bluuebunny/crossref_metadata_2025_split huggingface dataset:
Drivers of Rift Valley fever virus persistence and the impact of control measures in a spatially heterogeneous landscape: the case of the Comoros archipelago, 2004–2015
Authors: Tennant Warren S. D. , Cardinale Eric , Cêtre-Sossah Catherine , Moutroifi Youssouf , Le Godais Gilles , Colombi Davide , Spencer Simon E. F. , Tildesley Mike J. , Keeling Matt J. , Charafouddine Onzade , Colizza Vittoria , Edmunds W. John , Métras Raphaёlle 
Published: March 2021

AbstractRift Valley fever (RVF) is one of the many zoonotic arboviral haemorrhagic fevers present in Africa. The ability of the pathogen to persist in multiple geographically distinct regions has raised concerns about its potential for spread to and persistence within currently disease-free areas. However, the mechanisms for which RVF virus persistence occurs at both local and broader geographical scales have yet to be fully understood and rigorously quantified. Here, we developed a mathematical metapopulation model describing RVF virus transmission in livestock across the four islands of the Comoros archipelago and fitted this model in a Bayesian framework to surveillance data conducted in livestock across those islands between 2004 and 2015. In doing so, we estimated the importance of island-specific environmental factors and animal movements between those islands on the persistence of RVF virus in the archipelago, and we further tested the impact of different control scenarios on reducing disease burden. We demonstrated that the archipelago network was able to sustain viral transmission over 10 years after assuming only one introduction event during early 2007. Movement restrictions were only useful to control the disease in Anjouan and Mayotte, as Grande Comore and Mohéli were able to self-sustain RVF viral persistence, probably due to local environmental conditions that are more favourable for vectors. We also evidenced that repeated outbreaks during 2004-2020 may have gone under-detected by local surveillance in Grande Comore and Mohéli. Strengthened longterm and coordinated surveillance would enable the detection of viral re-emergence and evaluation of different relevant vaccination programmes.
Courtship ritual of male and female nuclei during fertilisation inNeurospora crassa
Authors: Brun Sylvain , Kuo Hsiao-Che , Jeffree Chris E. , Thomson Darren D. , Read Nick 
Published: March 2021

AbstractSexual reproduction is a key process influencing the evolution and adaptation of animals, plants and many eukaryotic microorganisms, such as fungi. Mycologists have described the different fungal fruiting bodies, while geneticists have partly unravelled the regulation of sexual development. However, the sequential fungal cell biology of fertilisation and the associated nuclear dynamics after plasmogamy are poorly understood. Using histone-fluorescent parental isolates, we tracked male and female nuclei during fertilisation in the model ascomycetesNeurospora crassausing live-cell-imaging. This study unravels the behaviour of trichogyne resident female nuclei and the extraordinary manner that male nuclei migrate up the trichogyne to the protoperithecium. Our observations raise new fundamental questions about themodus operandiof nuclei movements during sexual reproduction, male and female nuclear identity, guidance of nuclei within the trichogyne and, unexpectedly, the avoidance of “polyspermy” in fungi. The spatio-temporal dynamics of male nuclei within the trichogyne following plasmogamy are also described, where the speed and the deformation of male nuclei are of the most dramatic observed to date in a living organism.
New opabiniid diversifies the weirdest wonders of the euarthropod lower stem group
Authors: Pates Stephen , Wolfe Joanna M. , Lerosey-Aubril Rudy , Daley Allison C. , Ortega-Hernández Javier 
Published: March 2021

