bluuebunny/crossref_metadata_2025 huggingface dataset:
The role of V3 neurons in speed-dependent interlimb coordination during locomotion in mice
Authors: Zhang Han , Shevtsova Natalia A. , Deska-Gauthier Dylan , Mackay Colin , Dougherty Kimberly J. , Danner Simon M. , Zhang Ying , Rybak Ilya A.
Published: September 2021

Speed-dependent interlimb coordination allows animals to maintain stable locomotion under different circumstances. We have previously demonstrated that a subset of spinal V3 neurons contributes to stable locomotion by mediating mutual excitation between left and right lumbar rhythm generators (RGs). Here, we expanded our investigation to the V3 neurons involved in ascending long propriospinal interactions (aLPNs). Using retrograde tracing, we revealed a subpopulation of lumbar V3 aLPNs with contralateral cervical projections. V3OFF mice, in which all V3 neurons were silenced, had a significantly reduced maximal locomotor speed, were unable to move using stable trot, gallop, or bound, and predominantly used lateral-sequence walk. To understand the functional roles of V3 aLPNs, we adapted our previous model of spinal circuitry controlling quadrupedal locomotion (Danner et al., 2017), by incorporating diagonal V3 aLPNs mediating inputs from each lumbar RG to the contralateral cervical RG. The updated model reproduces our experimental results and suggests that locally projecting V3 neurons, mediating left–right interactions within lumbar and cervical cords, promote left–right synchronization necessary for gallop and bound, whereas the V3 aLPNs promote synchronization between diagonal fore and hind RGs necessary for trot. The model proposes the organization of spinal circuits available for future experimental testing.
The art of snacking: Innovative food extraction in a synanthropic species is associated with food exposure and food categorization
Authors: Dhananjaya Tejeshwar , Das Sayantan , Vyas Amal K. , Gahlot Prakhar , Singh Mewa
Published: September 2021

Extractive foraging is generally studied from the perspective of behavioral flexibility, cognitive ability, innovation and social learning. Despite its potential to elucidate synanthropic adaptation in species exploiting enclosed anthropogenic food, research on extractive foraging under urban conditions is limited. Since a large extent of anthropogenic food is packaged and contains highly processed food, processes of identification/extraction of food by nonhuman species become intriguing themes of research. We studied how processing status of embedded food determined extraction decisions across groups of a species differing in exposure and familiarity to the food. Further, we tested the generalizability of extraction methods. Experimenting with wild bonnet macaques (Macaca radiata), we found exposure- and form (native/shelled/peeled)-specific familiarity to peanuts, state (raw/boiled/roasted)-specific distinction in depeeling, and exposure- and state-specific differences in methods of depeeling. Group with the highest exposure to peanut differed in its propensity to use sophisticated extraction methods, e.g. depeeling by rubbing between palms (bimanual asymmetric action) and rubbing against horizontal substrata (unimanual action). The innovative methods were also extended to roasted peas and chickpeas by the urban group. Our study establishes a causal relationship between familiarity and processing status of food and shows the generalized extension of extraction methods based on food categorization.

Summary Statement

Nonhuman species in cities face upheaval challenges of accessing enclosed and highly processed anthropogenic food. We studied the effects of minor processing of enclosed food on its extraction decisions.
Three new Cenomanian conifers from El Chango (Chiapas, Mexico) offer a snapshot of the geographic mosaic of the Mesozoic conifer decline
Authors: González-Ramírez Ixchel , Cevallos-Ferriz Sergio R.S. , Rothfels Carl J.
Published: September 2021

Premise of study

“El Chango” is a recently discovered quarry that contains extremely well preserved fossils. The Cenomanian age of the locality corresponds to a time when the global flora was transitioning from gymnosperm- to angiosperm-dominated, yet conifers predominate in this locality. These fossils thus provide a rare opportunity to understand the replacement of conifers by angiosperms as the dominant group of plants.

Methods

We collected material from El Chango in annual expeditions (2010 to 2014). We selected the three most abundant and best preserved conifer morphotypes and conducted a total-evidence (i.e.,, including molecular and morphological data) phylogenetic analysis of a sample of 72 extant conifer species plus the three fossils. We use these results to inform our taxonomic decisions.

Results

We obtained four equally most-parsimonious trees (consistency index = 44.1%, retention index = 78.8%). Despite ambiguous relationships among some extant taxa, the three fossil conifers had the same phylogenetic position in all four most-parsimonious trees; we describe these species as new:Sequoiadendron helicalancifoliumsp. nov. (Cupressaceae), andMicrocachrys rhomboideasp. nov. andDacrydium bifoliosussp. nov (Podocarpaceae). The ecosystem is interpreted as a coastal humid mixed forest.

