bluuebunny/crossref_metadata_2025_split huggingface dataset:
Non-random organization of flux control mechanisms in yeast central metabolic pathways
Authors: Yu Rosemary , Vorontsov Egor , Sihlbom Carina , Nielsen Jens 
Published: December 2021

AbstractMetabolic flux can be regulated by a variety of different mechanisms, but the organization of these mechanisms within the metabolic network has remained unknown. Here we test the hypothesis that flux control mechanisms are not distributed randomly in the metabolic network, but rather organized according to pathway. Combining proteomics, phosphoproteomics, and metabolic modeling, we report the largest collection of flux-enzyme-phosphoenzyme relationships to date in Saccharomyces cerevisiae. In support of the hypothesis, we show that (i) amino acid metabolic pathways are predominantly regulated by enzyme abundance stemming from transcriptional regulation; (ii) upper glycolysis and associated pathways, by inactivating enzyme phosphorylation; (iii) lower glycolysis and associated pathways, by activating enzyme phosphorylation; and (iv) glycolipid/glycophospholipid pathways, by a combination of enzyme phosphorylation and metabolic compartmentalization. We delineate the evolutionary history for the observed organization of flux control mechanisms in yeast central metabolic pathways, furthering our understanding of the regulation of metabolism and its evolution.
Polymorphism-aware estimation of species trees and evolutionary forces from genomic sequences with RevBayes
Authors: Borges Rui , Boussau Bastien , Höhna Sebastian , Pereira Ricardo J. , Kosiol Carolin 
Published: December 2021

AbstractThe availability of population genomic data through new sequencing technologies gives unprecedented opportunities for estimating important evolutionary forces such as genetic drift, selection, and mutation biases across organisms. Yet, analytical methods that can handle polymorphisms jointly with sequence divergence across species are rare and not easily accessible to empiricists.We implemented polymorphism-aware phylogenetic models (PoMos), an alternative approach for species tree estimation, in the Bayesian phylogenetic software RevBayes. PoMos naturally account for incomplete lineage sorting, which is known to cause difficulties for phylogenetic inference in species radiations, and scale well with genome-wide data. Simultaneously, PoMos can estimate mutation and selection biases.We have applied our methods to resolve the complex phylogenetic relationships of a young radiation of Chorthippus grasshoppers, based on coding sequences. In addition to establishing a well-supported species tree, we found a mutation bias favoring AT alleles and selection bias promoting the fixation of GC alleles, the latter consistent with GC-biased gene conversion. The selection bias is two orders of magnitude lower than genetic drift, validating the critical role of nearly neutral evolutionary processes in species radiation.PoMos offer a wide range of models to reconstruct phylogenies and can be easily combined with existing models in RevBayes — e.g., relaxed clock and divergence time estimation — offering new insights into the evolutionary processes underlying molecular evolution and, ultimately, species diversification.
ZEB2 transduces HIF1α dependent regulation of Transglutaminase 2 in glomerular podocytes
Authors: Kolligundla Lakshmi P , Singh Ashish K , Kavvuri Rajesh , Pasupulati Anil K 
Published: December 2021

AbstractGlomerular podocytes are instrumental in ensuring glomerular permselectivity and regulating the integrity of glomerular biology. However, podocytes are vulnerable to various noxious stimuli such as hypoxia, and podocyte injury presented with glomerulosclerosis and impaired kidney function. The mechanism of hypoxia-induced podocyte injury vis-a-vis glomerulosclerosis has remained enigmatic. Hypoxia inducible factor 1α (HIF1α) that transduces hypoxic adaptations, induces Transglutaminase 2 (TG2), a calcium dependent enzyme that catalyzes intramolecular ε-(γ-glutamyl) lysine cross-links of extracellular matrix (ECM) proteins. In this study, we investigated the mechanism of regulation of TG2 by HIF1α. Stabilization of HIF1α by FG4592 (Roxadustat) and physiological hypoxia, resulted in elevated expression of ZEB2 (zinc-finger E-box-homeobox 2) and its downstream target TRPC6 (transient receptor potential channel 6). ZEB2 transcriptionally activates TG2 expression, whereas, via TRPC6, it induces calcium influx, inturn it increases the TG2 activity. Blocking the TRPC6 action or suppressing its expression only partially attenuated FG4592 induced TG2 activity, whereas suppression of ZEB2 expression significantly abolished TG2 activity. This study demonstrates that stabilization of HIF1α stimulates both TG2 expression and activity, whereas abrogation of HIF1α by metformin prevented HIF1α regulated TG2 and consequent glomerular injury.
GiPS: Genomics-informed parent selection uncovers the breeding value of wheat genetic resources
Authors: Schulthess Albert W. , Kale Sandip M. , Liu Fang , Zhao Yusheng , Philipp Norman , Rembe Maximilian , Jiang Yong , Beukert Ulrike , Serfling Albrecht , Himmelbach Axel , Fuchs Jörg , Oppermann Markus , Weise Stephan , Boeven Philipp H. G. , Schacht Johannes , Longin C. Friedrich H. , Kollers Sonja , Pfeiffer Nina , Korzun Viktor , Lange Matthias , Scholz Uwe , Stein Nils , Mascher Martin , Reif Jochen C. 
Published: December 2021

