bluuebunny/crossref_metadata_2025_split huggingface dataset:
Monosomy X in isogenic human iPSC-derived trophoblast model impacts expression modules preserved in human placenta
Authors: Ahern Darcy T. , Bansal Prakhar , Faustino Isaac , Kondaveeti Yuvabharath , Glatt-Deeley Heather R. , Banda Erin C. , Pinter Stefan F. 
Published: December 2021

SUMMARY/ABSTRACTMammalian sex chromosomes encode homologous X/Y gene pairs that were retained on the male Y and escape X chromosome inactivation (XCI) in females. Inferred to reflect X/Y-pair dosage sensitivity, monosomy X is a leading cause of miscarriage in humans with near full penetrance. This phenotype is shared with many other mammals but not the mouse, which offers sophisticated genetic tools to generate sex chromosomal aneuploidy but also tolerates its developmental impact. To address this critical gap, we generated X-monosomic human induced pluripotent stem cells (hiPSCs) alongside otherwise isogenic euploid controls from male and female mosaic samples. Phased genomic variants of these hiPSC panels enable systematic investigation of X/Y dosage-sensitive features using in vitro models of human development.Here, we demonstrate the utility of these validated hiPSC lines to test how X/Y-linked gene dosage impacts a widely-used model for the human syncytiotrophoblast. While these isogenic panels trigger a GATA2/3 and TFAP2A/C -driven trophoblast gene circuit irrespective of karyotype, differential expression implicates monosomy X in altered levels of placental genes, and in secretion of placental growth factor (PlGF) and human chorionic gonadotropin (hCG). Remarkably, weighted gene co-expression network modules that significantly reflect these changes are also preserved in first-trimester chorionic villi and term placenta. Our results suggest monosomy X may skew trophoblast cell type composition, and that the pseudoautosomal region likely plays a key role in these changes, which may facilitate prioritization of haploinsufficient drivers of 45,X extra-embryonic phenotypes.
Predicting the effects of multiple global change drivers on microbial communities remains challenging
Authors: Suleiman Marcel , Daugaard Uriah , Choffat Yves , Zheng Xue , Petchey Owen L 
Published: December 2021

AbstractMicrobial communities in many ecosystems are facing a broad range of global change drivers, such as nutrient enrichment, chemical pollution, and temperature change. These drivers can cause changes in the abundance of taxa, the composition of communities, and the properties of ecosystems. While the influence of single drivers is already described in numerous studies, the effect and predictability of multiple drivers changing simultaneously is still poorly understood. In this study, we used 240 highly replicable oxic/anoxic aquatic lab microcosms and four drivers (fertilizer, glyphosate, metal pollution, antibiotics) in all possible combinations at three different temperatures (20 °C, 24 °C, and 28 °C) to shed light into consequences of multiple drivers on different levels of organization, ranging from species abundance to community and ecosystem parameters. We found (i) that at all levels of ecological organisation, combinations of drivers can change the biological consequence and direction of effect compared to single drivers (ii), that effects of combinations are further modified by temperature, (iii) that a larger number of drivers occurring simultaneously is often quite closely related to their effect size, and (iv) that there is little evidence that any of these effects are associated with the level of ecological organisation of the state variable. These findings suggest that, at least in this experimental ecosystem approximating a stratified aquatic ecosystem, there may be relatively little scope for predicting the effects of combinations of drivers from the effects of individual drivers, or by accounting for the level of ecological organisation in question, though there may be some scope for prediction based on the number of drivers that are occurring simultaneous. A priority, though also a considerable challenge, is to extend such research to consider continuous variation in the magnitude of multiple drivers acting together.
A neuron, microglia, and astrocyte triple coculture model to study Alzheimer disease
Authors: Luchena Celia , Zuazo-Ibarra Jone , Valero Jorge , Matute Carlos , Alberdi Elena , Capetillo-Zarate Estibaliz 
Published: December 2021

