bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rbf/E2F1 control growth and endoreplication via steroid-independent Ecdysone Receptor signalling inDrosophilaprostate-like secondary cells
Authors: Sekar Aashika , Leiblich Aaron , Hellberg Josephine E.E.U. , Sarma Dhruv , Mendes Cláudia C. , Wainwright S. Mark , Gandy Carina , Goberdhan Deborah C.I. , Hamdy Freddie C. , Wilson Clive 
Published: March 2021

AbstractDysregulation of cell cycle components results in the development and progression of several cancer types. Unusually, loss of the tumour suppressor gene,Retinoblastoma(Rb), and consequent activation of transcription factor E2F1 have been linked to late-stage tumour progression in prostate cancer, rather than early-stage events. This change is associated with an androgen-independent form of cancer, castration-resistant prostate cancer (CRPC), which frequently still requires androgen receptor (AR) signalling. We have previously shown that binucleate secondary cells (SCs) of theDrosophila melanogastermale accessory gland (AG) share several functional and signalling similarities with human prostate epithelial cells. Upon mating, SC growth regulation switches from a steroid-dependent to a steroid-independent form of Ecdysone Receptor (EcR) control that induces genome endoreplication. Here, we demonstrate that theDrosophilaRb homologue, Rbf, and E2F1, as well as cell cycle regulators, Cyclin D (CycD) and Cyclin E (CycE), are key mediators of SC growth and endoreplication both in virgin and mated males. Importantly, we show that the CycD/Rbf/E2F1 axis requires the EcR, but not ecdysone, to trigger CycE-dependent endoreplication and associated growth in SCs after mating, mirroring changes in CRPC. We also demonstrate that excess Rbf activity reversibly suppresses binucleation in adult SCs. Overall, our work reveals mechanistic parallels between the physiological switch to hormone-independent EcR signalling in SCs, and the pathological switch seen in CRPC, and suggests that the latter may represent the dysregulation of a currently unidentified physiological process, which permits AR signalling when androgen levels are low.
Signal requirement for cortical potential of transplantable human neuroepithelial stem cells
Authors: Varga Balazs V. , Faiz Maryam , Yang Huijuan , Pivonkova Helena , Gao Shangbang , Khelifi Gabriel , Linderoth Emma , Zhen Mei , Hussein Samer M. , Nagy Andras 
Published: March 2021

SummaryThe cerebral cortex develops from dorsal forebrain neuroepithelial progenitor cells. Initial expansion of the progenitor cell pool is followed by the generation of neurons of all the cortical layers and later, astrocytes and oligodendrocytes. However, the regulatory pathways that control the expansion and maintenance of the neuroepithelial progenitor cell pool are currently unknown. Here we define six basic pathway components that regulate proliferation of cortically specified human neuroepithelial stem cells (cNESCs)in vitrowithout the loss of developmental potential. We show that activation of FGF and inhibition of BMP and ACTIVIN A signalling are required for long-term cNESC proliferation. We also demonstrate that cNESCs preserve dorsal telencephalon-specific potential when GSK3, AKT and nuclear CATENIN-β1 activity are low. Remarkably, regulation of these six pathway components supports the clonal expansion of cNESCs. Moreover, cNESCs differentiate to lower and upper layer cortical neurons bothin vitroandin vivo. Identifying the mechanisms that drive the self-renewal and fate of cNESCs decision of neuroepithelial stem cells is key to developing new stem cell-based therapeutic approaches to treat neurological conditions.
Single-cell motion of magnetotactic bacteria in microfluidic confinement: interplay between surface interaction and magnetic torque
Authors: Codutti Agnese , Charsooghi Mohammad A. , Cerdá-Doñate Elisa , Taïeb Hubert M. , Robinson Tom , Faivre Damien , Klumpp Stefan 
Published: March 2021