Conclusions

Our findings contribute to the understanding of Cenomanian equatorial regions, and support the hypothesis of a geographically and ecologically structured “rise of angiosperms”, with conifers remaining dominant in brackish-water and angiosperms becoming dominant in freshwater-ecosystems. These fossils fill in gaps in the evolutionary history of lineages likeMicrocachrys, which we demonstrate occurred in the Northern hemisphere before becoming restricted to its current range (Tasmania).
Innate immunity pathways activate cell proliferation after penetrating traumatic brain injury in adult Drosophila
Authors: Marischuk Khailee , Crocker Kassi L. , Ahern-Djamali Shawn , Boekhoff-Falk Grace
Published: September 2021

We are utilizing an adult penetrating traumatic brain injury (PTBI) model in Drosophila to investigate regenerative mechanisms after damage to the central brain. We focused on cell proliferation as an early event in the regenerative process. To identify candidate pathways that may trigger cell proliferation following PTBI, we utilized RNA-Seq. We find that transcript levels for components of both Toll and Immune Deficiency (Imd) innate immunity pathways are rapidly and highly upregulated post-PTBI. We then tested mutants for the NF-κB transcription factors of the Toll and Imd pathways, Dorsal-related immunity factor (Dif) and Relish (Rel) respectively. We find that loss of either or both Dif and Rel results in loss of cell proliferation after injury. We then tested canonical downstream targets of Drosophila innate immune signaling, the antimicrobial peptides (AMPs), and find that they are not required for cell proliferation following PTBI. This suggests that there are alternative targets of Toll and Imd signaling that trigger cell division after injury. Furthermore, we find that while AMP levels are substantially elevated after PTBI, their levels revert to near baseline within 24 hours. Finally, we identify tissue-specific requirements for Dif and Rel. Taken together, these results indicate that the innate immunity pathways play an integral role in the regenerative response. Innate immunity previously has been implicated as both a potentiator and an inhibitor of regeneration. Our work suggests that modulation of innate immunity may be essential to prevent adverse outcomes. Thus, this work is likely to inform future experiments to dissect regenerative mechanisms in higher organisms.
Fine mapping spatiotemporal mechanisms of genetic variants underlying cardiac traits and disease
Authors: D’Antonio Matteo , Arthur Timothy D. , Nguyen Jennifer P. , Matsui Hiroko , D’Antonio-Chronowska Agnieszka , Frazer Kelly A.
Published: September 2021

The causal variants and genes underlying thousands of cardiac GWAS signals have yet to be identified. Here, we leveraged spatiotemporal information on 966 RNA-seq cardiac samples and performed an expression quantitative trait locus (eQTL) analysis detecting eQTLs considering both eGenes and eIsoforms. We identified 2,578 eQTLs associated with a specific developmental stage-, tissue- and/or cell type. Colocalization between eQTL and GWAS signals of five cardiac traits identified variants with high posterior probabilities for being causal in 210 GWAS loci. Pulse pressure GWAS loci were enriched for colocalization with fetal- and smooth muscle- eQTLs; pulse rate with adult- and cardiac muscle- eQTLs; and atrial fibrillation with cardiac muscle- eQTLs. Fine mapping identified 79 credible sets with five or fewer SNPs, of which 15 were associated with spatiotemporal eQTLs. Our study shows that many cardiac GWAS variants impact traits and disease in a developmental stage-, tissue- and/or cell type-specific fashion.
The chromatin organization of a chlorarachniophyte nucleomorph genome
Authors: Marinov Georgi K. , Chen Xinyi , Wu Tong , He Chuan , Grossman Arthur R. , Kundaje Anshul , Greenleaf William J.
Published: September 2021

Nucleomoprhs are remnants of secondary endosymbiotic events between two eukaryote cells wherein the endosymbiont has retained its eukaryotic nucleus. Nucleomorphs have evolved at least twice independently, in chlorarachniophytes and cryptophytes, yet they have converged on a remarkably similar genomic architecture, characterized by the most extreme compression and miniaturization among all known eukaryotic genomes. Previous computational studies have suggested that nucleomorph chromatin likely exhibits a number of divergent features. In this work, we provide the first maps of open chromatin, active transcription, and three-dimensional organization for the nucleomorph genome of the chlorarachniophyte Bigelowiella natans. We find that the B. natans nucleomorph genome exists in a highly accessible state, akin to that of ribosomal DNA in some other eukaryotes, and that it is highly transcribed over its entire length, with few signs of polymerase pausing at transcription start sites (TSSs). At the same time, most nucleomorph TSSs show very strong nucleosome positioning. Chromosome conformation (Hi-C) maps reveal that nucleomorph chromosomes interact with one other at their telomeric regions, and show the relative contact frequencies between the multiple genomic compartments of distinct origin that B. natans cells contain.
Human IL-10-producing B cells have diverse states induced from multiple B cell subsets
Authors: Glass Marla C. , Glass David R. , Oliveria John Paul , Mbiribindi Berenice , Esquivel Carlos O. , Krams Sheri M. , Bendall Sean C. , Martinez Olivia M.
Published: September 2021

Regulatory B cells (Bregs) can suppress immune responses through the secretion of IL-10 and other anti-inflammatory cytokines. This immunomodulatory capacity holds therapeutic potential, yet a definitional immunophenotype for enumeration and prospective isolation of B cells capable of IL-10 production remains elusive. We therefore applied mass cytometry to simultaneously quantify cytokine production and immunophenotype in human peripheral B cells across a range of stimulatory conditions and timepoints. While multiple B cell subsets produced IL-10, no phenotype uniquely identified IL-10+ B cells and a significant portion of IL-10+ B cells co-expressed the proinflammatory cytokines IL-6 and TNFα. Despite this heterogeneity, we found operationally tolerant liver transplant recipients had a unique enrichment of IL-10+, but not TNFα+ or IL-6+, B cells as compared to transplant recipients receiving immunosuppression. Thus, human IL-10-producing B cells constitute an induced, transient state arising from a diversity of B cell subsets that may contribute to maintenance of immune homeostasis.
The nutritional environment is sufficient to select coexisting biofilm and quorum-sensing mutants of Pseudomonas aeruginosa
Authors: Scribner Michelle R. , Stephens Amelia C. , Huong Justin L. , Richardson Anthony R. , Cooper Vaughn S.
Published: September 2021