AbstractOnce considered ‘weird wonders’ of the Cambrian, the emblematic Burgess Shale animalsAnomalocarisandOpabiniaare now recognized as lower stem-group euarthropods.Anomalocarisand its relatives (radiodonts) had a worldwide distribution and survived until at least the Devonian, whereas - despite intense study -Opabiniaremains the only formally described opabiniid to date. Here we reinterpret a fossil from the Wheeler Formation of Utah as a new opabiniid, KUMIP 314087. By visualizing the sample of phylogenetic topologies in treespace, our results fortify support for the position of KUMIP 314087 beyond the nodal support traditionally applied. Our phylogenetic evidence expands opabiniids to multiple Cambrian Stages spanning approximately five million years. Our results underscore the power of treespace visualization for resolving imperfectly preserved fossils and expanding the known diversity and spatiotemporal ranges within the euarthropod lower stem group.Additional noteThis work contains a new biological name. New names in preprints are not considered available by the ICZN. To avoid ambiguity, the new biological name is not included in this preprint, and the specimen number (KUMIP 314087) is used as a placeholder.Abstract FigureCover image.Artistic reconstruction of the new opabiniid from the Wheeler Formation, Utah, USA (Cambrian: Drumian). Artwork by F. Anthony.
Growth differentiation factor 15 increases in both cerebrospinal fluid and serum during pregnancy
Authors: Andersson-Hall Ulrika , Svedin Pernilla , Mallard Carina , Blennow Kaj , Zetterberg Henrik , Holmäng Agneta 
Published: March 2021

AbstractAimGrowth differentiation factor 15 (GDF15) increases in serum during pregnancy to levels not seen in any other physiological state and is suggested to be involved in pregnancy-induced nausea, weight regulation and glucose metabolism. The main action of GDF15 is regulated through a receptor of the brainstem, i.e., through exposure of GDF15 in both blood and cerebrospinal fluid (CSF). The aim of the current study was to measure GDF15 in both CSF and serum during pregnancy, and to compare it longitudinally to non-pregnant levels.MethodsWomen were sampled at elective caesarean section (n=45, BMI=28.1±5.0) and were followed up 5 years after pregnancy (n=25). GDF15, insulin and leptin were measured in CSF and serum. In addition, glucose, adiponectin and Hs-CRP were measured in blood.ResultsGDF15 levels were higher during pregnancy compared with follow-up in both CSF (385±128 vs. 115±32 ng/l, p<0.001) and serum (73789±29198 vs. 404±102 ng/l, p<0.001). CSF levels correlated with serum levels during pregnancy (p<0.001), but not in the non-pregnant state (p=0.98). Both CSF and serum GDF15 were highest in women carrying a female fetus (p<0.001), previously linked to pregnancy-induced nausea. Serum GDF15 correlated with the homeostatic model assessment for beta-cell function and placental weight, and CSF GDF15 correlated inversely with CSF insulin levels.ConclusionThis, the first study to measure CSF GDF15 during pregnancy, demonstrated increased GDF15 levels in both serum and CSF during pregnancy. The results suggest that effects of GDF15 during pregnancy can be mediated by increases in both CSF and serum levels.
Activation of innate immunity by neutral polysaccharides from broccoli buds
Authors: Miyashita Atsushi , Kataoka Keiko , Sekimizu Kazuhisa 
Published: March 2021

AbstractEdible substances that stimulate the innate immune system are good candidates for functional foods to improve human health. We have previously reported that acidic polysaccharides from broccoli extract exhibit immunostimulatory effects, but neutral polysaccharides have been overlooked. In the present study, we found that neutral polysaccharides have significantly stronger (higher specific activity) immunostimulatory activity than acidic polysaccharides. The hot water extract of broccoli showed the immunostimulatory activity in the silkworm muscle contraction assay, suggesting that it stimulates innate immunityviaparalytic peptide pathway. The activity was concentrated in the buds, but not in the stems and stalk. The active substance was recovered in the flow-through fraction of diethylaminoethyl-cellulose column chromatography with neutral polysaccharides. The specific activity of the fraction was significantly higher than that of the acidic polysaccharides from broccoli reported previously. These results suggest that the neutral polysaccharide present in broccoli buds stimulates innate immunity and can be semi-purified by one-step chromatography.
Predicting the fitness costs of complex mutations
Authors: Yubero Pablo , Poyatos Juan F. 
Published: March 2021