AbstractSwimming microorganisms often experience complex environments in their natural habitat. The same is true for microswimmers in envisioned biomedical applications. The simple aqueous conditions typically studied in the lab differ strongly from those found in these environments and often exclude the effects of small volume confinement or the influence that external fields have on their motion. In this work, we investigate magnetically steerable microswimmers, specifically magnetotactic bacteria, in strong spatial confinement and under the influence of an external magnetic field. We trap single cells in micrometer-sized microfluidic chambers and track and analyze their motion, which shows a variety of different trajectories, depending on the chamber size and the strength of the magnetic field. Combining these experimental observations with simulations using a variant of an active Brownian particle model, we explain the variety of trajectories by the interplay between the wall interactions and the magnetic torque. We also analyze the pronounced cell-to-cell heterogeneity, which makes single-cell tracking essential for an understanding of the motility patterns. In this way, our work establishes a basis for the analysis and prediction of microswimmer motility in more complex environments.
High Throughput Virtual Screening and Validation of a SARS-CoV-2 Main Protease Non-Covalent Inhibitor
Authors: Clyde Austin , Galanie Stephanie , Kneller Daniel W. , Ma Heng , Babuji Yadu , Blaiszik Ben , Brace Alexander , Brettin Thomas , Chard Kyle , Chard Ryan , Coates Leighton , Foster Ian , Hauner Darin , Kertesz Vilmos , Kumar Neeraj , Lee Hyungro , Li Zhuozhao , Merzky Andre , Schmidt Jurgen G. , Tan Li , Titov Mikhail , Trifan Anda , Turilli Matteo , Van Dam Hubertus , Chennubhotla Srinivas C. , Jha Shantenu , Kovalevsky Andrey , Ramanathan Arvind , Head Martha S. , Stevens Rick 
Published: March 2021

Despite the recent availability of vaccines against the acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the search for inhibitory therapeutic agents has assumed importance especially in the context of emerging new viral variants. In this paper, we describe the discovery of a novel non-covalent small-molecule inhibitor, MCULE-5948770040, that binds to and inhibits the SARS-Cov-2 main protease (Mpro) by employing a scalable high throughput virtual screening (HTVS) framework and a targeted compound library of over 6.5 million molecules that could be readily ordered and purchased. Our HTVS framework leverages the U.S. supercomputing infrastructure achieving nearly 91% resource utilization and nearly 126 million docking calculations per hour. Downstream biochemical assays validate this Mproinhibitor with an inhibition constant (Ki) of 2.9µM [95% CI 2.2, 4.0]. Further, using room-temperature X-ray crystallography, we show that MCULE-5948770040 binds to a cleft in the primary binding site of Mproforming stable hydrogen bond and hydrophobic interactions. We then used multipleµs-timescale molecular dynamics (MD) simulations, and machine learning (ML) techniques to elucidate how the bound ligand alters the conformational states accessed by Mpro, involving motions both proximal and distal to the binding site. Together, our results demonstrate how MCULE-5948770040 inhibits Mproand offers a springboard for further therapeutic design.Significance StatementThe ongoing novel coronavirus pandemic (COVID-19) has prompted a global race towards finding effective therapeutics that can target the various viral proteins. Despite many virtual screening campaigns in development, the discovery of validated inhibitors for SARS-CoV-2 protein targets has been limited. We discover a novel inhibitor against the SARS-CoV-2 main protease. Our integrated platform applies downstream biochemical assays, X-ray crystallography, and atomistic simulations to obtain a comprehensive characterization of its inhibitory mechanism. Inhibiting Mprocan lead to significant biomedical advances in targeting SARS-CoV-2 treatment, as it plays a crucial role in viral replication.
A Synthesis of Game Theory and Quantitative Genetic Models of Social Evolution
Authors: McGlothlin Joel W. , Akçay Erol , Brodie Edmund D. , Moore Allen J. , Van Cleve Jeremy 
Published: March 2021