The evolution of bacterial populations during infections can be influenced by various factors including available nutrients, the immune system, and competing microbes, rendering it difficult to identify the specific forces that select on evolved traits. The genomes of Pseudomonas aeruginosa isolated from the airway of patients with cystic fibrosis (CF), for example, have revealed commonly mutated genes, but which phenotypes led to their prevalence is often uncertain. Here, we focus on effects of nutritional components of the CF airway on genetic adaptations by P. aeruginosa grown in either well-mixed (planktonic) or biofilm-associated conditions. After only 80 generations of experimental evolution in a simple medium with glucose, lactate, and amino acids, all planktonic populations diversified into lineages with mutated genes common to CF infections: morA, encoding a regulator of biofilm formation, or lasR, encoding a quorum sensing regulator that modulates the expression of virulence factors. Although mutated quorum sensing is often thought to be selected in vivo due to altered virulence phenotypes or social cheating, isolates with lasR mutations demonstrated increased fitness when grown alone and outcompeted the ancestral PA14 strain. Nonsynonymous SNPs in morA increased fitness in a nutrient concentration-dependent manner during planktonic growth and surprisingly also increased biofilm production. Populations propagated in biofilm conditions also acquired mutations in loci associated with chronic infections, including lasR and cyclic-di-GMP regulators roeA and wspF. These findings demonstrate that nutrient conditions and biofilm selection are alone sufficient to select mutants with problematic clinical phenotypes including increased biofilm and altered quorum sensing.

Importance

Pseudomonas aeruginosa produces dangerous chronic infections that are known for their rapid diversification and recalcitrance to treatment. We performed evolution experiments to identify adaptations selected by two specific aspects of the CF respiratory environment: nutrient levels and surface attachment. Propagation of P. aeruginosa in nutrients present within the CF airway was alone sufficient to drive diversification into subpopulations with identical mutations in regulators of biofilm and quorum sensing to those arising during infection. Thus, the adaptation of opportunistic pathogens to nutrients found in the host may select mutants with phenotypes that complicate treatment and clearance of infection.
Screening and Identification of Lujo Virus Entry Inhibitors from an FDA-Approved Drugs Library
Authors: Cao Junyuan , Liu Yang , Dong Siqi , Zhou Minmin , Guo Jiao , Jia Xiaoying , Zhang Yueli , Hou Yuxiao , Xiao Gengfu , Wang Wei
Published: September 2021

The Lujo virus (LUJV) belongs to the Old World (OW) genus Mammarenavirus (family Arenaviridae); it is categorized as a biosafety level (BSL) 4 agent. Currently, there are no U.S. Food and Drug Administration (FDA)-approved drugs or vaccines specifically for LUJV or other pathogenic OW mammarenaviruses. Here, a high-throughput screening of an FDA-approved drug library was conducted using pseudotype viruses bearing LUJV envelope glycoprotein (GPC) to identify inhibitors of LUJV entry. Three hit compounds, trametinib, manidipine, and lercanidipine, were identified as LUJV entry inhibitors in the micromolar range. Mechanistic studies revealed that trametinib inhibited LUJV GPC-mediated membrane fusion by targeting C410 (located in the transmembrane (TM) domain), while manidipine and lercanidipine inhibited LUJV entry by acting as calcium channel blockers. Meanwhile, all three hits extended their antiviral spectra to the entry of other pathogenic mammarenaviruses. Furthermore, all three could inhibit the authentic prototype mammarenavirus, lymphocytic choriomeningitis virus (LCMV), and could prevent infection at the micromolar level. This study shows that trametinib, manidipine, and lercanidipine are candidates for LUJV therapy, and highlights the critical role of calcium in LUJV infection. The presented findings reinforce the notion that the key residue(s) located in the TM domain of GPC provide an entry-targeted platform for designing mammarenavirus inhibitors.

IMPORTANCE

To date, only one LUJV outbreak has been recorded; it occurred in 2008 and resulted in a fatality rate of 80% (4/5 cases). Pathogenesis studies and therapeutic strategies are therefore urgently needed. Repurposing approved drugs can accelerate the development of drug design and facilitate the understanding of infectious mechanisms. Here, three compounds, trametinib, manidipine, and lercanidipine, were identified as entry inhibitors against LUJV. Studying the underling mechanisms revealed that a key residue (C410) in LUJV GPC modulates its sensitivity/resistance to trametinib and demonstrated the critical role of calcium in LUJV infection.
Whole genome sequencing identifies multiple loci for critical illness caused by COVID-19
Authors: Kousathanas Athanasios , Pairo-Castineira Erola , Rawlik Konrad , Stuckey Alex , Odhams Christopher A , Walker Susan , Russell Clark D , Malinauskas Tomas , Millar Jonathan , Elliott Katherine S , Griffiths Fiona , Oosthuyzen Wilna , Morrice Kirstie , Keating Sean , Wang Bo , Rhodes Daniel , Klaric Lucija , Zechner Marie , Parkinson Nick , Bretherick Andrew D. , Siddiq Afshan , Goddard Peter , Donovan Sally , Maslove David , Nichol Alistair , Semple Malcolm G , Zainy Tala , Maleady-Crowe Fiona , Todd Linda , Salehi Shahla , Knight Julian , Elgar Greg , Chan Georgia , Arumugam Prabhu , Fowler Tom A , Rendon Augusto , Shankar-Hari Manu , Summers Charlotte , Hinds Charles , Horby Peter , McAuley Danny , Montgomery Hugh , Openshaw Peter J.M. , Wu Yang , Yang Jian , Elliott Paul , Walsh Timothy ,   GenOMICC Investigators,   23andMe,   Covid-19 Human Genetics Initiative, Fawkes Angie , Murphy Lee , Rowan Kathy , Ponting Chris P , Vitart Veronique , Wilson James F , Scott Richard H , Clohisey Sara , Moutsianas Loukas , Law Andy , Caulfield Mark J , Baillie J. Kenneth
Published: September 2021