ABSTRACTThe fitness cost of complex pleiotropic mutations is generally difficult to assess. On the one hand, it is necessary to identify which molecular properties are directly altered by the mutation. On the other, this alteration modifies the activity of many genetic targets with uncertain consequences. Here, we examine the possibility of addressing these challenges by identifying unique predictors of these costs. To this aim, we consider mutations in the RNA polymerase (RNAP) inEscherichia colias a model of complex mutations. Changes in RNAP modify the global program of transcriptional regulation, with many consequences. Among others is the difficulty to decouple the direct effect of the mutation from the response of the whole system to such mutation. A problem that we solve quantitatively with data of a set of constitutive genes, which better read the global program. We provide a statistical framework that incorporates the direct effects and other molecular variables linked to this program as predictors, which leads to the identification that some genes are more suitable predictors than others. Therefore, we not only identified which molecular properties best anticipate costs in fitness, but we also present the paradoxical result that, despite pleiotropy, specific genes serve as better predictors. These results have connotations for the understanding of the architecture of robustness in biological systems.
Multiple introductions of multidrug-resistant typhoid associated with acute infection and asymptomatic carriage, Kenya
Authors: Kariuki Samuel , Dyson Zoe A , Mbae Cecilia , Ngetich Ronald , Kavai Susan M , Wairimu Celestine , Anyona Stephen , Gitau Naomi , Onsare Robert , Ongandi Beatrice , Duchene Sebastian , Ali Mohamed , Clemens John , Holt Kathryn E , Dougan Gordon 
Published: March 2021

AbstractUnderstanding the dynamics of infection and carriage of typhoid in endemic settings is critical to finding solutions to prevention and control. In a 3 year case-control study, we investigated typhoid among children aged <16 years (4,670 febrile cases and 8,549 age matched controls) living in an informal settlement, Nairobi, Kenya. 148S. Typhi isolates from cases and 95 from controls (stool culture) were identified; a carriage frequency of 1%. Whole-genome sequencing showed 97% of cases and 88% of controls were genotype 4.3.1 (Haplotype58), with the majority of each (76% and 88%) being multidrug-resistant strains in 3 sublineages of H58 genotype (East Africa 1 (EA1), EA2, and EA3), with sequences from cases and carriers intermingled. The high rate of multidrug-resistant H58S.Typhi, and the close phylogenetic relationships between carriers and controls, provides evidence for the role of carriers as a reservoir for the community spread of typhoid in this setting.
Bruton’s Tyrosine Kinase Supports Gut Mucosal Immunity and Commensal Microbiome Recognition in Autoimmune Arthritis
Authors: Bonami Rachel H. , Thurman Christina E. , Westlake Camille S. , Nyhoff Lindsay E. , Barron Bridgette B. , Kendall Peggy L. 
Published: March 2021

AbstractBruton’s tyrosine kinase (Btk) deficiency preferentially eliminates autoreactive B cells while sparing normal humoral responses, but has not been studied in mucosal immunity. Commensal microbes are essential for arthritis in K/BxN mice, used here to examine how BTK-mediated signaling interfaces with the microbiome.Btk-deficient K/BxN mice were found to have small Peyer’s Patches with reduced germinal center and IgA+B cells. Although lamina propria IgA+plasma cells were numerically normal, intestinal IgA was low and IgA coating of commensal bacteria was reduced. IgA-seq showed a shift in microbes that are normally IgA-coated into the uncoated fraction inBtk-deficient mice. In this altered microbial milieau, the proportion ofParabacteroides distasoniswas reduced inBtk-deficient K/BxN mice. To determine whetherP. distasoniscontributes to arthritis, it was reintroduced into antibiotic-protected K/BxN mice, where it restored disease. This suggests thatP. distasonis’inability to thrive inBtk-deficient mice may be a factor in disease protection. Thus, BTK supports normal intestinal IgA development, with downstream effects on the microbiome that may contribute to autoimmunity.
The bacterial amyloids phenol soluble modulins fromStaphylococcus aureuscatalyze alpha-synuclein aggregation
Authors: Haikal Caroline , Ortigosa Lei , Bernfur Katja , Svanbergsson Alexander , Linse Sara , Li Jia-Yi 
Published: March 2021

