bluuebunny/crossref_metadata_2025 huggingface dataset:
Persistent Inward Currents Increase With The Level Of Voluntary Drive In Plantar Flexor Low-Threshold Motor Units
Authors: Orssatto Lucas B. R. , Mackay Karen , Shield Anthony J. , Sakugawa Raphael L. , Blazevich Anthony J. , Trajano Gabriel S.
Published: December 2020

This study tested the hypothesis that estimates of persistent inward currents (PICs) in the human plantar flexors would increase with the level of voluntary drive. Twenty-one participants volunteered for this study (29.2±2.6 years). High-density surface electromyograms were collected fromsoleusandgastrocnemius medialisduring ramp-shaped isometric contractions to 10%, 20%, and 30% (torque rise of 2%/s and 30-s duration) of each participant’s maximal torque. Motor units identified in all the contraction intensities were included in the paired-motor unit analysis to calculate delta frequency (ΔF) and estimate the PICs. Increases in PICs were observed from 10% to 20% (Δ=0.6 pps; p<0.001) and 20% to 30% (Δ=0.5 pps; p<0.001) insoleus, and from 10% to 20% (Δ=1.2 pps; p<0.001) but not 20% to 30% (Δ=0.09 pps; p=0.724) ingastrocnemius medialis. Maximal discharge rate increased forsoleusandgastrocnemius medialisfrom 10% to 20% (respectively, Δ=1.75 pps, p<0.001; and Δ=2.43 pps, p<0.001) and 20% to 30% (respectively, Δ=0.80 pps, p<0.017; and Δ=0.92 pps, p=002). The repeated-measures correlation identified associations between ΔF and increases in maximal discharge rate for bothsoleus(r=0.64; p<0.001) andgastrocnemius medialis(r=0.77; p<0.001). An increase in voluntary drive tends to increase PIC strength, which has key implications for the control of force but also for comparisons between muscles or between studies when relative force levels might be different. These data indicate that increases in voluntary descending drive amplify PICs in humans and provide an important spinal mechanism for motor unit firing, and thus force output modulation.
Cross-species Transcriptomic Network Analysis Reveals Links Between Ribosomal Protein Mutation and Cancer
Authors: Denton Jai A , Velasque Mariana , Reed Floyd A
Published: December 2020

Ribosomal proteins (RPs) are critical to all cellular operations through their key roles in ribosome biogenesis and translation, as well as their extra-ribosomal functions. Leveraging previously identified RP mutants we characterised the RP macro transcriptome and sought to compare it with transcriptomes of pathologies associated with failures of ribosomal function, cancer and Zika virus (ZIKV). Single gene-based analysis revealed highly variable transcriptomes of RP mutations with little overlap in genes that were differentially expressed. In contrast, weighted gene co-expression network analysis revealed a highly conserved transcriptomic network pattern across all RP mutants studied. In addition, when we compared network changes in RP mutants, we observed similarities to transcriptome alterations in human cancer, and thus confirming the oncogenic role of RPs. Finally, it is known that ZIKV infection influences translational machinery, but this study shows infection network changes dissimilar to those of either the RP mutation or cancer.
Autonomous termination of proliferation in the Drosophila wing disc is TORC1 dependent
Authors: Strassburger Katrin , Lutz Marilena , Müller Sandra , Teleman Aurelio A.
Published: December 2020

Cells in a developing organ stop proliferating when the organ reaches a correct, final size. The underlying mechanisms are not understood. Although many signaling pathways and cell cycle components are required to sustain cell proliferation, which one of these turns off to terminate proliferation is not known. Here we study proliferation termination using Drosophila wing discs. We extend larval development to provide wing discs a constant growth-sustaining environment, allowing them to terminate proliferation autonomously. We find that the wing pouch, which forms the adult wing blade, terminates proliferation in the absence of brinker or warts, indicating that neither Dpp signaling nor Hippo/Yorkie signaling control final wing size. Instead, termination of proliferation coincides with reduced TORC1 activity and is bypassed by reactivating TORC1. Hence proliferation ceases due to reduced cell growth. Experimental manipulation of Dpp or Yki signaling can bypass proliferation termination in hinge and notum regions, suggesting that the mechanisms regulating proliferation termination may be distinct in different regions of the disc.