ABSTRACTGlial cells are essential to understand Alzheimer’s disease (AD) progression, given their role in neuroinflammation and neurodegeneration. There is a need for reliable and easy to manipulate models that allow studying the mechanisms behind neuron and glia communication. Currently available models such as cocultures require complex methodologies and/or might not be affordable for all laboratories. With this in mind, we aimed to establish a straightforward in vitro setting with neurons and glial cells to study AD.We generated a triple co-culture with neurons, microglia and astrocytes. Immunofluorescence, western blot and ELISA techniques were used to characterize the effects of oligomeric Aβ (oAβ) in this model.We found that, in the triple co-culture, microglia increased the expression of anti-inflammatory markers Arginase I and TGF-β1, and reduced pro-inflammatory iNOS and IL-1β, compared with microglia alone. Astrocytes reduced expression of pro-inflammatory A1 markers AMIGO2 and C3, and displayed a ramified morphology resembling physiological conditions. Lastly, neurons increased post-synaptic markers, and developed more and longer branches than in individual primary cultures. Addition of oAβ in the triple coculture reduced synaptic markers and increased microglial activation, which are hallmarks of AD.Consequently, we developed a reliable model, where cells better resemble physiological conditions: microglia are less inflammatory, astrocytes are less reactive and neurons display a more mature morphology than in individual primary cultures. Moreover, we were able to recapitulate Aβ-induced synaptic loss and inflammation. This model emerges as a powerful tool to study neurodegeneration and inflammation in the context of AD and other neurodegenerative diseases.Table of content imageMain pointsIn our model, microglia and astrocytes are less reactive, and neurons have a more mature morphology than in primary cultures.oAβ reduced synaptic markers and increased microglial activation.This triple co-culture is a reliable tool to study neurodegeneration and gliosis in vitro.
Ecology drives the degree of convergence in the gene expression of extremophile fishes
Authors: Tobler Michael , Greenway Ryan , Kelley Joanna L. 
Published: December 2021

AbstractConvergent evolution, where independent lineages evolve similar traits when adapting to similar habitats, is a common phenomenon and testament to the repeatability of evolutionary processes. Still, non-convergence is also common, and a major question is whether apparently idiosyncratic, lineage-specific evolutionary changes are reflective of chance events inherent to evolutionary processes, or whether they are also influenced by deterministic genetic or ecological factors. To address this question, we quantified the degree of convergence in genome-wide patterns of gene expression across lineages of livebearing fishes (family Poeciliidae) that span 40 million years of evolution and have colonized extreme environments in the form of toxic, hydrogen-sulfide-rich springs. We specifically asked whether the degree of convergence across lineage pairs was related to their phylogenetic relatedness or the ecological similarity of the habitats they inhabit. Using phylogenetic comparative analyses, we showed that the degree of convergence was highly variable across lineage pairs residing in sulfide springs. While closely related lineages did not exhibit higher degrees of convergence than distantly related ones, we uncovered a strong relationship between degree of convergence and ecological similarity. Our results indicate that variation in the degree of convergence is not merely noise associated with evolutionary contingency. Rather, cryptic environmental variation that is frequently ignored when we employ reductionist approaches can significantly contribute to adaptive evolution. This study highlights the importance of multivariate approaches that capture the complexities of both selective regimes and organismal design when assessing the roles of determinism and contingency in evolution.Significance StatementWhen different species adapt to similar environmental conditions, we frequently observe a mix between shared (convergent) and lineage-specific (nonconvergent) evolutionary changes. Shared changes provide evidence for the repeatability and predictability of evolution. However, it remains unclear whether lineage-specific changes are caused by random forces that limit the predictability of evolution, or whether they reflect deterministic processes shaped by unidentified genetic and environmental factors. By analyzing patterns of gene expression across fishes in extreme environments, we show that the degree of convergence between lineages is related to ecology, indicating that lineage-specific evolutionary changes are not just noise caused by random processes. Thus, acknowledging the complexity of nature in empirical research is critical if we want to predict evolution.
Enriching for orthologs increases support for Xenacoelomorpha and Ambulacraria sister relationship
Authors: Mulhair Peter O , McCarthy Charley GP , Siu-Ting Karen , Creevey Christopher J , O’Connell Mary J 
Published: December 2021