AbstractThe great efforts spent in the maintenance of past diversity in genebanks are rationalized by the potential role of plant genetic resources in future crop improvement – a concept whose practical implementation has fallen short of expectations. Here, we implement genomics-informed parent selection to expedite pre-breeding without discriminating against non-adapted germplasm. We collect dense genetic profiles for a large winter wheat collection and evaluate grain yield and resistance to yellow rust in representative coresets. Genomic prediction within and across genebanks identified the best parents for PGR x elite derived crosses that outyielded current elite cultivars in multiple field trials.
Metabolic alterations in a Drosophila model of Parkinson’s disease based on DJ-1 deficiency
Authors: Solana-Manrique Cristina , Sanz Francisco José , Torregrosa Isabel , Palomino-Schätzlein Martina , Hernández-Oliver Carolina , Pineda Antonio , Paricio Nuria 
Published: December 2021

ABSTRACTParkinson’s disease (PD) is the second most common neurodegenerative disorder whose physiopathology is still unclear. Besides, it is urgent to discover new biomarkers and therapeutic targets to facilitate its diagnosis and treatment. Previous studies performed in PD models and samples from PD patients already demonstrated that metabolic alterations were associated with this disease. In this context, the aim of this study is to give a better understanding of metabolic disturbances underlying PD pathogenesis. To achieve this goal, we used a Drosophila PD model based on inactivation of the DJ-1β gene (ortholog of human DJ-1). Metabolomic analyses were performed in 1-day-old and 15-day-old DJ-1β mutants and control flies using 1H nuclear magnetic resonance spectroscopy, combined with expression and enzymatic activity assays of proteins implicated in altered pathways. Our results showed that PD model flies exhibit protein metabolism alterations, a shift from tricarboxylic acid cycle to glycolytic pathway to obtain ATP, together with an increase in the expression of some urea cycle enzymes. Thus, these metabolic changes could be contributing to PD pathogenesis and might constitute possible therapeutic targets and/or biomarkers for this disease.
Regulation of effector gene expression as concerted waves inLeptosphaeria maculans: a two-players game
Authors: Clairet C. , Gay E.J. , Porquier A. , Blaise F. , Marais C.L. , Balesdent M.-H. , Rouxel T. , Soyer J.L. , Fudal I. 
Published: December 2021