AbstractAggregated α-synuclein (α-syn) is the main constituent of Lewy bodies, the main pathological hallmark of Parkinson’s disease (PD). Environmental factors are thought to be potential triggers capable of initiating the aggregation of the otherwise monomeric α-syn. Braak’s seminal work redirected attention to the intestine and recent reports of dysbiosis have highlighted the potential causative role that the microbiome might play in the pathology of PD.Staphylococcus aureusis a bacterium carried by 30-70% of the general population. It has been shown to produce functional amyloids, called Phenol Soluble Modulins (PSMαs). Here, we studied the kinetics of α-syn aggregation under quiescent conditions in the presence or absence of four different PSMα peptides and observed a remarkable shortening of the lag phase in their presence. Whereas pure α-syn monomer did not aggregate up to 450 h after initiation of the experiment in neither neutral nor mildly acidic buffer, the addition of different PSMα peptides resulted in an almost immediate increase in the Thioflavin T (ThT) fluorescence. Despite similar peptide sequences, the different PSMα peptides displayed distinct effects on the kinetics of α-syn aggregation. Kinetic analyses of the data suggest that while all four peptides catalyze α-syn aggregation, the underlying mechanisms might differ with a model of nucleation and elongation fitting the α-syn aggregation induced by PSMα2 but not PSMα1. The results of immunogold TEM imply that the aggregates are fibrillar and composed of α-syn. Addition of the co-aggregated materials to HEK cells expressing the A53T α-syn variant fused to GFP was found to catalyze α-syn aggregation and phosphorylation in the cells. Our results provide evidence of a potential trigger of synucleinopathies and could have implications for the prevention of the diseases.
A general model of multivalent binding with ligands of heterotypic subunits and multiple surface receptors
Authors: Tan Zhixin Cyrillus , Meyer Aaron S. 
Published: March 2021

AbstractMultivalent cell surface receptor binding is a ubiquitous biological phenomenon with functional and therapeutic significance. Predicting the amount of ligand binding for a cell remains an important question in computational biology as it can provide great insight into cell-to-cell communication and rational drug design toward specific targets. In this study, we extend a mechanistic, two-step multivalent binding model. This model predicts the behavior of a mixture of different multivalent ligand complexes binding to cells expressing various types of receptors. It accounts for the combinatorially large number of interactions between multiple ligands and receptors, optionally allowing a mixture of complexes with different valencies and complexes that contain heterogeneous ligand units. We derive the macroscopic predictions and demonstrate how this model enables large-scale predictions on mixture binding and the binding space of a ligand. This model thus provides an elegant and computationally efficient framework for analyzing multivalent binding.
Stability of DNA methylation and chromatin accessibility in structurally diverse maize genomes
Authors: Noshay Jaclyn M , Liang Zhikai , Zhou Peng , Crisp Peter A , Marand Alexandre P , Hirsch Candice N , Schmitz Robert J , Springer Nathan M 
Published: March 2021

AbstractAccessible chromatin and unmethylated DNA are associated with many genes and cis-regulatory elements. Attempts to understand natural variation for accessible chromatin regions (ACRs) and unmethylated regions (UMRs) often rely upon alignments to a single reference genome. This limits the ability to assess regions that are absent in the reference genome assembly and monitor how nearby structural variants influence variation in chromatin state. In this study,de novogenome assemblies for four maize inbreds (B73, Mo17, Oh43 and W22) are utilized to assess chromatin accessibility and DNA methylation patterns in a pan-genome context. The number of UMRs and ACRs that can be identified is more accurate when chromatin data is aligned to the matched genome rather than a single reference genome. While there are UMRs and ACRs present within genomic regions that are not shared between genotypes, these features are substantially enriched within shared regions, as determined by chromosomal alignments. Characterization of UMRs present within shared genomic regions reveals that most UMRs maintain the unmethylated state in other genotypes with only a small number being polymorphic between genotypes. However, the majority of UMRs between genotypes only exhibit partial overlaps suggesting that the boundaries between methylated and unmethylated DNA are dynamic. This instability is not solely due to sequence variation as these partially overlapping UMRs are frequently found within genomic regions that lack sequence variation. The ability to compare chromatin properties among individuals with structural variation enables pan-epigenome analyses to study the sources of variation for accessible chromatin and unmethylated DNA.Article summaryRegions of the genome that have accessible chromatin or unmethylated DNA are often associated with cis-regulatory elements. We assessed chromatin accessibility and DNA methylation in four structurally diverse maize genomes. There are accessible or unmethylated regions within the non-shared portions of the genomes but these features are depleted within these regions. Evaluating the dynamics of methylation and accessibility between genotypes reveals conservation of features, albeit with variable boundaries suggesting some instability of the precise edges of unmethylated regions.
Butyryl/Caproyl-CoA:Acetate CoA-Transferase: Cloning, Expression and Characterization of the Key Enzyme Involved in Medium-Chain Fatty Acid Biosynthesis
Authors: Yang Qingzhuoma , Guo Shengtao , Lu Qi , Tao Yong , Zheng Decong , Zhou Qinmao , Liu Jun 
Published: March 2021