One Sentence Summary

Using Drosophila, Strassburger et al. investigate the termination of proliferation of an organ when it reaches its final size, and show this occurs due to a drop in TORC1 signaling.
Canonical TGFβ signaling induces collective invasion in colorectal carcinogenesis through a Snail1- and Zeb1-independent partial EMT
Authors: Flum Marion , Dicks Severin , Schrempp Monika , Nyström Alexander , Boerries Melanie , Hecht Andreas
Published: December 2020

Local invasion is the initial step towards metastasis, the main cause of cancer mortality. In human colorectal cancer (CRC), malignant cells predominantly invade as cohesive collectives, and may undergo partial epithelial-mesenchymal transition (pEMT) at the invasive front. How this particular mode of stromal infiltration is generated is unknown. Here we investigated the impact of oncogenic transformation and the microenvironment on tumor cell invasion using genetically engineered organoids as CRC models. We found that inactivation of the Apc tumor suppressor combined with expression of oncogenic KrasG12D and dominant negative Trp53R172H did not cell-autonomously induce invasion in vitro. However, oncogenic transformation primed organoids for activation of a collective invasion program upon exposure to the prototypical microenvironmental factor TGFβ1. Execution of this program co-depended on a permissive extracellular matrix which was further actively remodeled by invading organoids. Although organoids shed some epithelial properties particularly at the invasive edge, TGFβ1-stimulated organoids largely maintained epithelial gene expression while additionally implementing a mesenchymal transcription pattern, resulting in a pEMT phenotype that did not progress to a fully mesenchymal state. Induction of this stable pEMT required canonical, Smad4-mediated TGFβ signaling, whereas the EMT master regulators Snail1 and Zeb1 were dispensable. Gene expression profiling provided further evidence for pEMT of TGFβ1-treated organoids and showed that their transcriptomes resemble those of human poor prognosis CMS4 cancers which likewise exhibit pEMT features. We propose that collective invasion in colorectal carcinogenesis is triggered by microenvironmental stimuli through activation of a novel, transcription-mediated form of non-progressive pEMT independently of classical EMT regulators.
CellMixS: quantifying and visualizing batch effects in single cell RNA-seq data
Authors: Lütge Almut , Zyprych-Walczak Joanna , Kunzmann Urszula Brykczynska , Crowell HelenaL , Calini Daniela , Malhotra Dheeraj , Soneson Charlotte , Robinson Mark D
Published: December 2020

A key challenge in single cell RNA-sequencing (scRNA-seq) data analysis are dataset- and batch-specific differences that can obscure the biological signal of interest. While there are various tools and methods to perform data integration and correct for batch effects, their performance can vary between datasets and according to the nature of the bias. Therefore, it is important to understand how batch effects manifest in order to adjust for them in a reliable way. Here, we systematically explore batch effects in a variety of scRNA-seq datasets according to magnitude, cell type specificity and complexity.

We developed a cell-specific mixing score (cms) that quantifies how well cells from multiple batches are mixed. By considering distance distributions (in a lower dimensional space), the score is able to detect local batch bias and differentiate between unbalanced batches (i.e., when one cell type is more abundant in a batch) and systematic differences between cells of the same cell type. We implemented cms and related metrics to detect batch effects or measure structure preservation in the CellMixS R/Bioconductor package.

We systematically compare different metrics that have been proposed to quantify batch effects or bias in scRNA-seq data using real datasets with known batch effects and synthetic data that mimic various real data scenarios. While these metrics target the same question and are used interchangeably, we find differences in inter- and intra-dataset scalability, sensitivity and in a metric’s ability to handle batch effects with differentially abundant cell types. We find that cell-specific metrics outperform cell type-specific and global metrics and recommend them for both method benchmarks and batch exploration.
Motor Imagery EEG neurofeedback skill acquisition in the context of declarative interference and sleep
Authors: Daeglau Mareike , Zich Catharina , Welzel Julius , Saak Samira Kristina , Scheffels Jannik Florian , Kranczioch Cornelia
Published: December 2020

Motor imagery (MI) practice in combination with neurofeedback (NF) is a promising supplement to facilitate the acquisition of motor abilities and the recovery of impaired motor abilities following brain injuries. However, the ability to control MI NF is subject to a wide range of inter-individual variability. A substantial number of users experience difficulties in achieving good results, which compromises their chances to benefit from MI NF in a learning or rehabilitation context. It has been suggested that context factors, that is, factors outside the actual motor task, can explain individual differences in motor skill acquisition. Retrospective declarative interference and sleep have already been identified as critical factors for motor execution (ME) and MI based practice. Here, we investigate whether these findings generalize to MI NF practice.