AbstractTwo popular approaches for modeling social evolution, evolutionary game theory and quantitative genetics, ask complementary questions but are rarely integrated. Game theory focuses on evolutionary outcomes, with models solving for evolutionarily stable equilibria, whereas quantitative genetics provides insight into evolutionary processes, with models predicting short-term responses to selection. Here we draw parallels between evolutionary game theory and interacting phenotypes theory, which is a quantitative genetic framework for understanding social evolution. First, we show how any evolutionary game may be translated into two quantitative genetic selection gradients, nonsocial and social selection, which may be used to predict evolutionary change from a single round of the game. We show that synergistic fitness effects may alter predicted selection gradients, causing changes in magnitude and sign as the population mean evolves. Second, we show how evolutionary games involving plastic behavioral responses to partners can be modeled using indirect genetic effects, which describe how trait expression changes in response to genes in the social environment. We demonstrate that repeated social interactions in models of reciprocity generate indirect effects and conversely, that estimates of parameters from indirect genetic effect models may be used to predict the evolution of reciprocity. We argue that a pluralistic view incorporating both theoretical approaches will benefit empiricists and theorists studying social evolution. We advocate the measurement of social selection and indirect genetic effects in natural populations to test the predictions from game theory, and in turn, the use of game theory models to aid in the interpretation of quantitative genetic estimates.
A Chemical-Enhanced System for CRISPR-Based Nucleic Acid Detection
Authors: Li Zihan , Zhao Wenchang , Ma Shixin , Li Zexu , Yao Yingjia , Fei Teng 
Published: March 2021

AbstractThe CRISPR-based nucleic acid detection systems such as SHERLOCK, DETECTR and HOLMES have shown great potential for point-of-care testing of viral pathogens, especially in the context of COVID-19 pandemic. Here we optimize several key parameters of reaction chemistry and develop a Chemical Enhanced CRISPR Detection system for nucleic acid (termed CECRID). For the Cas12a/Cas13a-based signal detection phase, we determine buffer conditions and substrate range for optimal detection performance. By comparing several chemical additives, we find that addition of L-proline can secure or enhance Cas12a/Cas13a detection capability. For isothermal amplification phase with typical LAMP and RPA methods, inclusion of L-proline can also enhance specific target amplification as determined by CRISPR detection. Using SARS-CoV-2 pseudovirus, we demonstrate CECRID has enhanced detection sensitivity over chemical additive-null method with either fluorescence or lateral flow strip readout. Thus, CECRID provides an improved detection power and system robustness towards practical application of CRISPR-based diagnostics.
A neural marker of eye contact highly impaired in autism spectrum disorder
Authors: Lio Guillaume , Corazzol Martina , Fadda Roberta , Doneddu Giuseppe , Demily Caroline , Sirigu Angela 
Published: March 2021

AbstractAttention to faces and eye contact are key behaviors for establishing social bonds in humans. In Autism Spectrum Disorders (ASD) a neurodevelopmental disturbance characterized by poor communication skills, impaired face processing and gaze avoidance are critical clinical features for its diagnosis. The biological alterations underlying these impairments are not clear yet. Using high-density electroencephalography coupled with multi-variate pattern classification and group blind source separation methods we searched for face- and face components-related neural signals that could best discriminate neurotypical and ASD visual processing. First, we isolated a face-specific neural signal in the superior temporal sulcus peaking at 240ms after stimulus onset. A machine learning algorithm applied on the extracted neural component reached 74% decoding accuracy at the same latencies, dissociating the neurotypical population from ASD subjects in whom this signal was weak. Further, by manipulating attention to face parts we found that the signal-evoked power in neurotypical subjects varied as a function of the distance of the eyes in the face stimulus with respect to the viewers’ fovea, i.e. it was strongest when the eyes were projected on the fovea and weakest when projected in the retinal periphery. Such selective face and face-components neural modulations were not found in ASD individuals although they showed typical early face related P100 and the N170 signals. These findings show that dedicated cortical mechanisms related to face perception set neural priority for attention to eyes and that these mechanisms are altered in individuals with ASD.
Multi-omic meta-analysis of transcriptomes and the bibliome uncovers novel hypoxia-inducible genes
Authors: Ono Yoko , Bono Hidemasa 
Published: March 2021

