bluuebunny/crossref_metadata_2025 huggingface dataset:
An objective-based prioritization approach to improve trophic complexity through ecological restoration
Authors: Ladouceur Emma , McGowan Jennifer , Huber Patrick , Possingham Hugh , Scridel Davide , van Klink Roel , Poschlod Peter , Cornelissen J. Hans C. , Bonomi Costantino , Jiménez-Alfaro Borja
Published: March 2021

Reassembling ecological communities and rebuilding habitats through active restoration treatments requires curating the selection of plant species to use in seeding and planting mixes. Ideally, these mixes should be assembled based on attributes that support ecosystem function and services, promote plant and animal species interactions and ecological networks in restoration while balancing project constraints. Despite these critical considerations, it is common for species mixes to be selected opportunistically. Reframing the selection of seed mixes for restoration around ecological objectives is essential for success but accessible methods and tools are needed to support this effort.

We developed a framework to optimize species seed mixes based on prioritizing plant species attributes to best support different objectives for ecosystem functions, services, and trophic relationships such as pollination, seed dispersal, and herbivory. We compared results to approaches where plant species are selected to represent plant taxonomic richness, dominant species, and at random. We tested our framework for 176 plant species found in European alpine grasslands and identified 163 associated attributes affiliated to trophic relationships, ecosystem functions, and services.

In all cases, trophic relationships, ecosystem functions, and services can be captured more efficiently through objective-based prioritization using the functional identity of plant species. Solutions (plant species lists) can be compared quantitatively, in terms of costs, species, or objectives. We confirm that a random draw of plant species from the regional plant species pool cannot be assumed to support other trophic groups and ecosystem functions and services.

Synthesis and Applications. Our framework is presented as a proof of concept to help restoration practitioners better apply quantitative decision–support to plant species selection in order to meet ecological restoration outcomes. Our approach may be tailored to any restoration initiative and habitat where seeding or planting mixes will be applied in active treatments. As global priority and resources are increasingly placed into restoration, this approach could be advanced to help make efficient decisions for many stages of the restoration process.
Effect of Voluntary Adolescent Alcohol Consumption on Encoding of Decision-Related Variables in Prefrontal Cortex
Authors: Corwin Samantha , Roitman Jamie D
Published: March 2021

The medial and orbitofrontal regions of prefrontal cortex (PFC) have been implicated in guiding optimal behavior and updating the economic value of rewards that result from choice behaviors. Both regions mature through adolescence into early adulthood and are thus vulnerable to exposure to neurotoxins, such as alcohol, during this critical developmental window. We sought to examine how voluntary alcohol consumption during adolescence would alter long-term PFC function and subsequent decision-making behavior in adulthood. Male and female rats were given adolescent intermittent ethanol (AIE) exposure to provide voluntary access to alcohol during the period of PFC maturation. In adulthood, we assessed the long-term effects on decision-making behavior using a risk task in adulthood, while concurrently recording neural activity in orbitofrontal cortex (OFC) and medial prefrontal cortex (mPFC). While control animals’ preferences for risky rewards increased with the likelihood of their delivery, AIE animals showed an overall reduction in their preferences for the risky option with higher levels of alcohol consumption, suggesting reduced discriminability of uncertain rewards and a shift away from the potential for reward omission. During task performance, neurons in mPFC and OFC responded to events (lever press, reward delivery). In mPFC, neurons with phasic increases at the time of lever press showed a reversal from larger elevations for risky presses in control animals to larger elevations for certain presses as prior alcohol consumption increased. Neurons in mPFC generally showed less discrimination of reward outcome with increased alcohol consumption as well. In OFC, responses to lever press were largely unaffected by AIE exposure. However, encoding of reward size in OFC showed differential effects in males and females. With higher alcohol consumption in males, OFC neurons showed largest excursions from baseline activity in response to largest reward, and smallest excursions for reward omission. This discrimination was reduced as prior alcohol consumption increased. In females, neurons with increased reward-activity, showed an overall higher level of activity due to stronger responses to certain rewards that were selected more frequently. Collectively the results show diminished capacity of PFC to encode decision-related elements to guide adaptive behavior and further clarify the lasting impact of adolescent alcohol use on neural function and behavior, even in the absence of continued use.
The dual function monoclonal antibodies VIR-7831 and VIR-7832 demonstrate potent in vitro and in vivo activity against SARS-CoV-2
Authors: Cathcart Andrea L. , Havenar-Daughton Colin , Lempp Florian A. , Ma Daphne , Schmid Michael A. , Agostini Maria L. , Guarino Barbara , Di iulio Julia , Rosen Laura E. , Tucker Heather , Dillen Joshua , Subramanian Sambhavi , Sloan Barbara , Bianchi Siro , Pinto Dora , Saliba Christian , Culap Katja , Wojcechowskyj Jason A , Noack Julia , Zhou Jiayi , Kaiser Hannah , Lee Sooyoung , Farhat Nisar , Chase Arthur , Montiel-Ruiz Martin , Dellota Exequiel , Park Arnold , Spreafico Roberto , Sahakyan Anna , Lauron Elvin J. , Czudnochowski Nadine , Cameroni Elisabetta , Ledoux Sarah , Kawaoka Yoshihiro , Werts Adam , Colas Christophe , Soriaga Leah , Telenti Amalio , Purcell Lisa A. , Hwang Seungmin , Snell Gyorgy , Virgin Herbert W. , Corti Davide , Hebner Christy M.
Published: March 2021