Critical illness in COVID-19 is caused by inflammatory lung injury, mediated by the host immune system. We and others have shown that host genetic variation influences the development of illness requiring critical care1or hospitalisation2;3;4following SARS-Co-V2 infection. The GenOMICC (Genetics of Mortality in Critical Care) study recruits critically-ill cases and compares their genomes with population controls in order to find underlying disease mechanisms.

Here, we use whole genome sequencing and statistical fine mapping in 7,491 critically-ill cases compared with 48,400 population controls to discover and replicate 22 independent variants that significantly predispose to life-threatening COVID-19. We identify 15 new independent associations with critical COVID-19, including variants within genes involved in interferon signalling (IL10RB, PLSCR1), leucocyte differentiation (BCL11A), and blood type antigen secretor status (FUT2). Using transcriptome-wide association and colocalisation to infer the effect of gene expression on disease severity, we find evidence implicating expression of multiple genes, including reduced expression of a membrane flippase (ATP11A), and increased mucin expression (MUC1), in critical disease.

We show that comparison between critically-ill cases and population controls is highly efficient for genetic association analysis and enables detection of therapeutically-relevant mechanisms of disease. Therapeutic predictions arising from these findings require testing in clinical trials.
Schema formation in a neural population subspace underlies learning-to-learn in flexible sensorimotor problem-solving
Authors: Goudar Vishwa , Peysakhovich Barbara , Freedman David J. , Buffalo Elizabeth A. , Wang Xiao-Jing
Published: September 2021

Learning-to-learn, a progressive speedup of learning while solving a series of similar problems, represents a core process of knowledge acquisition that draws attention in both neuroscience and artificial intelligence. To investigate its underlying brain mechanism, we trained a recurrent neural network model on arbitrary sensorimotor mappings known to depend on the prefrontal cortex. The network displayed an exponential time course of accelerated learning. The neural substrate of a schema emerges within a low-dimensional subspace of population activity; its reuse in new problems facilitates learning by limiting connection weight changes. Our work highlights the weight-driven modifications of the vector field, which determines the population trajectory of a recurrent network and behavior. Such plasticity is especially important for preserving and reusing the learnt schema in spite of undesirable changes of the vector field due to the transition to learning a new problem; the accumulated changes across problems account for the learning-to-learn dynamics.
Ether Lipid Biosynthesis Promotes Lifespan Extension and Enables Diverse Prolongevity Paradigms in Caenorhabditis elegans
Authors: Cedillo Lucydalila , Li Sainan , Ahsan Fasih M. , Stuhr Nicole L. , Zhou Yifei , Zhang Yuyao , Adedoja Adebanjo , Murphy Luke M. , Yerevanian Armen , Emans Sinclair , Dao Khoi , Li Zhaozhi , Peterson Nicholas D. , Watrous Jeramie , Jain Mohit , Das Sudeshna , Pukkila-Worley Read , Curran Sean P. , Soukas Alexander A.
Published: September 2021

Biguanides, including the world’s most commonly prescribed drug for type 2 diabetes, metformin, not only lower blood sugar, but also promote longevity in preclinical models. Epidemiologic studies in humans parallel these findings, indicating favorable effects of metformin on longevity and on reducing the incidence and morbidity associated with aging-related diseases. In spite of this promise, the full spectrum of molecular effectors responsible for these health benefits remains elusive. Through unbiased screening in C. elegans, we uncovered a role for genes necessary for ether lipid biosynthesis in the favorable effects of biguanides. We demonstrate that biguanides prompt lifespan extension by stimulating ether lipid biogenesis. Loss of the ether lipid biosynthetic machinery also mitigates lifespan extension attributable to dietary restriction, target of rapamycin (TOR) inhibition, and mitochondrial electron transport chain inhibition. A possible mechanistic explanation for this finding is that ether lipids are required for activation of longevity-promoting, metabolic stress defenses downstream of the conserved transcription factor Nrf2/skn-1. In alignment with these findings, overexpression of a single, key, ether lipid biosynthetic enzyme, fard-1/FAR1, is sufficient to promote lifespan extension. These findings illuminate the ether lipid biosynthetic machinery as a novel therapeutic target to promote healthy aging.
Exploring bycatch diversity of organisms in whole genome sequencing of Erebidae moths (Lepidoptera)
Authors: Ghanavi Hamid Reza , Twort Victoria , Duplouy Anne
Published: September 2021