AbstractHypoxia is a condition in which cells, tissues, or organisms are deprived of sufficient oxygen supply. Aerobic organisms have a hypoxic response system, represented by hypoxia-inducible factor 1-α (HIF1A), to adapt to this condition. Due to publication bias, there has been little focus on genes other than well-known signature hypoxia-inducible genes. Therefore, in this study, we performed a meta-analysis to identify novel hypoxia-inducible genes. We searched publicly available transcriptome databases to obtain hypoxia-related experimental data, retrieved the metadata, and manually curated it. We selected the genes that are differentially expressed by hypoxic stimulation, and evaluated their relevance in hypoxia by performing enrichment analyses. Next, we performed a bibliometric analysis using gene2pubmed data to examine genes that have not been well studied in relation to hypoxia. Gene2pubmed data that provides information about the relationship between gene and publication. We calculated and evaluated the number of reports and similarity coefficients of each gene to HIF1A, which is a representative gene in hypoxia studies. In this data-driven study, we report that several genes that were not known to be associated with hypoxia, including the G protein-coupled receptor 146 gene, are upregulated by hypoxic stimulation.
GCN5 Maintains Muscle Integrity by Acetylating YY1 to Promote Dystrophin Expression
Authors: Addicks Gregory C. , Zhang Hongbo , Ryu Dongryeol , Vasam Goutham , Marshall Philip L. , Green Alex E. , Patel Sonia , Kang Baeki E. , Kim Doyoun , Katsyuba Elena , Williams Evan G. , Renaud Jean-Marc , Auwerx Johan , Menzies Keir J. 
Published: March 2021

AbstractThis work identifies a novel role for the acetyltransferase GCN5 in regulating muscle integrity through inhibition of DNA binding activity of the transcriptional repressor YY1. Here we report that in mice a muscle-specific knockout of GCN5 (Gcn5skm-/-) reduces the expression of key structural muscle proteins, including dystrophin, resulting in myopathy. Supporting our observation, a meta-analysis between the differential transcriptome ofGcn5skm-/-muscle and all available open-access data sets identified top correlations with musculoskeletal diseases in humans. GCN5 was found to acetylate YY1 at two residues (K392 and K393), which disrupts the interaction between the YY1 zinc-finger region and DNA. De/acetylation mimics for these YY1 post-translational modifications modulated muscle structural gene expression and DNA binding. Analysis of human GTEx data also found positive and negative correlations between fiber diameter and GCN5 and YY1 respectively. Collectively, our results demonstrate that GCN5 acetyltransferase activity regulates YY1 DNA binding and expression of dystrophin to modulate muscle integrity.
Bacterial retrons enable precise gene editing in human cells
Authors: Zhao Bin , Chen Shi-An A. , Lee Jiwoo , Fraser Hunter B. 
Published: March 2021

AbstractRetrons are bacterial genetic elements involved in anti-phage defense. They have the unique ability to reverse transcribe RNA into multicopy single-stranded DNA (msDNA) that remains covalently linked to their template RNA. Retrons coupled with CRISPR-Cas9 in yeast have been shown to improve editing efficiency of precise genome editing via homology-directed repair (HDR). HDR editing efficiency has been limited by challenges associated with delivering extracellular donor DNA encoding the desired mutation. In this study, we tested the ability of retrons to produce msDNA as donor DNA and facilitate HDR by tethering msDNA to guide RNA in HEK293T and K562 cells. Through heterologous reconstitution of retrons from multiple bacterial species with the CRISPR-Cas9 system, we demonstrated HDR rates of up to 11.3%. Overall, our findings represent the first step in extending retron-based precise gene editing to human cells.
Biasing RNA coarse-grained folding simulations with Small–Angle X–ray Scattering (SAXS) data
Authors: Mazzanti L. , Alferkh L. , Frezza E. , Pasquali S. 
Published: March 2021

AbstractRNA molecules can easily adopt alternative structures in response to different environmental conditions. As a result, a molecule’s energy landscape is rough and can exhibits a multitude of deep basins. In the absence of a high-resolution structure, Small Angle X-ray Scattering data (SAXS) can narrow down the conformational space available to the molecule and be used in conjunction with physical modeling to obtain high-resolution putative structures to be further tested by experiments. Because of the low-resolution of this data, it is natural to implement the integration of SAXS data into simulations using a coarse-grained representation of the molecule, allowing for much wider searches and faster evaluation of SAXS theoretical intensity curves than with atomistic models. We present here the theoretical framework and the implementation of a simulation approach based on our coarse-grained model HiRE-RNA combined with SAXS evaluations “on-the-fly” leading the simulation toward conformations agreeing with the scattering data, starting from partially folded structures as the ones that can easily be obtained from secondary structures predictions based tools. We show on three benchmark systems how our approach can successfully achieve high-resolution structures with remarkable similarity with the native structure recovering not only the overall shape, as imposed by SAXS data, but also the details of initially missing base pairs.
Fast ontogenetic growth drives steep evolutionary scaling of metabolic rate
Authors: Norin Tommy 
Published: March 2021