Sotrovimab (VIR-7831) and VIR-7832 are dual action monoclonal antibodies (mAbs) targeting the spike glycoprotein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Sotrovimab and VIR-7832 were derived from a parent antibody (S309) isolated from memory B cells of a 2003 severe acute respiratory syndrome coronavirus (SARS-CoV) survivor. Both mAbs contain an “LS” mutation in the Fc region to prolong serum half-life. In addition, VIR-7832 encodes an Fc GAALIE mutation that has been shown previously to evoke CD8+ T-cells in the context of an in vivo viral respiratory infection. Sotrovimab and VIR-7832 neutralize wild-type and variant pseudotyped viruses and authentic virus in vitro. In addition, they retain activity against monoclonal antibody resistance mutations conferring reduced susceptibility to previously authorized mAbs. The sotrovimab/VIR-7832 epitope continues to be highly conserved among circulating sequences consistent with the high barrier to resistance observed in vitro. Furthermore, both mAbs can recruit effector mechanisms in vitro that may contribute to clinical efficacy via elimination of infected host cells. In vitro studies with these mAbs demonstrated no enhancement of infection. In a Syrian Golden hamster proof-of concept wildtype SARS-CoV-2 infection model, animals treated with sotrovimab had less weight loss, and significantly decreased total viral load and infectious virus levels in the lung compared to a control mAb. Taken together, these data indicate that sotrovimab and VIR-7832 are key agents in the fight against COVID-19.
The nuclear ubiquitin ligase adaptor SPOP is a conserved regulator of C9orf72 dipeptide toxicity
Authors: Snoznik Carley , Medvedeva Valentina , Mojsilovic-Petrovic Jelena , Rudich Paige , Oosten James , Kalb Robert G. , Lamitina Todd
Published: March 2021

A hexanucleotide repeat expansion in the C9orf72 gene is the most common cause of inherited amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Unconventional translation of the C9orf72 repeat produces dipeptide repeat proteins (DPRs). Previously, we showed that the DPRs (PR)50 and (GR)50 are highly toxic when expressed inC. elegansand this toxicity depends on nuclear localization of the DPR. In an unbiased genome-wide RNAi screen for suppressors of (PR)50 toxicity, we identified 12 genes that consistently suppressed either the developmental arrest and/or paralysis phenotype evoked by (PR)50 expression. All of these genes have vertebrate homologs and 7/12 contain predicted nuclear localization signals. One of these genes wasspop-1, theC. eleganshomolog of SPOP, a nuclear localized E3 ubiquitin ligase adaptor only found in metazoans. SPOP is also required for (GR)50 toxicity and functions in a genetic pathway that includescul-3, which is the canonical E3 ligase partner for SPOP. Genetic or pharmacological inhibition of SPOP in mammalian primary spinal cord motor neurons suppressed DPR toxicity without affecting DPR expression levels. Finally, we find that genetic inhibition ofbet-1, theC. eleganshomolog of the known SPOP ubiquitination targets BRD2/3/4, suppresses the protective effect of SPOP mutations. Together, these data suggest a model in which SPOP promotes the DPR-dependent ubiquitination and degradation of BRD proteins. We speculate the pharmacological manipulation of this pathway, which is currently underway for multiple cancer subtypes, could also represent a novel entry point for therapeutic intervention to treat C9 FTD/ALS.

