bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deep conservation of histone variants in Thermococcales archaea
Authors: Stevens Kathryn M , Hocher Antoine , Warnecke Tobias 
Published: September 2021

AbstractHistones are ubiquitous in eukaryotes where they assemble into nucleosomes, binding and wrapping DNA to form chromatin. One process to modify chromatin and regulate DNA accessibility is the replacement of histones in the nucleosome with paralogous variants. Histones are also present in archaea but whether and how histone variants contribute to the generation of different physiologically relevant chromatin states in these organisms remains largely unknown. Conservation of paralogs with distinct properties can provide prima facie evidence for defined functional roles. We recently revealed deep conservation of histone paralogs with different properties in the Methanobacteriales, but little is known experimentally about these histones. In contrast, the two histones of the model archaeon Thermococcus kodakarensis, HTkA and HTkB, have been examined in some depth, both in vitro and in vivo. HTkA and HTkB exhibit distinct DNA-binding behaviours and elicit unique transcriptional responses when deleted. Here, we consider the evolution of HTkA/B and their orthologs across the order Thermococcales. We find histones with signature HTkA- and HTkB-like properties to be present in almost all Thermococcales genomes. Phylogenetic analysis indicates the presence of one HTkA- and one HTkB-like histone in the ancestor of Thermococcales and long-term maintenance of these two paralogs throughout Thermococcales diversification. Our results support the notion that archaea and eukaryotes have convergently evolved histone variants that carry out distinct adaptive functions. Intriguingly, we also detect more highly diverged histone-fold proteins, related to those found in some bacteria, in several Thermococcales genomes. The functions of these bacteria-type histones remain entirely unknown, but structural modelling suggests that they can form heterodimers with HTkA/B-like histones.
Human electromagnetic and haemodynamic networks systematically converge in unimodal cortex and diverge in transmodal cortex
Authors: Shafiei Golia , Baillet Sylvain , Misic Bratislav 
Published: September 2021

AbstractWhole-brain neural communication is typically estimated from statistical associations among electromagnetic or haemodynamic time-series. The relationship between functional network architectures recovered from these two types of neural activity remains unknown. Here we map electromagnetic networks (measured using magnetoencephalography; MEG) to haemodynamic networks (measured using functional magnetic resonance imaging; fMRI). We find that the relationship between the two modalities is regionally heterogeneous and systematically follows the cortical hierarchy, with close correspondence in unimodal cortex and poor correspondence in transmodal cortex. Comparison with the BigBrain histological atlas reveals that electromagnetic-haemodynamic coupling is driven by laminar differentiation and neuron density, suggesting that the mapping between the two modalities can be explained by cytoarchitectural variation. Importantly, haemodynamic connectivity cannot be explained by electromagnetic activity in a single frequency band, but rather arises from the mixing of multiple neurophysiological rhythms. Correspondence between the two is largely driven by MEG functional connectivity at the beta (15-29 Hz) frequency band. Collectively, these findings demonstrate highly organized but only partly overlapping patterns of connectivity in MEG and fMRI functional networks, opening fundamentally new avenues for studying the relationship between cortical microarchitecture and multi-modal connectivity patterns.
In vitro discovery and optimization of a human monoclonal antibody that neutralizes neurotoxicity and lethality of cobra snake venom
Authors: Ledsgaard Line , Laustsen Andreas H. , Pus Urska , Wade Jack , Villar Pedro , Boddum Kim , Slavny Peter , Masters Edward W. , Arias Ana S. , Oscoz Saioa , Griffiths Daniel T. , Luther Alice M. , Lindholm Majken , Leah Rachael A. , Møller Marie Sofie , Ali Hanif , McCafferty John , Lomonte Bruno , Gutiérrez José M. , Karatt-Vellatt Aneesh 
Published: September 2021