ABSTRACTDuring infection, plant pathogenic fungi secrete a set of molecules collectively known as effectors, involved in overcoming the host immune system and in disease establishment. Effector genes are concertedly expressed as waves all along plant pathogenic fungi lifecycle. However, little is known about how coordinated expression of effector genes is regulated. Since many effector genes are located in repeat-rich regions, the role of chromatin remodeling in the regulation of effector expression was recently investigated. InLeptosphaeria maculans, causing stem canker of oilseed rape, we established that the repressive histone modification H3K9me3 (trimethylation of Lysine 9 of Histone H3), deposited by the histone methyltransferase KMT1, was involved in the regulation of expression of genes highly expressed during infection, including effectors. Nevertheless, inactivation ofKMT1did not induce expression of these genes at the same level as observed during infection of oilseed rape, suggesting that a second regulator, such as a transcription factor (TF), might be involved. Pf2, a TF belonging to the Zn2Cys6 fungal specific TF family, was described in several Dothideomycete species as essential for pathogenicity and effector gene expression. We identified the orthologue of Pf2 inL. maculans, LmPf2, and investigated the role of LmPf2 together with KMT1, by inactivating and over-expressingLmPf2in a wild type (WT) strain and aΔkmt1mutant. Functional analyses of the corresponding transformants highlighted an essential role of LmPf2 in the establishment of pathogenesis. Transcriptomic analyses during axenic growth showed that LmPf2 is involved in the control of effector gene expression. We observed an enhanced effect of the over-expression ofLmPf2on effector gene expression in aΔkmt1background, suggesting an antagonist role between KMT1 and LmPf2.
Insulin exposed endometrial epithelial cells cultured in a microfluidic device alters transcripts involved in translation that may contribute to reduced implantation capacity of the endometrium
Authors: Baik Soo Young , Tinning Haidee , Wang Dapeng , Forde Niamh 
Published: December 2021

ABSTRACTObesity is a rapidly growing public health issue among women of reproductive age. It is also associated with decreased reproductive function including implantation failure. Implantation failure can result from a myriad of factors including impaired gametes and endometrial dysfunction. The mechanisms of how obesity-related hyperinsulinaemia disrupts endometrial function and implantation are poorly understood. Our study aims to investigate potential mechanisms by which insulin alters endometrial transcript expression, which may affect endometrial receptivity. Ishikawa cells mimicking human endometrial epithelium were seeded into a microfluidics organ-on-chip device to produce anin vitroendometrium. Syringe pump was attached to the microfluidics device to deliver three varying treatments into Ishikawa cells: 1) media control 2) vehicle control (PBS acidified to pH3 with acetic acid) 3) Insulin (2mg/mL) at a constant flow rate of 1uL/min for 24 hours to mimic secretionin vivo. Three biological replicates were obtained. Insulin-induced transcriptomic response of thein vitroendometrium was quantified via RNA sequencing, and subsequently analysed using DAVID and Webgestalt to identify Gene Ontology (GO) terms and signalling pathways. A Total of 29 transcripts showed differential expression levels across two comparison groups (control v vehicle control; vehicle control v insulin). There were nine transcripts significantly differentially expressed in vehicle control v insulin group (p<0.05). Functional annotation analysis of transcripts altered by insulin (n=9) identified three significantly enriched GO terms: SRP-dependent cotranslational protein targeting to membrane, poly(A) binding, and RNA binding (p<0.05). Over-representation analysis found three significantly enriched signalling pathways relating to insulin-induced transcriptomic response: protein export, glutathione metabolism, and ribosome pathways (p<0.05). Insulin-induced dysregulation of biological functions and pathways highlight potential mechanisms by which high insulin concentrations within maternal circulation may perturb endometrial receptivity.
Detecting and quantifying clonal selection in somatic stem cells
Authors: Körber Verena , Ansari-Pour Naser , Jakobsen Niels Asger , Moore Rachel , Claudino Nina , Metzner Marlen , Hörsch Franziska , Usukhbayar Batchimeg , Salazar Mirian Angulo , Newman Simon , Kendrick Benjamin JL , Taylor Adrian H , Afinowi-Luitz Rasheed , Gundle Roger , Watkins Bridget , Wheway Kim , Beazley Debra , Dakin Stephanie G , Carr Andrew J , Vyas Paresh , Höfer Thomas 
Published: December 2021

AbstractAs DNA variants accumulate in somatic stem cells, become selected or evolve neutrally, they may ultimately alter tissue function. When, and how, selection occurs in homeostatic tissues is incompletely understood. Here, we introduce SCIFER, a scalable method that identifies selection in an individual tissue, without requiring knowledge of the underlying driver event. Moreover, SCIFER infers the self-renewal and mutation dynamics of the tissue’s stem cells, and, if selection is present, the size and growth rate of the largest selected clone. We benchmark SCIFER with published data and then probe bone marrow of 22 non-leukemic individuals for clonal hematopoiesis (CH), identifying CH with known and unknown driver events. Unexpectedly, we find accelerated division of all stem cells in CH, compared to age-matched non-CH individuals, suggesting that the bone marrow environment alters stem cell dynamics in individuals with CH. SCIFER is broadly applicable to renewing somatic tissues to detect and quantify selection.
Non-invasive Chromatin Deformation and Measurement of Differential Mechanical Properties in the Nucleus
Authors: Seelbinder B. , Jain M. , Erben E. , Klykov S. , Stoev I. D. , Kreysing M. 
Published: December 2021