Significance statement

The G4C2 repeat expansion in theC9orf72gene is a major cause of Fronto-Temporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS). Unusual translation of the repeat sequence produces two highly toxic dipeptide repeat proteins, PRXand GRX, which accumulate in the brain tissue of individuals with these diseases. Here, we show that PR and GR toxicity in bothC. elegansand mammalian neurons depends on the E3 ubiquitin ligase adaptor SPOP. SPOP acts through the bromodomain protein BET-1 to mediate dipeptide toxicity. SPOP inhibitors, which are currently being developed to treat SPOP-dependent renal cancer, also protect neurons against DPR toxicity. Our findings identify a highly conserved and ‘druggable’ pathway that may represent a new strategy for treating these currently incurable diseases.
Dynamic sampling bias and overdispersion induced by skewed offspring distributions
Authors: Okada Takashi , Hallatschek Oskar
Published: March 2021

Natural populations often show enhanced genetic drift consistent with a strong skew in their offspring number distribution. The skew arises because the variability of family sizes is either inherently strong or amplified by population expansions, leading to so-called ‘jackpot’ events. The resulting allele frequency fluctuations are large and, therefore, challenge standard models of population genetics, which assume sufficiently narrow offspring distributions. While the neutral dynamics backward in time can be readily analyzed using coalescent approaches, we still know little about the effect of broad offspring distributions on the dynamics forward in time, especially with selection. Here, we employ an exact asymptotic analysis combined with a scaling hypothesis to demonstrate that over-dispersed frequency trajectories emerge from the competition of conventional forces, such as selection or mutations, with an emerging time-dependent sampling bias against the minor allele. The sampling bias arises from the characteristic time-dependence of the largest sampled family size within each allelic type. Using this insight, we establish simple scaling relations for allele frequency fluctuations, fixation probabilities, extinction times, and the site frequency spectra that arise when offspring numbers are distributed according to a power lawn−(1+α). To demonstrate that this coarse-grained model captures a wide variety of non-equilibrium dynamics, we validate our results in traveling waves, where the phenomenon of ‘gene surfing’ can produce any exponent 1 <α< 2. We argue that the concept of a dynamic sampling bias is useful generally to develop both intuition and statistical tests for the unusual dynamics of populations with skewed offspring distributions, which can confound commonly used tests for selection or demographic history.
RNA-silencing induces target gene relocalization toward a specialized nuage domain
Authors: Yang Yuchen , Grunwald David , Priess James R. , Mello Craig C.
Published: March 2021

The authors wish to withdraw this manuscript and apologize for errors in the initial submission. All the original experiments were performed by YY. Unfortunately, JP and members of the Mello lab have not been able to replicate some aspects of the study. JP has failed to independently reproduce the specific results showing RNAi-triggered relocalization of target RNA, and P granule specific accumulation of (the P granule component GLH-1) as reported. The conditions/strains analyzed by JP were as follows: (1)oma-1FISH on WT worms [control, 6 hr and 12 hroma-1(RNAi)]. (2)oma-1FISH on OMA-1:GFP worms [control, 6 hr oma-1(RNAi), or 6 hr gfp(RNAi)]. (3)oma-1FISH on WT worms [control, 4hr, 6hr, 8 hr, and 10 hroma-1(RNAi)]. 10-23 gonads were analyzed per experiment. Fixation conditions were essentially as described, with the only known difference being that gonads were not exposed to detergent prior to fixation. Using YYs reagents and protocol the Mello lab has not observed an obvious relocalization of target RNA to P granules (marked by GFP::GLH-1) after 6 hrsoma-1(RNAi);n=92 gonads. CM, JP and DG consider that the published images accurately represent the image stacks provided by YY as representative, raw data, but JP and CM note configurations of FISH signals in germ nuclei and gonad anatomy that they consider unusual. CM, JP and DG have not detected any evidence of image manipulation.

YY states that none of the raw image data were manipulated beyond standard adjustments for brightness and contrast prior to processing images for publication as described. However, YY reports that the images were not representative of the majority of sample gonads, and instead were pre-selected under low magnification for rare examples with asymmetrical, expanded P granules.