AbstractThe monocled cobra (Naja kaouthia) is one of the most feared snakes in Southeast Asia. It is a highly dangerous species with a potent venom deriving its toxicity predominantly from abundant long-chain α-neurotoxins. The only specific treatment for snakebite envenoming is antivenom, which is based on animal-derived polyclonal antibodies. Despite the lifesaving importance of these medicines over the past 120 years, and their ongoing role in combating snakebite disease, major limitations in safety, supply consistency, and efficacy creates a need for a new generation of improved treatments based on modern biotechnological techniques. Here, we describe the initial discovery and subsequent optimization of a recombinant human monoclonal immunoglobin G (IgG) antibody against α-cobratoxin using phage display technology. Affinity maturation of the parental antibody by light chain-shuffling resulted in an 8-fold increase in affinity, translating to a significant increase in in vitro neutralization potency and in vivo efficacy. While the parental antibody prolonged survival of mice challenged with purified α-cobratoxin, the optimized antibody prevented lethality when incubated with N. kaouthia whole venom prior to intravenous injection. This study is the first to demonstrate neutralization of whole snake venom by a single recombinant monoclonal antibody. Importantly, this suggests that for venoms whose toxicity relies on a single predominant toxin group, such as that of N. kaouthia, as little as one monoclonal antibody may be sufficient to prevent lethality, thus providing a tantalizing prospect of bringing recombinant antivenoms based on human monoclonal or oligoclonal antibodies to the clinic.One Sentence SummaryA recombinant human monoclonal immunoglobulin G antibody, discovered and optimized using in vitro methods, was demonstrated to neutralize the lethal effect of whole venom from the monocled cobra in mice via abrogation of α-neurotoxin-mediated neurotoxicity.
How do I bite thee? Let me count the ways: Exploring the Implications of Individual Biting Habits of Aedes aegypti for Dengue Transmission
Authors: Christofferson Rebecca C. , Wearing Helen J. , Turner Erik A. , Walsh Christine S. , Salje Henrik , Kiem Cécile Tran , Cauchemez Simon 
Published: September 2021

AbstractIn models of mosquito-borne transmission, the mosquito biting rate is an influential parameter, and understanding the heterogeneity of the process of biting is important, as biting is usually assumed to be relatively homogeneous across individuals, with time-between-bites described by an exponentially distributed process. However, these assumptions have not been addressed through laboratory experimentation. We experimentally investigated the daily biting habits of Ae. aegypti at three temperatures (24°C, 28°C, and 32°C) and determined that there was individual heterogeneity in biting habits (number of bites, timing of bites, etc.). We further explored the consequences of biting heterogeneity using an individual-based model designed to examine whether a particular biting profile determines whether a mosquito is more or less likely to 1) become exposed given a single index case of dengue (DENV) and 2) transmit to a susceptible human individual. Our experimental results indicate that there is heterogeneity among individuals and among temperature treatments. We further show that this results in altered probabilities of transmission of DENV to and from individual mosquitoes based on biting profiles. While current model representation of biting may work under some conditions, it might not uniformly be the best fit for this process. Our data also confirm that biting is a non-monotonic process with temperatures around 28°C being optimum.Author SummaryMosquito biting is a necessary and critical part of arbovirus transmission. The mosquito must bite once to acquire a virus and again to transmit, and these two bites must be separated by sufficient time for the virus to get to the salivary glands of the mosquito. Thus, both the number and timing of bites is important. We experimentally investigated how these bite characteristics might be different among individuals and further explored how temperature affected the overall heterogeneity of biting in Aedes aegypti mosquitoes, which carry many arboviruses like dengue virus (DENV). We found that the biting profiles – including number and timing thereof – did vary within temperature groups among individuals and compared outcomes associated with each individual in an individual based model of household DENV transmission. Our results further confirmed that temperatures around 28°C are optimal for mosquito biting (and transmission), that correlations between biting characteristics and transmission were not uniform across temperature, which represents another layer of heterogeneity, and that – at least at 28°C – the null assumption of an exponential or an exponential like (geometric) distribution of biting in mathematical models of transmission is not the best and offer an alternative.
Freeze-thaw Cycles Enable a Prebiotically Plausible and Continuous Pathway from Nucleotide Activation to Nonenzymatic RNA Copying
Authors: Zhang Stephanie J. , Duzdevich Daniel , Carr Christopher E. , Szostak Jack W. 
Published: September 2021