SummaryConflicting studies place a group of bilaterian invertebrates containing xenoturbellids and acoelomorphs, the Xenacoelomorpha, as either the primary emerging bilaterian phylum, or within Deuterostomia, sister to Ambulacraria. While their placement as sister to the rest of Bilateria supports relatively simple morphology in the ancestral bilaterian, their alternative placement within Deuterostomia suggests a morphologically complex ancestral Bilaterian along with extensive loss of major phenotypic traits in the Xenacoelomorpha. More recently, further studies have brought into question whether Deuterostomia should be considered monophyletic at all. Hidden paralogy presents a major challenge for reconstructing species phylogenies. Here we assess whether hidden paralogy has contributed to the conflict over the placement of Xenacoelomorpha. Our approach assesses previously published datasets, enriching for orthogroups whose gene trees support well resolved clans elsewhere in the animal tree of life. We find that the majority of constituent genes in previously published datasets violate incontestable clans, suggesting that hidden paralogy is rife at this depth. We demonstrate that enrichment for genes with orthologous signal alters the final topology that is inferred, whilst simultaneously improving fit of the model to the data. We discover increased, but ultimately not conclusive, support for the existence of Xenambulacraria in our orthology enriched set of genes. At a time when we are steadily progressing towards sequencing all of life on the planet, we argue that long-standing contentious issues in the tree of life will be resolved using smaller amounts of better quality data that can be modelled adequately.
Variability in mosquito community composition associated with estuarine wetlands in Northern NSW, Australia
Authors: Webb Cameron Ewart , Hanford Jayne , Bald Michael , Roberts Scott 
Published: December 2021

AbstractThe Northern Rivers region of NSW, Australia, is well documented as being impacted by nuisance-biting mosquitoes and mosquito-borne disease. Mosquitoes of greatest concern are those associated with estuarine and brackish water habitats associated with coastal wetlands and understanding the spatial variability in abundance and diversity will assist the assessment of risk and inform surveillance and control programs. Adult mosquito populations were sampled, using carbon dioxide baited traps, at four locations within the Richmond River estuary at Ballina, NSW, Australia, during January and February 2021. Concomitant sampling of habitats for immature mosquitoes was also undertaken. A total of 16,467 mosquitoes was collected at all sites across two sampling periods with the most abundant mosquitoes, Verrallina funerea, Aedes vigilax, and Culex sitiens, those typically associated with estuarine environments. Culex annulirostris, a mosquito associated with freshwater habitats, and Aedes notoscriptus, a mosquito associated with water-holding containers, were also commonly collected. The mosquito communities differed, in relative abundance and species richness, between the four locations. The result highlighted the need for authorities to understand the variability in productivity of potential mosquito habitats, beyond those determinants associated with vegetation communities alone, when assessing suitable locations of mosquito surveillance and integrated mosquito management.
Validated Determination of NRG1 Ig-like Domain Structure by Mass Spectrometry Coupled with Computational Modeling
Authors: Khaje Niloofar Abolhasani , Eletsky Alexander , Biehn Sarah E. , Mobley Charles K. , Rogals Monique J. , Kim Yoonkyoo , Mishra Sushil K. , Doerksen Robert J. , Lindert Steffen , Prestegard James , Sharp Joshua S. 
Published: December 2021

AbstractHigh resolution hydroxyl radical protein footprinting (HR-HRPF) is a mass spectrometry-based method that measures the solvent exposure of multiple amino acids in a single experiment, offering constraints for experimentally-informed computational modeling. HR-HRPF-based modeling has previously been used to accurately model the structure of proteins of known structure, but the technique has never been used to determine the structure of a protein of unknown structure leaving questions of unintentional bias and applicability to unknown structures unresolved. Here, we present the use of HR-HRPF-based modeling to determine the structure of the Ig-like domain of NRG1, a protein with no close homolog of known structure. Independent determination of the protein structure by both HR-HRPF-based modeling and heteronuclear NMR was carried out, with results compared only after both processes were complete. The HR-HRPF-based model was highly similar to the lowest energy NMR model, with a backbone RMSD of 1.6 Å. To our knowledge, this is the first use of HR-HRPF-based modeling to determine a previously uncharacterized protein structure.
Broad misappropriation of developmental splicing profile by cancer in multiple organs
Authors: Singh Arashdeep , Rajeevan Arati , Gopalan Vishaka , Agrawal Piyush , Day Chi-Ping , Hannenhalli Sridhar 
Published: December 2021