Efforts to identify conditions that explain the rare gonads imaged by YY continue in the Mello lab, as do efforts to reproduce independently each of the other reported results; we plan to provide an update in the near future.
A redox-dependent mechanism for AMPK dysregulation interrupts metabolic adaptation of cancer under glucose deprivation
Authors: Lee Younghwan , Itahana Yoko , Ong Choon Chen , Itahana Koji
Published: March 2021

Accelerated aerobic glycolysis is a distinctive metabolic property of cancer cells that confers dependency on glucose for survival. However, the selective therapeutic targeting of this vulnerability has yielded mixed results owing to the different sensitivities of each cancer type to glucose removal and lack of insight into the underlying mechanisms of glucose deprivation-induced cell death.

Here, we screened multiple cell lines to determine their sensitivities to glucose deprivation and found that the cell lines most sensitive to glucose deprivation failed to activate AMPK, a major regulator of metabolic adaptation, resulting in metabolic catastrophe.

Notably, glucose deprivation-induced AMPK dysregulation and rapid cell death were observed only in cancer cell lines with high expression of cystine/glutamate antiporter xCT. While this phenomenon was prevented by pharmacological or genetic inhibition of xCT, overexpression of xCT sensitized resistant cancer cells to glucose deprivation. We found that cystine uptake and glutamate export through xCT under glucose deprivation contributes to rapid NADPH depletion, leading to the collapse of the redox system, which subsequently inactivates AMPK by inhibitory oxidation and phosphorylation. This AMPK dysregulation caused a failure of metabolic switch to fatty acid oxidation upon glucose deprivation, resulting in mitochondrial dysfunction and cell death.

Taken together, these findings suggest a novel cross-talk between the metabolic and signal transduction and reveal a metabolic vulnerability in xCT-high expressing cancer cells to glucose deprivation and provide a rationale for targeting glucose metabolism in these cancer cells.
ExoBow: A transgenic strategy to study CD63 exosomesin vivo
Authors: Adem Bárbara , Bastos Nuno , Ruivo Carolina F. , F. Vieira Patrícia , Seidler Barbara , C. Machado José , Saur Dieter , Cai Dawen , Melo Sonia A.
Published: March 2021

Exosomes are described as central players in a myriad of biological processes. However, the available methodologies to study their function in complex biological systemsin vivoare still very limited. The biodistribution of endogenously produced exosomes, the ability to trace their spontaneous flow in order to identify the cell types they interact with, remains a major challenge. New tools to identify comprehensive networks of communication established by exosomes originated in distinct cell typesin vivo, are fundamental for a better understanding of their biology. Here, we describe the development of a genetically engineered mouse model that allows the expression of the mouse CD63 exosomal marker fused with one (monocolor) or up to four fluorescent proteins (multireporter), the ExoBow. The genetic design of the ExoBow transgene allows the conditional expression of the reporters in any tissue/cell-type in an inducible or non-inducible fashion. In addition, communication mediated by CD63 positive (CD63+) exosomes can be identified amongst the same tissue/cell types using the multireporter version of the model, in order to map intra-organ/tissue communication. We demonstrate the applicability of the ExoBow transgene in normal physiological conditions and in the context of cancer, using pancreas as a working model. The ExoBow comprises a unique strategy to identify intra- and inter-organ/cell-type communication mediated by CD63+exosomes. We believe this tool will contribute for a better understanding of the complex interactions occurringin vivothat underly the biology of exosomes in health and disease.
An updated genome-scale metabolic network reconstruction ofPseudomonas aeruginosaPA14 to characterize mucin-driven shifts in bacterial metabolism
Authors: Payne Dawson D. , Renz Alina , Dunphy Laura J. , Lewis Taylor , Dräger Andreas , Papin Jason A.
Published: March 2021