AbstractNonenzymatic template-directed RNA copying using chemically activated nucleotides is thought to have played a key role in the emergence of genetic information on the early Earth. A longstanding question concerns the number and nature of different environments that might have been necessary to enable all of the steps from nucleotide synthesis to RNA replication. Here we explore three sequential steps from this overall pathway: nucleotide activation, synthesis of imidazolium-bridged dinucleotides, and template-directed primer extension. We find that all three steps can take place in one reaction mixture, under conditions of multiple freeze-thaw cycles. Recent experiments have demonstrated a potentially prebiotic methyl isocyanide-based nucleotide activation chemistry. Unfortunately, the original version of this approach is incompatible with nonenzymatic RNA copying because the high required concentration of the imidazole activating group prevents the accumulation of the essential imidazolium-bridged dinucleotide needed for primer extension. Here we report that ice eutectic phase conditions facilitate not only the methyl isocyanide-based activation of ribonucleotide 5′-monophosphates with stoichiometric 2-aminoimidazole, but also the subsequent conversion of these activated mononucleotides into imidazolium-bridged dinucleotides. Furthermore, this one pot approach is compatible with template-directed primer extension in the same reaction mixture. Our results suggest that the simple and common environmental fluctuation of freeze-thaw cycles could have played an important role in prebiotic nucleotide activation and nonenzymatic RNA copying.Significance StatementThe replication of RNA without the aid of evolved enzymes may have enabled the inheritance of useful molecular functions during the origin of life. Several key steps on the path to RNA replication have been studied in isolation, including chemical nucleotide activation, synthesis of a key reactive intermediate, and nonenzymatic RNA copying. Here we report a prebiotically plausible scenario under which these reactions can happen together under mutually compatible conditions. Thus, this pathway could potentially have operated in nature without the complicating requirement for exchange of materials between distinct environments.
Sex biases in cancer and autoimmune disease incidence are strongly positively correlated with mitochondrial gene expression across human tissues
Authors: Crawford David R. , Sinha Sanju , Nair Nishanth Ulhas , Ryan Bríd M. , Barnholtz-Sloan Jill S. , Mount Stephen M. , Erez Ayelet , Aldape Ken , Castle Philip E. , Rajagopal Padma S. , Day Chi-Ping , Schäffer Alejandro A. , Ruppin Eytan 
Published: September 2021

AbstractCancer occurs more frequently in men while autoimmune diseases (AIDs) occur more frequently in women. To explore whether these sex biases have a common basis, we collected 167 AID incidence studies from many countries for tissues that have both a cancer type and an AID that arise from that tissue. Analyzing a total of 182 country-specific, tissue-matched cancer-AID incidence rate sex bias data pairs, we find that, indeed, the sex biases observed in the incidence of AIDs and cancers that occur in the same tissue are positively correlated across human tissues. The common key factor whose levels across human tissues are most strongly associated with these incidence rate sex biases is the sex bias in the expression of the 37 genes encoded in the mitochondrial genome.
Empirical estimates of the mutation rate for an alphabaculovirus
Authors: Boezen Dieke , Ali Ghulam , Wang Manli , Wang Xi , van der Werf Wopke , Vlak Just M. , Zwart Mark P. 
Published: September 2021