Models estimate that up to 80% of all butterfly and moth species host vertically transmitted endosymbiotic microorganisms, which can affect the host fitness, metabolism, reproduction, population dynamics, and genetic diversity, among others. The supporting empirical data are however currently highly biased towards the generally more colourful butterflies, and include less information about moths. Additionally, studies of symbiotic partners of Lepidoptera predominantly focus on the common bacterium Wolbachia pipientis, while infections by other inherited microbial partners have more rarely been investigated. Here, we mine the whole genome sequence data of 47 species of Erebidae moths, with the aims to both inform on the diversity of symbionts potentially associated with this Lepidoptera group, and discuss the potential of metagenomic approaches to inform on their associated microbiome diversity. Based on the result of Kraken2 and MetaPhlAn2 analyses, we found clear evidence of the presence of Wolbachia in four species. Our result also suggests the presence of three other bacterial symbionts (Burkholderia spp., Sodalis spp. and Arsenophonus spp.), in three other moth species. Additionally, we recovered genomic material from bracovirus in about half of our samples. The detection of the latter, usually found in mutualistic association to braconid parasitoid wasps, may inform on host-parasite interactions that take place in the natural habitat of the Erebidae moths, suggesting either contamination with material from species of the host community network, or horizontal transfer of members of the microbiome between interacting species.
Neurodevelopmental clustering of gene expression identifies lipid metabolism genes associated with neuroprotection and neurodegeneration
Authors: Kohane Akiva A. , Wood Tim R.
Published: September 2021

APOE variants present the strongest association with sporadic Alzheimer’s Disease. APOE is also highly expressed during neurodevelopment in the Central Nervous System (CNS) and has been shown to be neuroprotective in infancy and gestation. We explored other lipid metabolism genes to determine whether they show a similar neurodevelopmental expression trajectory and are associated with neurodegeneration. APOE was by far the most highly expressed of the lipid metabolism genes in the CNS. Two other genes, Apolipoprotein C1 (APOC1) Glutamate-Ammonia Ligase (GLUL—also known as glutamine synthetase), co-clustered with Apolipoprotein E (APOE) in its developmental trajectory in late gestation through early childhood. These three genes highlight brain structures and developmental time-windows distinct from other lipid metabolism genes. In the CNS they are primarily expressed in astrocytes and are implicated in neuroprotection and neurodegeneration.
Alignment of multiple metabolomics LC-MS datasets from disparate diseases to reveal fever-associated metabolites
Authors: Năstase Ana-Maria , Barrett Michael P. , Cárdenas Washington B. , Cordeiro Fernanda Bertuccez , Zambrano Mildred , Andrade Joyce , Chang Juan , Regato Mary , Carrillo Eugenia , Botana Laura , Moreno Javier , Milne Kathryn , Spence Philip J. , Rowe J. Alexandra , Rogers Simon
Published: September 2021

Acute febrile illnesses are still a major cause of mortality and morbidity globally, particularly in low to middle income countries. The aim of this study was to determine any possible metabolic commonalities of patients infected with disparate pathogens that cause fever. Three liquid chromatography-mass spectrometry (LC-MS) datasets investigating the metabolic effects of malaria, leishmaniasis and Zika virus infection were used. The retention time (RT) drift between the datasets was determined using landmarks obtained from the standard reference mixtures generally used in the quality control of the LC-MS experiments. We used fitted Gaussian Process models (GPs) to perform a high level correction of the RT drift between the experiments, followed by standard peakset alignment between the samples with corrected RTs of the three LC-MS datasets. Statistical analysis, annotation and pathway analysis of the integrated peaksets were subsequently performed. Metabolic dysregulation patterns common across the datasets were identified, with kynurenine pathway being the most affected pathway between all three fever-associated datasets.
Freshwater dissolved oxygen dynamics: changes due to glyphosate, 2,4-D and their mixture, both under clear and turbid-organic conditions
Authors: Lozano V.L. , Miranda C.E. , Vinocur A.L. , Sabio y García C.A. , Vera M.S. , González C. , Wolansky M.J. , Pizarro H.N.
Published: September 2021

We performed two independent outdoor mesocosm experiments where we measured the variation of DO saturation (DO%) in freshwater after a single input of Roundup Max®(G) (glyphosate-based formulation), AsiMax 50®(2,4-D) (2,4-D-based formulation) and their mixture (M). Two concentration levels were tested; 0.3 mg/L G and 0.135 mg/L 2,4-D (Low; L) and 3 mg/L G and 1.35 mg/L 2,4-D (High; H). We assayed consolidated microbial communities coming from a system in organic turbid eutrophic status and a system in clear mesotrophic status during 21 and 23 days, respectively. A sample of phytoplankton (micro+nano, pico-eukaryotes, pico-cyanobacteria), mixotrophic algae and heterotrophic bacteria was collected to determine abundances at each of four sampling dates. The clear and turbid systems showed similar, but not synchronized, patterns of daily DO% changes in relation to the controls (DO%v), after exposure to both single and combined formulations. Under glyphosate scenarios (GL, GH, ML and MH), the two types of systems showed similar DO%vbut different microbial abundances, being associated to an increase in the micro+nano and pico-eukaryotic phytoplankton fractions for the clear system. In contrast, in the turbid system changes were associated with increased pico-cyanobacteria and decreased mixotrophic algae. Effects of 2,4-D were only observed in the turbid system, leading to decreased micro+nano phytoplankton abundances. Under the turbid scenario, the herbicide mixture at high concentration had a synergistic effect on DO%vand recovery was not detected by the end of the experiment. Our results revealed that herbicides inputs induced changes in phytoplankton abundances that leads to measurable DO variations.
Public human microbiome data dominated by highly developed countries
Authors: Abdill Richard J. , Adamowicz Elizabeth M. , Blekhman Ran
Published: September 2021