AbstractOncogenesis mimics key aspects of embryonic development. However, the underlying molecular determinants are not completely understood. Leveraging temporal transcriptomic data during development in multiple human organs, we demonstrate that the ‘embryonic positive (EP)’ alternative splicing events, specifically active during human organogenesis, are broadly reactivated in the organ-specific tumor. EP events are associated with key oncogenic processes and their reactivation predicts proliferation rates in cancer cell lines as well as patient survival. EP exons are significantly enriched for nitrosylation and transmembrane domains coordinately regulating splicing in multiple genes involved in intracellular transport and N-linked glycosylation respectively, known critical players in cancer. We infer critical splicing factors (CSF) potentially regulating these EP events and show that CSFs exhibit copy number amplifications in cancer and are upregulated specifically in malignant cells in the tumor microenvironment. Mutational inactivation of CSFs results in decreased EP splicing, further supporting their causal role. Multiple complementary analyses point to MYC and FOXM1 as potential transcriptional regulators of CSFs in brain and liver, which can be potentially targeted using FDA approved drugs. Our study provides the first comprehensive demonstration of a splicing-mediated link between development and cancer, and suggest novel targets including splicing events, splicing factors, and transcription factors.
Proximity-assisted photoactivation (PAPA): Detecting molecular interactions in live-cell single-molecule imaging
Authors: Graham Thomas G.W. , Ferrie John J. , Dailey Gina M. , Tjian Robert , Darzacq Xavier 
Published: December 2021

AbstractSingle-molecule imaging provides a powerful way to study biochemical processes in live cells, yet it remains challenging to track single molecules while simultaneously detecting their interactions. Here we describe a novel property of rhodamine dyes, proximity-assisted photoactivation (PAPA), in which one fluorophore (the “sender”) can reactivate a second fluorophore (the “receiver”) from a dark state. PAPA requires proximity between the two fluorophores, yet it operates at a longer average intermolecular distance than Förster resonance energy transfer (FRET). We show that PAPA can be used in live cells both to detect protein-protein interactions and to highlight a sub-population of labeled protein complexes in which two different labels are in proximity. In proof-of-concept experiments, PAPA detected the expected correlation between androgen receptor self-association and chromatin binding at the single-cell level. These results establish a new way in which a photophysical property of fluorophores can be harnessed to study molecular interactions in single-molecule imaging of live cells.
GZMKhigh CD8+ T effector memory cells are associated with CD15high neutrophil abundance in early-stage colorectal tumors and predict poor clinical outcome
Authors: Tiberti Silvia , Catozzi Carlotta , Scirgolea Caterina , Croci Ottavio , Ballerini Mattia , Cagnina Danilo , Soriani Chiara , Nava Lauson Carina B. , Macandog Angeli D. , Bertalot Giovanni , Petz Wanda L. , Ravenda Simona P. , Licursi Valerio , Paci Paola , Rasponi Marco , Fazio Nicola , Ren Guangwen , Fumagalli-Romario Uberto , Shaefer Martin H. , Campaner Stefano , Lugli Enrico , Nezi Luigi , Manzo Teresa 
Published: December 2021