AbstractMutation rates are of key importance for understanding evolutionary processes and predicting their outcomes. Empirical estimates of mutation rate are available for a number of RNA viruses, but few are available for DNA viruses, which tend to have larger genomes. Whilst some viruses have very high mutation rates, lower mutation rates are expected for viruses with large genomes to ensure genome integrity. Alphabaculoviruses are insect viruses with large genomes and often have high levels of polymorphism, suggesting high mutation rates despite evidence of proofreading activity by the replication machinery. Here, we report an empirical estimate of the mutation rate per base per strand copying (s/n/r) of Autographa californica multiple nucleopolyhedrovirus (AcMNPV). To avoid biases due to selection, we analyzed mutations that occurred in a stable, non-functional genomic insert after five serial passages in Spodoptera exigua larvae. Population bottlenecks, viral mode of replication and thresholds for mutation detection likely affect mutation rate estimates, and we therefore used population genetic models that account for these processes to infer the mutation rate. We estimated a mutation rate of 1×10−7 s/n/r. This estimate was not sensitive to different model assumptions or including whole genome data. The rates at which different classes of mutations accumulate provide good evidence for neutrality of mutations occurring within the inserted region. We therefore present a robust approach for mutation rate estimation for viruses with stable genomes, and strong evidence of a much lower alphabaculovirus mutation rate than supposed based on the high levels of polymorphism observed.Author SummaryVirus populations can evolve rapidly, driven by the large number of mutations that occur during virus replication. It is challenging to measure mutation rates because selection will affect which mutations are observed: beneficial mutations are overrepresented in virus populations, while deleterious mutations are selected against and therefore underrepresented. Few mutation rates have been estimated for viruses with large DNA genomes, and there are no estimates for any insect virus. Here, we estimate the mutation rate for an alphabaculovirus, a virus that infects caterpillars and has a large, 134 kilobase pair DNA genome. To ensure that selection did not bias our estimate of mutation rate, we studied which mutations occurred in a large artificial region inserted into the virus genome, where mutations did not affect viral fitness. We deep sequenced evolved virus populations, and compared the distribution of observed mutants to predictions from a simulation model to estimate mutation rate. We found evidence for a relatively low mutation rate, of one mutation in every 10 million bases replicated. This estimate is in line with expectations for a virus with self-correcting replication machinery and a large genome.
Lifespan analysis of dystrophic mdx fast-twitch muscle morphology and its impact on contractile function
Authors: Kiriaev Leonit , Kueh Sindy , Morley John W. , North Kathryn N. , Houweling Peter J. , Head Stewart I. 
Published: September 2021

ABSTRACTDuchenne muscular dystrophy is caused by the absence of the protein dystrophin from skeletal muscle and is characterized by progressive cycles of necrosis/regeneration. Using the dystrophin deficient mdx mouse model we studied the morphological and contractile chronology of dystrophic skeletal muscle pathology in fast twitch EDL muscles from animals 4-22 months of age containing 100% regenerated muscle fibers. Catastrophically, the older age groups lost ∼80% of their maximum force after one eccentric contraction of 20% strain, with the greatest loss ∼93% recorded in senescent 22 month old mdx mice. In old age groups there was minimal force recovery ∼24% after 120 minutes, correlated with a dramatic increase in the number and complexity of branched fibers. This data supports our two-stage model where a “tipping point” is reached when branched fibers rupture irrevocably on eccentric contraction. These findings have important implications for pre-clinical drug studies and genetic rescue strategies.
Sapogenin based self-assembly structures activating a non-apoptotic cell death via multiple pathways
Authors: Üner Göklem , Bedir Erdal , Serçinoğlu Onur , Kırmızıbayrak Petek Ballar 
Published: September 2021

AbstractInduction of distinct cell death pathways is critical to deal with tumor heterogeneity and therapeutic resistance. In our previous study, we reported a promising saponin analog (AG-08) for cancer therapy inducing non-canonical necrotic cell death. Here, we describe that AG-08 forms unique supramolecular structures responsible for its biological activity. After internalization via non-canonical endocytosis pathway, these structures affect several cell signaling pathways including unfolded protein response, immune response, oxidative stress and heat stress. Moreover, we prepared 18 analogs to reveal the role of residues on the formation of supramolecular structures and biological activities. The results have demonstrated that unique structural features are required for particulate structures and unprecedented cell death mechanism. Although small molecule based supramolecular assemblies have widely been accepted as nuisance for drug discovery studies, our results indicate that they may provide a new research field for anti-cancer drug development studies.
Retrospective analysis of enhancer activity and transcriptome history
Authors: Boers Ruben , Boers Joachim , Tan Beatrice , Wassenaar Evelyne , Sanchez Erlantz Gonzalez , Sleddens Esther , Tenhagen Yasha , van Leeuwen Marieke E. , Mulugeta Eskeatnaf , Laven Joop , Creyghton Menno , Baarends Willy , van IJcken Wilfred F. J. , Gribnau Joost 
Published: September 2021