The importance of sampling from globally representative populations has been well established in human genomics. In human microbiome research, however, we lack a full understanding of the global distribution of sampling in research studies. This information is crucial to better understand global patterns of microbiome-associated diseases and to extend the health benefits of this research to all populations. Here, we analyze the country of origin of all 444,829 human microbiome samples that have been collected to date and are available from the world’s three largest genomic data repositories, including the Sequence Read Archive (SRA). We show that more than 71% of publicly available human microbiome samples with a known origin come from Europe, the United States, and Canada, including 46.8% from the United States alone, despite the country representing only 4.3% of the global population. We also find that central and southern Asia is the most underrepresented region: Countries such as India, Pakistan, and Bangladesh account for more than a quarter of the world population but make up only 1.8 percent of human microbiome samples. These results demonstrate a critical need to ensure more global representation of participants in microbiome studies.
Systematic and quantitative view of the antiviral arsenal of prokaryotes
Authors: Tesson Florian , Hervé Alexandre , Touchon Marie , d’Humières Camille , Cury Jean , Bernheim Aude
Published: September 2021

Facing the abundance and diversity of phages, bacteria have developed multiple anti-phage mechanisms. In the past three years, the number of known anti-phage mechanisms has been expanded by at least 5-fold rendering our view of prokaryotic immunity obsolete. Most anti-phage systems have been studied as standalone mechanisms, however many examples demonstrate strains encode not one but several anti-viral mechanisms. How these different systems integrate into an anti-viral arsenal at the strain level remains to be elucidated. Much could be learned from establishing fundamental description of features such as the number and diversity of anti-phage systems encoded in a given genome. To address this question, we developed DefenseFinder, a tool that automatically detects known anti-phage systems in prokaryotic genomes. We applied DefenseFinder to >20 000 fully sequenced genomes, generating a systematic and quantitative view of the anti-viral arsenal of prokaryotes. We show prokaryotic genomes encode on average five anti-phage systems from three different families of systems. This number varies drastically from one strain to another and is influenced by the genome size and the number of prophages encoded. Distributions of different systems are also very heterogenous with some systems being enriched in prophages and in specific clades. Finally, we provide a detailed comparison of the anti-viral arsenal of 15 common bacterial species, revealing drastic differences in anti-viral strategies. Overall, our work provides a free and open-source software, available as a command line tool or, on a webserver. It allows the rapid detection of anti-phage systems, enables a comprehensive description of the anti-viral arsenal of prokaryotes and paves the way for large scale genomics study in the field of anti-phage defense.
Evaluation of rubber tree transcriptome and discovery of SNP and SSR from candidate genes involved in cellulose and lignin biosynthesis
Authors: Othman Ahmad Sofiman , Abu Bakar Mohd Fahmi
Published: September 2021

Hevea brasiliensis (the rubber tree) is a well-known species with high economic value, and it is the primary source of natural rubber globally. Increasing demand for furniture and related industries has made rubberwood production as important as latex production. Molecular markers such as Single Nucleotide Polymorphisms (SNPs) and Simple Sequence Repeats (SSRs) are widely used for Marker Assisted Selection (MAS) which can be detected in large quantity by transcriptome sequencing. MAS is thought to be a useful method for the development of new rubberwood clones for its shorter breeding cycle compared to a conventional breeding procedure. In this study we performed RNA sequencing (RNA-seq) on four H. brasiliensis clones (RRIM 712, RRIM 2025, RRIM 3001 and PB 314) from three tissues including bark, latex and leaf samples to identify SSRs and SNPs associated with wood-formation related genes. The RNA sequencing using the Illumina NextSeq 500 v2 platform, generated 1,697,491,922 raw reads. A total of 101,269 transcripts over 400 bp in size were obtained and similarity search of the non-redundant (nr) protein database returned 83,748 (83%) positive BLASTx hits. The transcriptome analysis was annotated using the NCBI NR (National Center for Biotechnology Information Non-Redundant), UniProtKB/Swiss-Prot, gene ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. Differential expression analysis between later-timber rubber clone and non-later-timber rubber clone on wood-formation related genes, showed genes encoding phenylalanine ammonia-lyase (PAL), caffeic acid O-methyltransferase (COMT) and cinnamoyl-CoA reductase (CCR) were highly up-regulated in a latex-timber rubber clone. In total, about 3,210,629 SNPs and 14,956 SSRs were detected with 1,786 SNPs and 31 SSRs were found for wood-formation biosynthesis of H. brasilensis from 11 lignin and cellulose gene toolboxes. After filtering and primer selection, 103 SNPs and 18 SSR markers were successfully amplified and could be useful as molecular tool for marker assisted breeding to produce new timber rubber clones.
Assessment of genome packaging in AAVs using Orbitrap-based charge detection mass spectrometry
Authors: Wörner Tobias P. , Snijder Joost , Friese Olga , Powers Thomas , Heck Albert J. R.
Published: September 2021

Adeno-associated viruses (AAV) represent important gene therapy vectors with several approved clinical applications and numerous more in clinical trials. Genome packaging is an essential step in the bioprocessing of AAVs and needs to be tightly monitored to ensure the proper delivery of transgenes and the production of effective drugs. Current methods to monitor genome packaging have limited sensitivity, a high demand on labour, and struggle to distinguish between packaging of the intended genome or unwanted side-products. Here we show that Orbitrap based charge detection mass spectrometry allows the ultra-sensitive quantification of all these different AAV bioprocessing products. A protocol is presented that allows the quantification of genome packed AAV preparations in under half an hour, requiring only micro-liter quantities of typical AAV preparations with ~1013 viral genome copies per millilitre. The method quickly assesses the integrity and amount of genome packed AAV particles to support AAV bioprocessing and characterization of this rapidly emerging class of advanced drug therapies.
Sigma Oscillations Protect or Reinstate Motor Memory Depending on their Temporal Coordination with Slow Waves
Authors: Nicolas Judith , King Bradley R. , Levesque David , Lazzouni Latifa , Coffey Emily , Swinnen Stephan , Doyon Julien , Carrier Julie , Albouy Geneviève
Published: September 2021