Three groups underwent three blocks of MI NF practice each on two subsequent days. In two of the groups, MI NF blocks were followed by either immediate or delayed declarative memory tasks. The control group performed only MI NF and no specific interference tasks. Two of the MI NF blocks were run on the first day of the experiment, the third in the morning of the second day. Significant within-block NF gains in mu and beta frequency event-related desynchronization (ERD) where evident for all groups. However, effects of sleep on MI NF ERD were not found. Data did also not indicate an impact of immediate or delayed declarative interference on MI NF ERD.

Our results indicate that effects of sleep and declarative interference context on ME or MI practice cannot unconditionally be generalized to MI NF skill acquisition. The findings are discussed in the context of variable experimental task designs, inter-individual differences, and performance measures.
Systematic characterization of gene function in a photosynthetic organism
Authors: Vilarrasa-Blasi Josep , Fauser Friedrich , Onishi Masayuki , Ramundo Silvia , Patena Weronika , Millican Matthew , Osaki Jacqueline , Philp Charlotte , Nemeth Matthew , Salomé Patrice A. , Li Xiaobo , Wakao Setsuko , Kim Rick G. , Kaye Yuval , Grossman Arthur R. , Niyogi Krishna K. , Merchant Sabeeha , Cutler Sean , Walter Peter , Dinneny José R. , Jonikas Martin C. , Jinkerson Robert E.
Published: December 2020

Photosynthetic organisms are essential for human life, yet most of their genes remain functionally uncharacterized. Single-celled photosynthetic model systems have the potential to accelerate our ability to connect genes to functions. Here, using a barcoded mutant library of the model eukaryotic algaChlamydomonas reinhardtii, we determined the phenotypes of more than 58,000 mutants under more than 121 different environmental growth conditions and chemical treatments. 78% of genes are represented by at least one mutant that showed a phenotype, providing clues to the functions of thousands of genes. Mutant phenotypic profiles allow us to place known and previously uncharacterized genes into functional pathways such as DNA repair, photosynthesis, the CO2-concentrating mechanism, and ciliogenesis. We illustrate the value of this resource by validating novel phenotypes and gene functions, including the discovery of three novel components of a defense pathway that counteracts actin cytoskeleton inhibitors released by other organisms. The data also inform phenotype discovery in land plants: mutants inArabidopsis thalianagenes exhibit similar phenotypes to those we observed in their Chlamydomonas homologs. We anticipate that this resource will guide the functional characterization of genes across the tree of life.
Quantum Approximated Graph Cutting: A Rapid Replacement for T-REMD?
Authors: Sandeep Samarth , Aramyan Sona , Poghosyan Armen H. , Gupta Vaibhav
Published: December 2020

Determining an optimal protein configuration for the employment of protein binding analysis as completed by Temperature based Replica Exchange Molecular Dynamics (T-REMD) is an important process in the accurate depiction of a protein’s behavior in different solvent environments, especially when determining a protein’s top binding sites for use in protein-ligand and protein-protein docking studies. However, the completion of this analysis, which pushes out top binding sites through configurational changes, is an polynomial-state computational problem that can take multiple hours to compute, even on the fastest supercomputers. In this study, we aim to determine if graph cutting provide approximated solutions the MaxCut problem can be used as a method to provide similar results to T-REMD in the determination of top binding sites of Surfactant Protein A (SP-A) for binding analysis. Additionally, we utilize a quantum-hybrid algorithm within Iff Technology’s Polar+ package using an actual quantum processor unit (QPU), an implementation of Polar+ using an emulated QPU, or Quantum Abstract Machine (QAM), on a large scale classical computing device, and an implementation of a classical MaxCut algorithm on a supercomputer in order to determine the types of advantages that can be gained through using a quantum computing device for this problem, or even using quantum algorithms on a classical device. This study found that Polar+ provides a dramatic speedup over a classical implementation of a MaxCut approximation algorithm or the use of GROMACS T-REMD, and produces viable results, in both its QPU and QAM implementations. However, the lack of direct configurational changes carried out onto the structure of SP-A after the use of graph cutting methods produces different final binding results than those produced by GROMACS T-REMD. Thus, further work needs to be completed into translating quantum-based probabilities into configurational changes based on a variety of noise conditions to better determine the accuracy advantage that quantum algorithms and quantum devices can provide in the near future.
Single cell transcriptomic analysis of bloodstream formTrypanosoma bruceireconstructs cell cycle progression and differentiation via quorum sensing
Authors: Briggs Emma M. , McCulloch Richard , Matthews Keith R. , Otto Thomas D.
Published: December 2020