AbstractCell state changes in development and disease are controlled by gene regulatory networks, the dynamics of which are difficult to track in real time. Here, we utilize an inducible DCM-RNA-polymerase-subunit-b fusion protein, to label active genes and enhancers with a bacterial methylation mark that does not affect gene transcription and is propagated in S-phase. We applied this DCM-time-machine (DCM-TM) technology to study intestinal homeostasis, following enterocyte differentiation back in time, revealing rapid and simultaneous activation of enhancers and nearby genes during intestinal stem cell (ISC) differentiation. We provide new insights in the absorptive-secretory lineage decision in ISC differentiation, and show that ISCs retain a unique chromatin landscape required to maintain ISC identity and delineate future expression of differentiation associated genes. DCM-TM has wide applicability in tracking cell states, providing new insights in the regulatory networks underlying cell state changes in development and differentiation.
Disruption of c-MYC binding and chromosomal looping involving genetic variants associated with ankylosing spondylitis upstream of RUNX3 promoter
Authors: Cohen Carla J , Davidson Connor , Selmi Carlo , Bowness Paul , Knight Julian C , Wordsworth B Paul , Vecellio Matteo 
Published: September 2021

ABSTRACTBackgroundAnkylosing Spondylitis (AS) is a common form of inflammatory spinal arthritis with a complex aetiology and high heritability, involving more than 100 genetic associations. These include several AS-associated single nucleotide polymorphisms (SNPs) upstream of RUNX3, which encodes the multifunctional RUNT-related transcription factor (TF) 3. The lead associated SNP rs6600247 (p= 2.6 x 10-15) lies ~13kb upstream of the RUNX3 promoter adjacent to a c-MYC TF binding-site. The effect of rs6600247 genotype on DNA binding and chromosome looping were investigated by electrophoretic mobility gel shift assays (EMSA), Western blotting-EMSA (WEMSA) and Chromosome Conformation Capture (3C).ResultsInterrogation of ENCODE published data showed open chromatin in the region overlapping rs6600247 in primary human CD14+ monocytes in contrast to Jurkat T cell line or primary T-cells. The rs6600247 AS-risk allele is predicted to specifically disrupt a c-MYC binding-site. Using a 50bp DNA probe spanning rs6600247 there was consistently less binding to the AS-risk “C” allele of both purified c-MYC protein and nuclear extracts (NE) from monocyte-like U937 cells. WEMSA on U937 NE and purified c-MYC protein confirmed these differences (n=2; p<0.05). 3C experiments demonstrated negligible interaction between the region encompassing rs6600247 and the RUNX3 promoter. A stronger interaction frequency was demonstrated between the RUNX3 promoter and the previously characterised AS-associated SNP rs4648889.ConclusionsThe lead SNP rs6600247, located in an enhancer-like region upstream of the RUNX3 promoter, modulates c-MYC binding. However, the region encompassing rs6600247 has rather limited physical interaction with the promoter of RUNX3. In contrast a clear chromatin looping event between the region encompassing rs4648889 and the RUNX3 promoter was observed. These data provide further evidence for complexity in the regulatory elements upstream of the RUNX3 promoter and the involvement of RUNX3 transcriptional regulation in AS.
The impact of fast radiation on the phylogeny ofBactrocerafruit flies
Authors: Valerio Federica , Zadra Nicola , Stabelli Omar Rota , Ometto Lino 
Published: September 2021

AbstractTrue fruit flies (Tephritidae) include several species that cause extensive damage to agriculture worldwide. Among them, species of the genusBactroceraare widely studied to understand the traits associated to their invasiveness and ecology. Comparative approaches based on a reliable phylogenetic framework are particularly effective, but, to date, molecular phylogenies ofBactroceraare still controversial. Here, we employed a comprehensive genomic dataset to infer a robust backbone phylogeny of eleven representativeBactroceraspecies and two outgroups. We further provide the first genome scaled inference of their divergence using calibrated relaxed clock. The results of our analyses support a closer relationship ofB. dorsalistoB. latifronsthan toB. tryoni, in contrast to all mitochondrial-based phylogenies. By comparing different evolutionary models, we show that this incongruence likely derives from the fast and recent radiation of these species that occurred around 2 million years ago, which may be associated with incomplete lineage sorting and possibly (ongoing) hybridization. These results can serve as basis for future comparative analyses and highlight the utility of using large datasets and efficient phylogenetic approaches to study the evolutionary history of species of economic importance.