ABSTRACTThe nucleus is highly organized to facilitate coordinated gene transcription. Measuring the rheological properties of the nucleus and its sub-compartments will be crucial to understand the principles underlying nuclear organization. Here, we show that strongly localized temperature gradients (approaching 1°C /μm) can lead to substantial intra-nuclear chromatin displacements (>1 μm), while nuclear area and lamina shape remain unaffected. Using particle image velocimetry (PIV), intra-nuclear displacement fields can be calculated and converted into spatio-temporally resolved maps of various strain components. Using this approach, we show that chromatin displacements are highly reversible, indicating that elastic contributions are dominant in maintaining nuclear organization on the time scale of seconds. In genetically inverted nuclei, centrally compacted heterochromatin displays high resistance to deformation, giving a rigid, solid-like appearance. Correlating spatially resolved strain maps with fluorescent reporters in conventional interphase nuclei reveals that various nuclear compartments possess distinct mechanical identities. Surprisingly, both densely and loosely packed chromatin showed high resistance to deformation, compared to medium dense chromatin. Equally, nucleoli display particularly high rigidity and strong local anchoring to heterochromatin. Our results establish how localized temperature gradients can be used to drive nuclear compartments out of mechanical equilibrium to obtain spatial maps of their material responses.Main FindingsNovel non-invasive active micro-rheology method to probe spatial intranuclear material responses, unhindered by the nuclear lamina, using strongly localized temperature gradientsChromatin shows both elastic and viscous properties at the mesoscale with a retardation time of τ ∼ 1sCompacted heterochromatin in a model of nuclear inversion shows high resistance to deformation, suggesting dominantly solid-like behaviorThe nucleus displays spatially distinct material properties for different compartmentsThe nucleolus shows high resistance to deformation on the time scale of secondsImmobile nucleoli appear solidly anchored to and retain the deformation of surrounding chromatin
Soluble MAC is primarily released from MAC-resistant bacteria that potently convert complement component C5
Authors: Doorduijn Dennis J. , Lukassen Marie V. , van ’t Wout Marije F.L. , Franc Vojtech , Ruyken Maartje , Bardoel Bart W. , Heck Albert J.R. , Rooijakkers Suzan H. M. 
Published: December 2021

AbstractThe Membrane Attack Complex (MAC or C5b-9) is an important effector of the immune system to kill invading microbes. MAC is formed when complement enzymes on the bacterial surface convert complement component C5 into C5b. Although the MAC is a membrane-inserted complex, soluble forms of MAC (sMAC, or terminal complement complex (TCC)) are often detected in sera of patients suffering from infections. Consequently, sMAC has been proposed as a biomarker, but it remains unclear when and how it is formed during infections. Here, we studied mechanisms of MAC formation on bacteria and found that sMAC is primarily formed in human serum by bacteria resistant to MAC-dependent killing. Surprisingly, C5 was converted into C5b more potently by MAC-resistant compared to MAC-sensitiveEscherichia colistrains. Both the increase in C5 conversion and sMAC generation were linked to the expression of lipopolysaccharide (LPS) O-Antigen in the bacterial outer membrane. In addition, we found that MAC precursors are released from the surface of MAC-resistant bacteria during MAC assembly. Release of MAC precursors from bacteria induced lysis of bystander human erythrocytes in the absence of other serum components. However, serum regulators vitronectin (Vn) and clusterin (Clu) can prevent this bystander lysis. Combining size exclusion chromatography with mass spectrometry profiling, we show that sMAC released from bacteria in serum is a heterogeneous mixture of complexes composed of C5b-8, up to 3 copies of C9 and multiple copies of Vn and Clu. Altogether, our data provide molecular insight into how sMAC is generated during bacterial infections. This fundamental knowledge could form the basis for exploring the use of sMAC as biomarker.
Comprehensive Benchmarking of CITE-seq versus DOGMA-seq Single Cell Multimodal Omics
Authors: Xu Zhongli , Heidrich-O’Hare Elisa , Chen Wei , Duerr Richard H. 
Published: December 2021