The life cycles of African trypanosomes are dependent on several differentiation steps, where parasites transition between replicative and non-replicative forms specialised for infectivity and survival in mammal and tsetse fly hosts. Here, we use single cell transcriptomics (scRNA-seq) to dissect the asynchronous differentiation of replicative slender to transmissible stumpy bloodstream formTrypanosoma brucei. Using oligopeptide-induced differentiation, we accurately modelled stumpy developmentin vitroand captured the transcriptomes of 9,344 slender and stumpy stage parasites, as well as parasites transitioning between these extremes. Using this framework, we detail the relative order of biological events during development, profile dynamic gene expression patterns and identify putative novel regulators. Using marker genes to deduce the cell cycle phase of each parasite, we additionally map the cell cycle of proliferating parasites and position stumpy cell cycle exit at early G1, with subsequent progression to a distinct G0 state. We also explored the role of one gene, ZC3H20, with transient elevated expression at the key slender to stumpy transition point. By scRNA-seq analysis of ZC3H20 null parasites exposed to oligopeptides and mapping the resulting transcriptome to our atlas of differentiation, we identified the point of action for this key regulator. Using a developmental transition relevant for both virulence in the mammalian host and disease transmission, our data provide a paradigm for the temporal mapping of differentiation events and regulators in the trypanosome life cycle.
BNT162b vaccines are immunogenic and protect non-human primates against SARS-CoV-2
Authors: Vogel Annette B. , Kanevsky Isis , Che Ye , Swanson Kena A. , Muik Alexander , Vormehr Mathias , Kranz Lena M. , Walzer Kerstin C. , Hein Stephanie , Güler Alptekin , Loschko Jakob , Maddur Mohan S. , Ota-Setlik Ayuko , Tompkins Kristin , Cole Journey , Lui Bonny G. , Ziegenhals Thomas , Plaschke Arianne , Eisel David , Dany Sarah C. , Fesser Stephanie , Erbar Stephanie , Bates Ferdia , Schneider Diana , Jesionek Bernadette , Sänger Bianca , Wallisch Ann-Kathrin , Feuchter Yvonne , Junginger Hanna , Krumm Stefanie A. , Heinen André P. , Adams-Quack Petra , Schlereth Julia , Schille Stefan , Kröner Christoph , de la Caridad Güimil Garcia Ramón , Hiller Thomas , Fischer Leyla , Sellers Rani S. , Choudhary Shambhunath , Gonzalez Olga , Vascotto Fulvia , Gutman Matthew R. , Fontenot Jane A. , Hall-Ursone Shannan , Brasky Kathleen , Griffor Matthew C. , Han Seungil , Su Andreas A.H. , Lees Joshua A. , Nedoma Nicole L. , Mashalidis Ellene H. , Sahasrabudhe Parag V. , Tan Charles Y. , Pavliakova Danka , Singh Guy , Fontes-Garfias Camila , Pride Michael , Scully Ingrid L. , Ciolino Tara , Obregon Jennifer , Gazi Michal , Carrion Ricardo , Alfson Kendra J. , Kalina Warren V. , Kaushal Deepak , Shi Pei-Yong , Klamp Thorsten , Rosenbaum Corinna , Kuhn Andreas N. , Türeci Özlem , Dormitzer Philip R. , Jansen Kathrin U. , Sahin Ugur
Published: December 2020