Mucins are present in mucosal membranes throughout the body and play a key role in the microbe clearance and infection prevention. Understanding the metabolic responses of pathogens to mucins will further enable the development of protective approaches against infections. We update the genome-scale metabolic network reconstruction (GENRE) of one such pathogen,Pseudomonas aeruginosaPA14, through metabolic coverage expansion, format update, extensive annotation addition, and literature-based curation to produce iPau21. We then validate iPau21 through MEMOTE, growth rate, carbon source utilization, and gene essentiality testing to demonstrate its improved quality and predictive capabilities. We then integrate the GENRE with transcriptomic data in order to generate context-specific models ofP. aeruginosametabolism. The contextualized models recapitulated known phenotypes of unaltered growth and a differential utilization of fumarate metabolism, while also revealing an increased utilization of propionate metabolism upon MUC5B exposure. This work serves to validate iPau21 and demonstrate its utility for providing biological insights.
Developmental innovations promote species diversification in mushroom-forming fungi
Authors: Varga Torda , Földi Csenge , Bense Viktória , Nagy László G.
Published: March 2021

Fungi evolved complex fruiting body (‘mushroom’) morphologies as adaptations to efficient spore dispersal in terrestrial habitats. Mushroom-forming fungi (Agaricomycetes) display a graded series of developmental innovations related to fruiting body morphology, however, how these evolved is largely unknown, leaving the functional biology and evolutionary principles of complex multicellularity in the third largest multicellular kingdom poorly known. Here, we show that developmental innovations of mushroom-forming fungi that enclose the spore-producing surface (hymenophore) in a protected environment display significant asymmetry in their evolution and are associated with increased diversification rates. ‘Enclosed’ development and related tissues (partial and universal veils) evolved convergently and became a widespread developmental type in clades in which it emerged. This probably mirrors increased fitness for protected fruiting body initials in terrestrial habitats, by better coping with environmental factors such as desiccation or predators, among others. We observed similar patterns in the evolution of complex hymenophore architectures, such as gills, pores or teeth, which optimize biomass-to-propagule number ratios and were found to spur diversification in mushrooms. Taken together, our results highlight new morphological traits associated with the adaptive radiation of mushroom-forming fungi and present formal phylogenetic testing of hypotheses on the reproductive ecology of a poorly known but hyperdiverse clade.
The rise and fall of the photoinhibition-related energy dissipation qI
Authors: Nawrocki Wojciech J. , Liu Xin , Raber Bailey , Hu Chen , de Vitry Catherine , Bennett Doran I. G. , Croce Roberta
Published: March 2021

Photosynthesis converts sunlight into chemical energy, sustaining the vast majority of the biosphere. Photosystem II (PSII), the oxygen-forming enzyme that initiates photosynthesis, is however particularly prone to light-induced damage in a process known as photoinhibition, which limits the productivity of both aquatic and land photosynthesis. Photoinhibition is associated with an energy dissipation process of unknown origin, termed qI. Here, we present a detailed biophysical and biochemical in vivo study of qIin model green alga Chlamydomonas reinhardtii. Time-resolved fluorescence measurements demonstrate the origin of qI, and indicate the PSII reaction centre as the site of the quencher. Oxygen-dependence of quenching site formation, but not photoinhibition itself, is shown, suggesting that two types of PSII damage – donor and acceptor-side impairment – can be separated. We then demonstrate that the quenching loss takes place in the absence of PSII repair, and is mediated by the degradation of photoinhibited PSII cores by the FtsH protease. Finally, we integrate data ranging from picoseconds to hours in the context of structure-function excitation energy-transferring membrane patches, revealing the extent of PSII heterogeneity from the onset of photoinhibition until the breakdown of damaged PSII.

Graphical Abstract

Highlights

Upon photoinhibition, oxygen sensitization results in an irreversible formation of quenching (qI) and inactivation of Photosystem II

qItakes place in the PSII reaction centre

Photoinhibition-induced D1 cleavage is much slower than qIformation

FtsH metalloprotease is required to degrade quenching PSII reaction centres

A multiscale energy transfer model describes heterogeneity of PSII during photoinhibition
A genome-annotated bacterial collection of the barley rhizosphere microbiota
Authors: Robertson-Albertyn Senga , Concas Federico , Brown Lynn H , Orr Jamie N , Abbott James C , George Timothy S , Bulgarelli Davide
Published: March 2021