AbstractCoenzyme A transferases (CoATs) are important enzymes involved in carbon chain elongation contributing to medium-chain fatty acid (MCFA) biosynthesis. For example, butyryl-CoA:acetate CoA transferase (BCoAT) is responsible for the final step of butyrate synthesis from butyryl-CoA. However, little is known about caproyl-CoA:acetate CoA-transferase (CCoAT), which is responsible for the final step of caproate synthesis from caproyl-CoA. In this study, two CoAT genes fromRuminococcaceaebacterium CPB6 andClostridium tyrobutyricumBEY8 were identified by gene cloning and expression analysis. The enzyme assays and kinetic studies were carried out using butyryl-CoA or caproyl-CoA as the substrate. CPB6-CoAT can catalyze the conversion of both butyryl-CoA to butyrate and caproyl-CoA to caproate, but its catalytic efficiency with caproyl-CoA as the substrate was 3.8 times higher than that with butyryl-CoA. In contrast, BEY8-CoAT had only BCoAT activity, not CCoAT activity. This demonstrated the existence of a specific CCoAT involved in chain elongation via the reverse β-oxidation pathway. Comparative bioinformatics analysis showed the presence of a highly conserved motif (GGQXDFXXGAXX) in CoATs, which is predicted to be the active center of CoATs. Single point mutations in the conserved motif of CPB6-CoAT (Asp346 and Ala351) led to marked decreases in the activity for butyryl-CoA and caproyl-CoA, indicating that the conserved motif is the active center of CPB6-CoAT, and sites Asp346 and Ala351 were critical residues that affect enzymatic activity. This work provides insight into the function of CCoAT in caproic acid biosynthesis and improves the understanding of the chain elongation pathway for MCFA production.
Bi-directional flow of the funny current (If) during the pacemaking cycle in murine sinoatrial node myocytes
Authors: Peters Colin H. , Liu Pin W. , Morotti Stefano , Gantz Stephanie C. , Grandi Eleonora , Bean Bruce P. , Proenza Catherine 
Published: March 2021

AbstractSinoatrial node myocytes (SAMs) act as cardiac pacemaker cells by firing spontaneous action potentials (APs) that initiate each heartbeat. The funny current, If, is critical for the generation of these spontaneous APs; however, its precise role during the pacemaking cycle remains unresolved. We used the AP-clamp technique to quantify Ifduring the cardiac cycle in mouse SAMs. We found that Ifis persistently active throughout the sinoatrial AP, with surprisingly little voltage-dependent gating. As a consequence, it carries both inward and outward current around its reversal potential of -30 mV. Despite operating at only 2-5% of its maximal conductance, Ifcarries a substantial fraction of both depolarizing and repolarizing net charge movement during the firing cycle. We also show that β-adrenergic receptor stimulation increases the percentage of net depolarizing charge moved by If, consistent with a contribution of Ifto the fight-or-flight increase in heart rate. These properties were confirmed by heterologously-expressed HCN4 channels and by mathematical models of If. Modelling further suggested that the slow activation and deactivation of the HCN4 isoform underlie the persistent activity of Ifduring the sinoatrial AP. These results establish a new conceptual framework for the role of Ifin pacemaking, in which it operates at a very small fraction of maximal activation but nevertheless drives membrane potential oscillations in SAMs by providing substantial driving force in both inward and outward directions.Significance StatementCardiac pacemaker cells trigger each heartbeat by virtue of spontaneous oscillations in their membrane voltage. Although the funny current (If) is critical for these oscillations and for setting heart rate, its precise role remains an enigma because it activates mostly outside of the physiological voltage range and quite slowly relative to the pacemaker cycle. Here we show that Ifis persistently active in pacemaker cells; once opened, the small fraction of ion channels that conduct Ifdo not re-close. Consequently, Ifflows both inward and outward to help propel the voltage oscillations and it paradoxically conducts a large fraction of the net charge movement. These results establish a new conceptual framework for the role of Ifin driving cardiac pacemaking.