AbstractMetabolic rate (MR) changes with body mass (BM) as MR = aBMb, where a is a normalisation constant (log–log intercept) and b the scaling exponent (log–log slope). This scaling relationship is fundamental to biology and widely applied, yet a century of research has provided little consensus on why and how steeply metabolic rate scales with body mass. I here show that ontogenetic (within-individual) b can be strongly and positively related to growth rates of juvenile fish when food availability is naturally restricted, with fast growing individuals having steep and near-isometric metabolic scaling (b ≈ 1). I suggest that the steep evolutionary (among-species) scaling also found for fishes (b also approaching 1) is a by-product of natural selection for these fast growing individuals early in ontogeny, and that a weaker relationship between metabolic scaling and growth later in life causes variation in b at lower taxonomic levels (within orders or species). I support these ideas by showing that b within fish orders is linked to natural mortality rates of fish larvae.
PD-1 expression on NK cells can be related to cytokine stimulation and tissue residency
Authors: Wagner Arnika K , Kadri Nadir , Tibbitt Chris , van de Ven Koen , Bagawath-Singh Sunitha , Oliinyk Denys , LeGresly Eric , Campbell Nicole , Trittel Stephanie , Riese Peggy , Sandalova Tatyana , Achour Adnane , Kärre Klas , Chambers Benedict J 
Published: March 2021

ABSTRACTAlthough PD-1 was shown to be a hallmark of T cells exhaustion, controversial studies have been reported on the role of PD-1 on NK cells. Here, we found by flow cytometry and single cell RNA sequencing analysis that PD-1 can be expressed on MHC class I-deficient tumor-infiltrating NK cellsin vivo. We also demonstrate distinct alterations in the phenotype ofPD-1-deficient NK cells which in part could be attributed to a decrease in tumor-infiltrating NK cells inPD-1-deficient mice. NK cells fromPD-1-deficient mice exhibited a more mature phenotype which might reduce their capacity to migrate and killin vivo. Finally, our results demonstrate that PD-L1 molecules in membranes ofPD-1-deficient NK cells migrate faster than in NK cells from wildtype mice, suggesting that PD-1 and PD-L1 formcisinteractions with each other on NK cells.
Sexual maturation in Atlantic salmon male parr may be triggered both in early spring and late summer under standard farming conditions
Authors: Ciani Elia , von Krogh Kristine , Nourizadeh-Lillabadi Rasoul , Mayer Ian , Fontaine Romain , Weltzien Finn-Arne 
Published: March 2021

AbstractMale Atlantic salmon (Salmo salar) display different sexual strategies, maturing either as parr during the freshwater phase (as sneaky spawners), or as post smolts following one or several years at sea. First sexual maturation (puberty) occurs at different times depending on environmental and genetic factors. To improve our knowledge on the timing (age and season) of first sexual maturation in Atlantic salmon male parr, we investigated pubertal activation in second generation farmed salmon from the Norwegian river Figgjo, reared under natural conditions of photoperiod and water temperature. Histological analysis, in combination with morphometric measurements, plasma androgen levels and pituitary gonadotropin gene expression analysis revealed that, as previously reported, some male parr initiated early sexual maturation in spring at one year of age. Interestingly, some male parr were observed to initiate sexual maturation already in autumn, six months after hatching (under-yearlings), much earlier than reported in previous studies. One-year old maturing males showed a low induction in gonadotropin levels, while under-yearling maturing males displayed a significant increase infshbtranscripts as compared to immature fish. Plasma testosterone, detectable also in immature males, increased constantly during testes development, while 11-ketotestosterone, undetectable in immature and early maturing males, increased during more advanced stages of maturation. A mild feminization of the testes (ovotestes) was detected in a subset of samples. This study brings new knowledge on the little investigated field of sexually maturing under-yearlings in Atlantic salmon. This is also the first study comparing the physiology of under-yearling vs one-year old maturing male parr, thus bringing new insights to the remarkable plasticity of Atlantic salmon puberty.