A safe and effective vaccine against COVID-19 is urgently needed in quantities sufficient to immunise large populations. We report the preclinical development of two BNT162b vaccine candidates, which contain lipid-nanoparticle (LNP) formulated nucleoside-modified mRNA encoding SARS-CoV-2 spike glycoprotein-derived immunogens. BNT162b1 encodes a soluble, secreted, trimerised receptor-binding domain (RBD-foldon). BNT162b2 encodes the full-length transmembrane spike glycoprotein, locked in its prefusion conformation (P2 S). The flexibly tethered RBDs of the RBD-foldon bind ACE2 with high avidity. Approximately 20% of the P 2S trimers are in the two-RBD ‘down,’ one-RBD ‘up’ state. In mice, one intramuscular dose of either candidate elicits a dose-dependent antibody response with high virus-entry inhibition titres and strong TH1 CD4+and IFNγ+CD8+T-cell responses. Prime/boost vaccination of rhesus macaques with BNT162b candidates elicits SARS-CoV-2 neutralising geometric mean titres 8.2 to 18.2 times that of a SARS-CoV-2 convalescent human serum panel. The vaccine candidates protect macaques from SARS-CoV-2 challenge, with BNT162b2 protecting the lower respiratory tract from the presence of viral RNA and with no evidence of disease enhancement. Both candidates are being evaluated in phase 1 trials in Germany and the United States. BNT162b2 is being evaluated in an ongoing global, pivotal Phase 2/3 trial (NCT04380701,NCT04368728).
Diagnosis of central serous chorioretinopathy by deep learning analysis ofen faceimages of choroidal vasculature
Authors: Aoyama Yukihiro , Maruko Ichiro , Kawano Taizo , Yokoyama Tatsuro , Ogawa Yuki , Maruko Ruka , Iida Tomohiro
Published: December 2020

Purpose

To classify central serous chorioretinopathy (CSC) by deep learning (DL) analyses ofen faceimages of choroidal vasculature obtained by optical coherence tomography (OCT) and to analyze the regions of interest for DL from heatmaps.

Methods

One-hundred eyes were studied; 53 eyes with CSC and 47 normal eyes. Volume scans of 12×12 mm square were obtained at the same time as the OCT angiographic (OCTA) scans (Plex Elite 9000 Swept-Source OCT®, Zeiss). High-qualityen faceimages of the choroidal vasculature of the segmentation slab of one-half of the subfoveal choroidal thickness were created for the analyses. The entire 100en faceimages were divided into 80 for training (100 times) and 20 for validation. The Neural Network Console (NNC) developed by Sony and the Keras-Tensorflow backend developed by Google were used as the software for the classification with 16 layers of convolutional neural networks. The active region of the heatmap based on the feature quantity extracted by DL was also evaluated as the percentages with gradient-weighted class activation mapping implementation in Keras.

Results

In the 20 eyes used for validation including 8 eyes with CSC, the accuracy rate of the validation was 100% (20/20) for NNC and 95% (19/20) for Keras. This difference was not significant (P=0.33). The mean active region in the heatmap image was 12.5% in CSC eyes which was significantly lower than the 79.8% in normal eyes (P<0.01).

Conclusions

CSC can be automatically classified with high accuracy fromen faceimages of the choroidal vasculature by DLs with different programs, convolutional layer structures, and small data sets. Heatmap analyses showed that DL focused on the area occupied by the choroidal vessels and their uniformity. We conclude that DL can help in the diagnosis of CSC.
High expression of JAM2 indicates better prognosis and immunotherapy response in breast cancer
Authors: Peng Yang , Qu Chi , Zhang Yingzi , Zong Beige , Jian Bin , Fu Yong , Xie Jian , Liu Shengchun
Published: December 2020

