that reflect mobilome dynamics are difficult to track using short reads. To address these challenges, we combined Cas9-targeted Nanopore sequencing (CANS) with the novel pipeline NanoCasTE to trace both genetically inherited and somatic TEIs in plants. We performed CANS of theEVADÉ(EVD) retrotransposon in wild-typeArabidopsis thalianaand rapidly obtained up to 40x sequence coverage. Analysis of hemizygous T-DNA insertion sites and genetically inherited insertions of theEVDtransposon in theddm1genome uncovered the crucial role of DNA methylation in shapingEVDinsertion preference. We also investigated somatic transposition events of theONSENtransposon family, finding that genes that are downregulated during heat stress are preferentially targeted byONSENs. Finally, we detected hypomethylation of novel somatic insertions for twoONSENs. CANS and NanoCasTE are effective tools for detecting TEIs and exploring mobilome organization in plants in response to stress and in different genetic backgrounds, as well as screening T-DNA insertion mutants and transgenic plants.
The incentive circuit: memory dynamics in the mushroom body of Drosophila melanogaster
Authors: Gkanias Evripidis , McCurdy Li Yan , Nitabach Michael N , Webb Barbara 
Published: June 2021

AbstractInsects adapt their response to stimuli, such as odours, according to their pairing with positive or negative reinforcements, such as sugar or shock. Recent electrophysiological and imaging findings in Drosophila melanogaster allow detailed examination of the neural mechanisms supporting the acquisition, forgetting and assimilation of memories. We propose that this data can be explained by the combination of a dopaminergic plasticity rule that supports a variety of synaptic strength change phenomena, and a circuit structure (derived from neuroanatomy) between dopaminergic and output neurons that creates different roles for specific neurons. Computational modelling shows that this circuit allows for rapid memory acquisition, transfer from short-term to long-term, and exploration/exploitation trade-off. The model can reproduce the observed changes in the activity of each of the identified neurons in conditioning paradigms and can be used for flexible behavioural control.
Provenance Attestation of Human Cells Using Physical Unclonable Functions
Authors: Li Yi , Bidmeshki Mohammad Mahdi , Kang Taek , Nowak Chance M. , Makris Yiorgos , Bleris Leonidas 
Published: June 2021

AbstractWe introduce a novel methodology, namely CRISPR-Engineered Attestation of Mammalian Cells using Physical Unclonable Functions (CREAM-PUFs), which can serve as the cornerstone for formally verifying transactions in human cell line distribution networks. A PUF is a physical entity which provides a measurable output that can be used as a unique and irreproducible identifier for the artifact wherein it is embedded. Popularized by the electronics industry, silicon PUFs leverage the inherent physical variations of semiconductor manufacturing to establish intrinsic security primitives for attesting integrated circuits. Owing to the stochastic nature of these variations and the multitude of steps involved, photo-lithographically manufactured silicon PUFs are impossible to reproduce (thus unclonable). Inspired by the success of silicon PUFs, we sought to exploit a combination of sequence-restricted barcodes and the inherent stochasticity of CRISPR-induced non-homologous end joining DNA error repair to create the first generation of genetic physical unclonable functions in three distinct human cells (HEK293, HCT116, and HeLa). We demonstrate that these CREAM-PUFs are robust (i.e., they repeatedly produce the same output), unique (i.e., they do not coincide with any other identically produced PUF), and unclonable (i.e., they are virtually impossible to replicate). Accordingly, CREAM-PUFs can serve as a foundational principle for establishing provenance attestation protocols for protecting intellectual property and confirming authenticity of engineered cell lines.
Disruption of folate metabolism causes poor alignment and spacing of mouse conceptuses for multiple generations
Authors: Wilkinson Amy L. , Menelaou Katerina , Rakoczy Joanna , Tan Xiu S. , Watson Erica D. 
Published: June 2021

ABSTRACTAbnormal uptake or metabolism of folate increases risk of human pregnancy complications, though the mechanism is unclear. Here, we explore how defective folate metabolism influences early development by analysing mice with anMtrrgthypomorphic mutation. MTRR is necessary for methyl group utilisation from the folate cycle, and theMtrrgtallele disrupts this process. We show that the spectrum of phenotypes previously observed inMtrrgt/gtconceptuses at embryonic day (E) 10.5 is apparent from E8.5 including developmental delay, congenital malformations, and placental phenotypes (e.g., eccentric chorioallantoic attachment). Notably, we report misalignment of someMtrrgtconceptuses within their implantation sites from E6.5. The degree of skewed growth occurs across a continuum, with eccentric chorioallantoic attachment now re-characterised as a severe form of conceptus misalignment. Additionally, someMtrrgt/gtconceptuses display twinning. Therefore, we implicate folate metabolism in blastocyst orientation and spacing at implantation. Embryo development is influenced by skewed growth since developmental delay and heart malformations (but not neural tube defects) associate with severe misalignment ofMtrrgt/gtconceptuses. Patterning of trophoblast lineage markers is largely unaffected in skewedMtrrgt/gtconceptuses at E8.5 indicating trophoblast differentiation was normal when misaligned. Typically, the uterus guides conceptus orientation. Accordingly, we manipulate the maternalMtrrgenotype and assess conceptus alignment.Mtrr+/gt, andMtrrgt/gtmothers, plusMtrr+/+mothers, exhibit misaligned conceptuses at E6.5. While progesterone and/or BMP2 signalling required for decidualisation might be disrupted, normal gross decidual morphology, patterning, and blood perfusion is evident regardless of conceptus alignment, arguing against a uterine defect. Given the important finding thatMtrr+/+mothers also display conceptus misalignment, a grandparental effect is explored. Multigenerational phenotype inheritance is characteristic of theMtrrgtmodel, though the mechanism remains unclear. Genetic pedigree analysis reveals that severe skewing associates with theMtrrgenotype of either maternal grandparent. Moreover, misalignment is independent of the uterus and instead is attributed to an embryonic mechanism based on blastocyst transfer experiments. Overall, our data indicates that abnormal folate metabolism influences conceptus orientation over multiple generations with implications for subsequent development. Our study casts light on the complex role of folate metabolism during development beyond a direct maternal effect.
Mechanisms for Electron Uptake byMethanosarcina acetivoransDuring Direct Interspecies Electron Transfer
Authors: Holmes Dawn E. , Zhou Jinjie , Ueki Toshiyuki , Woodard Trevor , Lovley Derek R. 
Published: June 2021