Targeted memory reactivation (TMR) during post-learning sleep is known to enhance motor memory consolidation but the underlying neurophysiological processes remain unclear. Here, we confirm the beneficial effect of auditory TMR on motor performance. At the neural level, TMR enhanced slow wave (SW) characteristics. Additionally, greater TMR-related phase-amplitude coupling between slow (0.5-2 Hz) and sigma (12-16 Hz) oscillations after the SW peak was related to higher TMR effect on performance. Importantly, sounds that were not associated to learning strengthened SW-sigma coupling at the SW trough and the increase in sigma power nested in the trough of the potential evoked by these unassociated sounds was related to the TMR benefit. Altogether, our data suggest that, depending on their precise temporal coordination during post learning sleep, slow and sigma oscillations play a crucial role in either memory reinstatement or protection against irrelevant information; two processes that critically contribute to motor memory consolidation.
A GID E3 ligase assembly ubiquitinates an Rsp5 E3 adaptor and regulates plasma membrane transporters
Authors: Langlois Christine R. , Beier Viola , Karayel Ozge , Chrustowicz Jakub , Sherpa Dawafuti , Mann Matthias , Schulman Brenda A.
Published: September 2021

Cells rapidly remodel their proteomes to align their cellular metabolism to environmental conditions. Ubiquitin E3 ligases enable this response, by facilitating rapid and reversible changes to protein stability, localization, or interaction partners. In S. cerevisiae, the GID E3 ligase regulates the switch from gluconeogenic to glycolytic conditions through induction and incorporation of the substrate receptor subunit Gid4, which promotes the degradation of gluconeogenic enzymes. Here, we show an alternative substrate receptor, Gid10, which is induced in response to changes in temperature, osmolarity and nutrient availability, and regulates the ART-Rsp5 pathway. Art2 levels are elevated upon GID10 deletion, a crystal structure shows the basis for Gid10-Art2 interactions, and Gid10 directs a GID E3 ligase complex to ubiquitinate Art2. We also find that the GID E3 ligase affects the flux of plasma membrane nutrient transporters during heat stress. The data reveal GID as a system of E3 ligases with metabolic regulatory functions outside of glycolysis and gluconeogenesis, controlled by distinct stress-specific substrate receptors.
Macrophages induce inflammation by efferocytosis of apoptotic prostate cancer cells via HIF-1α stabilization
Authors: Mendoza-Reinoso Veronica , Schnepp Patricia M. , Baek Dah Youn , Rubin John R. , Schipani Ernestina , Keller Evan T. , McCauley Laurie K. , Roca Hernan
Published: September 2021

Clearance of apoptotic cancer cells by macrophages, known as efferocytosis, fuels the bone-metastatic growth of prostate cancer cells via pro-inflammatory and immunosuppressive processes. However, the exact molecular mechanisms remain unclear. In this study, single-cell transcriptomics of bone marrow macrophages undergoing efferocytosis of apoptotic prostate cancer cells revealed a significant enrichment of a cellular response to hypoxia. Here we show that efferocytic macrophages promote HIF-1α stabilization under normoxic conditions through interaction with phosphorylated STAT3. Inflammatory cytokine gene expression analysis of efferocytic HIF-1α-mutant macrophages revealed a reduced expression of the pro-tumorigenic Mif. Furthermore, stabilization of HIF-1α using the HIF-prolyl-hydroxylase inhibitor, Roxadustat, enhanced MIF expression in macrophages. Finally, macrophages treated with recombinant MIF protein activated NF-κB (p65) signaling and increased the expression of pro-inflammatory cytokines. Altogether, these findings suggest that the clearance of apoptotic cancer cells by tumor-associated macrophages triggers p-STAT3/HIF-1α/MIF signaling to enhance tumor-promoting inflammation in bone, suggesting this axis as a target for metastatic prostate cancer.
Diffusion MRI Anisotropy in the Cerebral Cortex is Determined by Unmyelinated Tissue Features
Authors: Reveley Colin , Ye Frank Q , Mars Rogier B , Matrov Denis , Chudasama Yogita , Leopold David A
Published: September 2021

Diffusion magnetic resonance imaging (dMRI) is commonly used to assess the tissue and cellular substructure of the human brain. In the white matter, myelinated axons are the principal neural elements that shape dMRI through the restriction of water diffusion; however, in the gray matter the relative contributions of myelinated axons and other tissue features to dMRI are poorly understood. Here we investigate the determinants of diffusion in the cerebral cortex. Specifically, we ask whether myelinated axons significantly shape dMRI fractional anisotropy (dMRI-FA), a measure commonly used to characterize tissue properties in humans. We compared ultra-high resolution ex vivo dMRI data from the brain of a marmoset monkey with both myelin- and Nissl-stained histological sections obtained from the same brain after scanning. We found that cortical diffusion was only minimally related to the density and arrangement of myelinated fibers. Instead, the spatial pattern of dMRI-FA in the cortex was more closely related to anisotropy of tissue features indicated in the Nissl stained sections. Our results suggest that unmyelinated neurites such as large caliber apical dendrites are the primary features shaping dMRI measures in the cerebral cortex.
Tracking transitional probabilities and segmenting auditory sequences are dissociable processes in adults and neonates
Authors: Benjamin Lucas , Fló Ana , Palu Marie , Naik Shruit , Melloni Lucia , Dehane-Lambertz Ghislaine
Published: September 2021