We generated a bacterial collection from the rhizosphere of cultivated barley (Hordeum vulgareL. ssp.vulgare) to assess taxonomic distribution of culturable members of the barley microbiota and their plant growth-promoting potential. From this we retrieved strains belonging to the dominant phyla of the plant microbiota— Actinobacteria, Bacteroidetes, Firmicutes and Proteobacteria—and gathered evidence they code for functional genes implicated in nitrogen fixation, hydrogen cyanide channels and phosphate solubilisation. Here we present an initial comparative genomic analysis of the collection revealing that plant growth-promoting potential of the culturable barley bacterial microbiota appears to have a relatively broad phylogenetic base while retaining some strain-specificity.
Mitochondrial genome sequencing of marine leukemias reveals cancer contagion between clam species in the Seas of Southern Europe
Authors: Garcia-Souto Daniel , Bruzos Alicia L. , Diaz Seila , Rocha Sara , Pequeño Ana , Roman-Lewis Camila F. , Alonso Juana , Rodriguez Rosana , Costas Damian , Rodriguez-Castro Jorge , Villanueva Antonio , Silva Luis , Valencia Jose Maria , Annona Giovanni , Tarallo Andrea , Ricardo Fernando , Cetinic Ana Bratos , Posada David , Pasantes Juan Jose , Tubio Jose M. C.
Published: March 2021

Clonally transmissible cancers are tumour lineages that are transmitted between individuals via the transfer of living cancer cells. In marine bivalves, leukemia-like transmissible cancers, called hemic neoplasia, have demonstrated the ability to infect individuals from different species. We performed whole-genome sequencing in eight warty venus clams that were diagnosed with hemic neoplasia, from two sampling points located more than 1,000 nautical miles away in the Atlantic Ocean and the Mediterranean Sea Coasts of Spain. Mitochondrial genome sequencing analysis in tumour tissues from neoplastic animals revealed the coexistence of haplotypes from two different clam species. Phylogenies estimated from mitochondrial and nuclear markers confirmed this leukemia originated in striped venus clams and later transmitted to clams of the species warty venus, in which it survives as a contagious cancer. The analysis of mitochondrial and nuclear gene sequences supports all studied tumours belong to a single neoplastic lineage that spreads in the Seas of Southern Europe.
Coding Recognition of the Dose-Effect Interdependence of Small Biomolecules Encrypted on Paired Chromatographic-Based Microassay Arrays
Authors: Deng Yifeng , Lin Zhenpeng , Cheng Yuan
Published: March 2021

The discovery of small biomolecules suffers from the lack of a comprehensive framework to express the intrinsic correlation between bioactivity and contributing small molecules in complex samples with molecular and bioactivity diversity. Here, by mapping a sample’s 2D-HPTLC fingerprint to microplates, the paired chromatographic-based microassay arrays are created, which can be used as quasi-chip to characterize multiple attributes of chromatographic components; and as the array differential expression of the bioactivity and molecular attributes of irregular chromatographic spots for dose-effect interdependent encoding; and also as the automatic-collimated array mosaics of the multi-attributes of each component itself encrypted by its chromatographic fingerprint. Based on this homologous framework, we propose a correlating recognition strategy for small-biomolecules through their self-consistent chromatographic behavior characteristics. In the approach, the small-biomolecule recognition in diverse compounds is transformed into a constraint satisfaction problem, which is addressed through examining the dose-effect interdependence of the homologous 2D code pairs by array matching algorithm, instead of preparing diverse compound monomers of complex test sample for identifying item-by-item. Furtherly, considering the dose-effect interdependent 2D code pairs as links and the digital-specific quasimolecular ions as nodes, an extendable self-consistent framework that correlates mammalian cell phenotypic and target-based bioassays with small biomolecules is established. Therefore, the small molecule contributions and the correlations of bioactivities, as well as their pathway can be comprehensively revealed, so as to improve the reliability and efficiency of screening. This strategy was successfully applied to galangal, and practiced the high-throughput digital preliminary screening of small-biomolecules in a natural product.

Highlight

Rapid self-recognition of small biomolecules in diverse samples without pre-isolation Recognized by dose-effect interdependency developed from homologous TLC fingerprint Matching of HPTLC-based molecular imprinting and bioautography on microassay arrays Microarray-based differential expression of substance attributes instead of spot scan An array framework for combining phenotype-based and target-based assays with TLC-MS

ToC graphic
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

Rift 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

Sexual 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

Once 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 note

This 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 Figure

Cover 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

Aim

Growth 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.

Methods

Women 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.

Results

GDF15 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.

Conclusion

This, 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

Edible 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

The 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

Understanding 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

Bruton’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

Aggregated 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

Multivalent 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

Accessible 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 summary

Regions 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.