ABSTRACTTumor contexture has emerged as a major prognostic determinant and tumor infiltrating CD8+ T cells have been associated with a better prognosis in several solid tumors, including early-stage colorectal cancer (CRC). However, the tumor immune infiltrate is highly heterogeneous and understanding how the interplay between different immune cell compartments impacts on the clinical outcome is still in its infancy.Here, we describe in a prospective cohort a novel CD8+ T effector memory population, which is characterized by high levels of Granzyme K (GZMKhigh CD8+ TEM) and is correlated with CD15high tumor infiltrating neutrophils. We provide both in vitro and in vivo evidence of the role of stromal cell-derived factor 1 (CXCL12/SDF-1) in driving functional changes on neutrophils at the tumor site, promoting their retention and increasing the crosstalk with CD8+ T cells. Mechanistically, as a consequence of the interaction with neutrophils, CD8+ T cells are skewed towards a CD8+ TEM phenotype and produce high levels of GZMK, which in turn decreases E-cadherin pathway. The correlations of GZMKhigh CD8+ TEM and neutrophils with both tumor progression in mice and early relapse in CRC patients demonstrate the role of GZMKhigh CD8+ TEM in promoting malignancy. Indeed, a gene signature defining GZMKhigh CD8+ TEM was associated with worse prognosis on a larger independent cohort of CRC patients and a similar analysis was extended to lung cancer (TCGA).Overall, our results highlight the emergence of GZMKhigh CD8+ TEM in early-stage CRC tumors as a hallmark driven by the interaction with neutrophils, which could implement current patient stratification and be targeted by novel therapeutics.
Sex-specific topology of the nociceptive circuit shapes dimorphic behavior in C. elegans
Authors: Pechuk Vladyslava , Salzberg Yehuda , Goldman Gal , Chaubey Aditi H. , Bola R. Aaron , Hoffman Jonathon R. , Endreson Morgan L. , Miller Renee M. , Reger Noah J. , Portman Douglas S. , Ferkey Denise M. , Schneidman Elad , Oren-Suissa Meital 
Published: December 2021

SUMMARYHow sexually dimorphic behavior is encoded in the nervous system is poorly understood. Here, we characterize the dimorphic nociceptive behavior in C. elegans and study the underlying circuits, which are composed of the same neurons but are wired differently. We show that while sensory transduction is similar in the two sexes, the downstream network topology markedly shapes behavior. We fit a network model that replicates the observed dimorphic behavior in response to external stimuli, and use it to predict simple network rewirings that would switch the behavior between the sexes. We then show experimentally that these subtle synaptic rewirings indeed flip behavior. Strikingly, when presented with aversive cues, rewired males were compromised in finding mating partners, suggesting that network topologies that enable efficient avoidance of noxious cues have a reproductive “cost”. Our results present a deconstruction of the design of a neural circuit that controls sexual behavior, and how to reprogram it.
LRRFIP2 modulates the response to hypoxia during embryonic cardiogenesis
Authors: Driss Laura Ben , Houbron Christophe , Britto Florian , Schmitt Alain , Gall Morgane Le , Daubas Philippe , Maire Pascal 
Published: December 2021

ABSTRACTOxygen is crucial for appropriate embryonic and fetal development, including cardiogenesis. The heart is the first organ formed in the embryo and is required to provide oxygen and nutrients to all cells in the body. Embryonic cardiogenesis is a complex process finely regulated and prone to congenital malformations. It takes place in a hypoxic environment that activates the HIF-1α signaling pathway which mediates cellular and systemic adaptations to low oxygen levels. Since inhibition or overactivation of the HIF-1α signaling pathway in the myocardium lead to severe cardiac malformations and embryonic lethality, it is important that the cellular response to hypoxia be precisely regulated. While many gene regulatory networks involved in embryonic cardiogenesis have been characterized in detail, the modulation of the response of cardiomyocytes (CM) to hypoxia has remained less studied. We identified LRRFIP2 as a new negative cofactor of HIF-1α. Indeed, we have shown that the absence of Lrrfip2 expression in a mouse KI model led to an enhance of many HIF-1α target genes including Igfbp3, Bnip3 and Ndufa4l2 in embryonic CM during development. As results, the absence of Lrrfip2 led to the inhibition of the PI3K/Akt survival pathway, growth defects, mitochondrial dysfunction and to a precocious maturation of the embryonic CMs. Altogether, these defects led to the formation of a smaller heart unable to provide sufficient oxygen to the embryo and finally to a severe hypoxia and a precocious lethality.Graphical abstractHighlightsLRRFIP2 regulates negatively the HIF-1α activityLrrfip2 deletion leads to an embryonic lethality between E11.5 and E13.5LRRFIP2 controls ROS production and CM maturation