Since speech is a continuous stream with no systematic boundaries between words, how do pre-verbal infants manage to discover words? A proposed solution is that they might use the transitional probability between adjacent syllables, which drops at word boundaries. Here, we tested the limits of this mechanism by increasing the size of the word-unit to 4 syllables, and its automaticity by testing asleep neonates. Using markers of statistical learning in neonates’ EEG, compared to adult’ behavioral performances in the same task, we confirmed that statistical learning is automatic enough to be efficient even in sleeping neonates. But we also revealed that: 1) Successfully tracking transition probabilities in a sequence is not sufficient to segment it 2) Prosodic cues, as subtle as subliminal pauses, enable to recover segmenting capacities 3) Adults’ and neonates’ capacities are remarkably similar despite the difference of maturation and expertise. Finally, we observed that learning increased the similarity of neural responses across infants, providing a new neural marker to monitor learning. Thus, from birth, infants are equipped with adult-like tools, allowing to extract small coherent word-like units within auditory streams, based on the combination of statistical analyses and prosodic cues.
A cerebellar-prepontine circuit for tonic immobility triggered by inescapable threat
Authors: Bhandiwad Ashwin A , Chu Nickolas , Semenova Svetlana A , Burgess Harold A
Published: September 2021

Sudden changes in the sensory environment are frequently perceived as threats and may provoke defensive behavioral states. One such state is tonic immobility, a conserved defensive strategy characterized by a powerful suppression of movement and motor reflexes. Tonic immobility has been associated with multiple brainstem regions and cell types, but the underlying circuit is not known. Here, we demonstrate that a strong vibratory stimulus evokes tonic immobility in larval zebrafish defined by suppression of exploratory locomotion and sensorimotor responses. Using a circuit-breaking screen and targeted neuron ablations, we show that cerebellar granule cells and a cluster of glutamatergic ventral prepontine neurons (vPPNs) that express key stress-associated neuropeptides are critical components of the circuit that suppresses movement. The complete sensorimotor circuit transmits information from primary sensory neurons through the cerebellum to vPPNs to regulate reticulospinal premotor neurons. These results show that cerebellar regulation of a neuropeptide-rich prepontine structure governs a conserved and ancestral defensive behavior that is triggered by inescapable threat.
The serine/threonine kinase MINK1 directly regulates the function of promigratory proteins
Authors: Daulat Avais M. , Wagner Mônica S. , Audebert Stéphane , Kowalczewska Malgorzata , Ariey-Bonnet Jeremy , Finetti Pascal , Bertucci François , Camoin Luc , Borg Jean-Paul
Published: September 2021

Upregulation of the developmental Wnt/planar cell polarity pathway is observed in many cancers and is associated with cancer development at early and late stages. We recently showed that PRICKLE1 and VANGL2, two core Wnt/PCP components, are overexpressed in triple negative breast cancer and associated with poor prognosis. PRICKLE1 is a cytoplasmic protein phosphorylated by the poorly described serine/threonine kinase MINK1 which triggers its localization at the plasma membrane, a key step for its function. Knockdown experiments have demonstrated that MINK1 and PRICKLE1 contribute to TNBC cell motility and spreading in vitro and in vivo. However, the identity of MINK1 substrates and the role of MINK1 enzymatic activity in this process have not yet been addressed issues.

We carried out a phosphoproteomic strategy and identified novel MINK1 substrates including LL5β. LL5β is a membrane scaffold molecule that anchors microtubules at the cell cortex through its association with the plus-end MT proteins CLASPs to trigger focal adhesion disassembly. LL5β is a prominent member of the MINK1-PRICKLE1 protein complex and is directly phosphorylated by MINK1 that promotes its interaction with CLASP. Using a kinase inhibitor, we demonstrate that the enzymatic activity of MINK1 is involved in the protein complex assembly and localization, and cell migration. Analysis of gene expression data show that the concomitant up-regulation of PRICKLE1 and LL5β mRNA levels encoding MINK1 substrates is associated with a poor metastasis-free survival for TNBC patients. Altogether, our results suggest that MINK1 may represent a potential target in TNBC.
Characterising sex differences of autosomal DNA methylation in whole blood using the Illumina EPIC array
Authors: Grant Olivia A , Wang Yucheng , Kumari Meena , Zabet Nicolae Radu , Schalkwyk Leonard
Published: September 2021

Sex differences are known to play a role in disease etiology, progression and outcome. Previous studies have revealed autosomal epigenetic differences between males and females in some tissues, including differences in DNA methylation patterns. Here, we report for the first time an analysis of autosomal sex differences in DNAme using the Illumina EPIC array in human whole blood (n=1171). We identified 554 sex-associated differentially methylated CpG sites (saDMPs) with the majority found to be hypermethylated in females (70%). These saDMP’s are enriched in CpG islands and CpG shores and located preferentially at 5’UTRs, 3’UTRs and enhancers. Additionally, we identified 311 significant sex associated differentially methylated regions (saDMRs). Transcription factor binding site enrichment revealed enrichment of transcription factors related to critical developmental processes and sex determination such as SRY and SOX9. Our study reports a reliable catalogue of sex associated CpG sites and elucidates several characteristics of these sites.