AbstractThe recently developed transcription, epitopes, and chromatin accessibility by sequencing (TEA-seq) and similar DOGMA-seq single-cell trimodal omics assays provide unprecedented opportunities for understanding cell biology, but independent optimization, benchmarking and evaluation are lacking. We explored the utility, pros and cons of DOGMA-seq compared to the bimodal cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) assay in activated and stimulated human peripheral blood T cells. We identified an optimal incubation time and concentration of digitonin (DIG) for cell permeabilization and found that single-cell trimodal omics measurements after DIG permeabilization were generally better than after an alternative “low-loss lysis” (LLL) permeabilization condition. Next, we found that DOGMA-seq with optimized DIG permeabilization and its ATAC library provides more information, even though its mRNA and cell surface protein antibody-derived tag (ADT) libraries have slightly inferior quality, compared to CITE-seq. Finally, we recognized the additional value of DOGMA-seq for studying lineage-specific T helper cells.
Pseudomonas aeruginosa utilises host-derived polyamines to facilitate antimicrobial tolerance
Authors: Hasan Chowdhury M. , Green Angharad E. , Cox Adrienne A. , White Jack , Jones Trevor , Winstanley Craig , Kadioglu Aras , Wright Megan , Neill Daniel R. , Fothergill Joanne L. 
Published: December 2021

AbstractPseudomonas aeruginosa undergoes diversification during infection of the cystic fibrosis (CF) lung. Understanding these changes requires model systems that capture the complexity of the CF lung environment. We previously identified loss-of-function mutations in the two-component regulatory system sensor kinase gene pmrB, in P. aeruginosa from CF and from experimental infection of mice. Here, we demonstrate that whilst such mutations lower in vitro MICs for multiple antimicrobial classes, this is not reflected in increased antibiotic susceptibility in vivo. Loss of PmrB impairs aminoarabinose modification of lipopolysaccharide, increasing the negative charge of the outer membrane and promoting uptake of cationic antimicrobials. However, in vivo, this can be offset by increased membrane binding of other positively charged molecules present in lungs. The polyamine spermidine readily coats the surface of PmrB-deficient P. aeruginosa, reducing susceptibility to antibiotics that rely on charge differences to bind the outer membrane and increasing biofilm formation. Spermidine is elevated in lungs during P. aeruginosa infection in mice and during episodes of antimicrobial treatment in people with CF. These findings highlight the need to study antimicrobial resistance under clinically relevant environmental conditions. Microbial mutations carrying fitness costs in vitro may be advantageous during infection, where host resources can be utilised.
Coevolution with Spatially Structured Rice Landraces Maintains Multiple Generalist Lineages in the Rice Blast Pathogen
Authors: Ali Sajid , Gladieux Pierre , Ravel Sebastien , Adreit Henri , Meusnier Isabelle , Milazzo Joelle , Cros-Arteil Sandrine , Bonnot François , Jin Baihui , Dumartinet Thomas , Charriat Florian , Lassagne Alexandre , He Xiahong , Tharreau Didier , Huang Huichuan , Morel Jean-Benoît , Fournier Elisabeth 
Published: December 2021

ABSTRACTTraditional agrosystems, where humans, crops and microbes have coevolved over long periods, can serve as models to understand the eco-evolutionary determinants of disease dynamics and help the engineering of durably resistant agrosystems. Here, we investigated the genetic and phenotypic relationship between rice (Oryza sativa) landraces and their rice blast pathogen (Magnaporthe oryzae) in the traditional Yuanyang terraces of flooded rice paddies in China, where rice landraces have been grown and bred over centuries without significant disease outbreaks. Analyses of genetic subdivision revealed that indica rice plants clustered according to landrace names. Three new diverse lineages of rice blast specific to the Yuanyang terraces coexisted with lineages previously detected at the worldwide scale. Population subdivision in the pathogen population did not mirror pattern of population subdivision in the host. Measuring the pathogenicity of rice blast isolates on landraces revealed generalist life histories. Our results suggest that the implementation of disease control strategies based on the emergence or maintenance of a generalist lifestyle in pathogens may sustainably reduce the burden of disease in crops.