AbstractDirect interspecies electron transfer (DIET) between bacteria and methanogenic archaea appears to be an important syntrophy in both natural and engineered methanogenic environments. However, the electrical connections on the outer surface of methanogens and the subsequent processing of electrons for carbon dioxide reduction to methane are poorly understood. Here we report that the genetically tractable methanogenMethanosarcina acetivoranscan grow via DIET in co-culture withGeobacter metallireducensserving as the electron-donating partner. Comparison of gene expression patterns inM. acetivoransgrown in co-culture versus pure culture growth on acetate revealed that transcripts for the outer-surface, multi-heme,c-type cytochrome MmcA were higher during DIET-based growth. Deletion ofmmcAinhibited DIET. The high aromatic amino acid content ofM. acetivoransarchaellins suggests that they might assemble into electrically conductive archaella. A mutant that could not express archaella was deficient in DIET. However, this mutant grew in DIET-based co-culture as well as the archaella-expressing parental strain in the presence of granular activated carbon, which was previously shown to serve as a substitute for electrically conductive pili as a conduit for long-range interspecies electron transfer in other DIET-based co-cultures. Transcriptomic data suggesting that the membrane-bound Rnf, Fpo, and HdrED complexes also play a role in DIET were incorporated into a charge-balanced model illustrating how electrons entering the cell through MmcA can yield energy to support growth from carbon dioxide reduction. The results are the first genetics-based functional demonstration of likely outer-surface electrical contacts for DIET in a methanogen.ImportanceThe conversion of organic matter to methane plays an important role in the global carbon cycle and is an effective strategy for converting wastes to a useful biofuel. The reduction of carbon dioxide to methane accounts for approximately a third of the methane produced in anaerobic soils and sediments as well as waste digesters. Potential electron donors for carbon dioxide reduction are H2or electrons derived from direct interspecies electron transfer (DIET) between bacteria and methanogens. Elucidating the relative importance of these electron donors has been difficult due to a lack of information on the electrical connects on the outer surface of methanogens and how they process the electrons received from DIET. Transcriptomic patterns and gene deletion phenotypes reported here provide insight into how a group ofMethanosarcinathat play an important role in methane production in soils and sediments participate in DIET.
Oncomodulin Delays Age-Related Hearing Loss in C57 and CBA Mice
Authors: Climer Leslie K. , Hornak Aubrey J. , Murtha Kaitlin , Yang Yang , Cox Andrew M. , Simpson Preston L. , Le Andy , Simmons Dwayne D. 
Published: June 2021

ABSTRACTCa2+ signaling is a major contributor to sensory hair cell function in the cochlea. Oncomodulin (OCM) is a Ca2+ binding protein preferentially expressed in outer hair cells of the cochlea and few other specialized cell types. Here, we expand on our previous reports and show that OCM prevents early progressive hearing loss in mice of two different genetic backgrounds: CBA/CaJ and C57BI/6J. In both backgrounds, genetic disruption of Ocm leads to early progressive hearing loss as measured by auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE). In both strains, loss of Ocm reduced hearing across lifetime (hearing span) by more than 50% relative to wild type (WT). Even though the two WT strains have very different hearing spans, OCM plays a considerable and similar role within their genetic environment to regulate hearing function. The accelerated ARHL of the Ocm KO illustrates the importance of Ca2+ signaling in maintaining hearing health.
Complete loss of mitochondrial complex I genes in mistletoes (Viscaceae) and evidence of polyadenylated mitochondrial transcripts shown by whole transcriptome sequencing
Authors: Zervas Athanasios , Takenaka Mizuki , Leebens-Mack James , Seberg Ole , Petersen Gitte 
Published: June 2021

AbstractThe profound absence of mitochondrial complex I (NADH-ubiquinone oxidoreductase) genes from the mitogenome of Viscum spp. and the rapid rates of molecular evolution characterizing most of their remaining mitochondrial genes raise questions regarding the possible transfer of the entire nad gene set to the nucleus, as well as for the functionality of the remaining highly divergent genes. Using whole transcriptome sequencing in three species of Viscaceae: V. album, V. crassulae, and Phoradendron leucarpum we were able to confirm transcription of all previously identified genes. However, we did not detect any nad gene transcripts, thus, providing further evidence of the complete loss of complex I in Viscaceae. The results from transcriptome sequencing also revealed that levels and patterns of RNA editing were not different from those found in autotrophic plant species. Hence, RNA editing is not a means of restoring conserved domains or folding sites of the proteins coded for by the divergent mitochondrial genes. Since we were able to recover mitochondrial genes transcripts following a sequencing protocol targeted towards polyadenylated mRNA molecules, it is suggested that mitochondrial genes undergo post-transcriptional polyadenylation in Viscaceae.