In our study, multiple databases were used to explore the potential role and underlying mechanism of junctional adhesion molecule B (JAM2) in breast cancer (BRCA). The data of JAM2 was downloaded from The Cancer Cell Line Encyclopedia (CCLE), the Genotype-Tissue Expression (GTEx), The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) databases. Receiver operating characteristic (ROC) curve analysis was performed to analyze the area under the curve (AUC) of JAM2 expression correlated with normal breast tissue and breast cancer tissue. Gene set enrichment analysis (GSEA) was used to identify the potential biological mechanisms of the JAM2. The expression of JAM2 mRNA were downregulated In most tumors, including BRCA, which may be due to the hypermethylated status. The AUCs, which were 0.929 and 0.887 by the logistic regression and random forest algorithms, indicated that JAM2 mRNA expression have good diagnostic value in BRCA. Univariate and multivariate analyses indicated JAM2 as an independent prognostic factor for the overall survival of BRCA patients in both the TCGA cohort (HR = 0.62, P = 0.034) and METABRIC cohort (HR = 0.77, P = 0.001). GSEA showed that multiple tumor pathways were suppressed in the JAM2 high expression group. The expression of JAM2 was most positively related to the epithelial-mesenchymal transition (EMT) score (r = 0.38; P <0.01) by the reverse-phase protein array (RPPA) analysis. Patients with high JAM2 expression may be more sensitive to immunotherapy. 18 chemotherapy drugs that patients in the JAM2 low expression group were more sensitive to were identified. Our results demonstrated the diagnostic and prognostic value of JAM2. Analysis of the molecular mechanisms indicates the potential role of JAM2 as a tumor suppressor, and high JAM2 expression may predict a better immunotherapy response in BRCA.
Temporal scaling of human scalp-recorded potentials
Authors: Hassall Cameron D. , Harley Jack , Kolling Nils , Hunt Laurence T.
Published: December 2020

Much of human behaviour is governed by common processes that unfold over varying timescales. Standard event-related potential analysis assumesfixed-durationresponses relative to experimental events. However, recent single unit recordings in animals have revealed neural activityscalesto span different durations during behaviours demanding flexible timing. Here, we employed a general linear modelling approach using a novel combination of fixed-duration and variable-duration regressors to unmix fixed-time and scaled-time components in human magneto/electroencephalography (M/EEG) data. We use this to reveal consistent temporal scaling of human scalp-recorded potentials across four independent EEG datasets, including interval perception, production, prediction and value-based decision making. Between-trial variation in the temporally scaled response predicts between-trial variation in subject reaction times, demonstrating the relevance of this temporally scaled signal for temporal variation in behaviour. Our results provide a general approach for studying flexibly timed behaviour in the human brain.

Significance Statement

Neural activity is traditionally thought to occur over fixed time scales. However, recent animal work has suggested that some neural responses occur over varying timescales. We extended this animal result to humans by detecting temporally scaled signals non-invasively at the scalp in four different tasks. Our results suggest that temporal scaling is an important feature of cognitive processes known to unfold over varying timescales.
Pointing in depth is shaped by a natural grasping distance prior
Authors: Wiesing Michael , Kartashova Tatiana , Zimmermann Eckart
Published: December 2020

Vision in depth is distorted. A similar distortion can be observed for pointing to visual targets in depth. It has been suggested that pointing errors in depth reflect the visual distortion. However, much research has suggested that in case visual information is not rich enough, the sensorimotor system involves prior knowledge to optimally plan movement trajectories. Here, we show that pointing in depth is guided by a prior that biases movements toward the natural grasping distance at which object manipulation is usually performed. To dissociate whether pointing is guided by distorted vision only or whether it takes into account a natural grasping distance prior, we adapted pointing movements. Participants received visual feedback about the success of their pointing once the movement was finished. We distorted the feedback to signal either that pointing was not far enough or in separate sessions that pointing was too far. Participants adapted to this artificial error by either extending or shortening their pointing movements. The generalization of pointing adaptation revealed a bias in movement planning that is inconsistent with pointing being guided only by distorted vision but with the involvement of knowledge about the natural grasping distance. Adaptation was strongest for pointing movements to a middle position that corresponds to the natural grassing distance and it was weakest for movements leading away from it. It has been demonstrated that pointing adaptation in depth changes visual perception (Volcic et al., 2013). We also wondered how effects of pointing adaptation on visual space would generalize in depth.
Myogenin controls via AKAP6 non-centrosomal microtubule organizing center formation at the nuclear envelope
Authors: Becker Robert , Vergarajauregui Silvia , Billing Florian , Sharkova Maria , Lippolis Eleonora , Mamchaoui Kamel , Ferrazzi Fulvia , Engel Felix B.
Published: December 2020

Non-centrosomal microtubule organizing centers (MTOC) are pivotal for the function of multiple cell types, but the processes initiating their formation are unknown. Here, we find that the transcription factor myogenin is required in myoblasts for the localization of MTOC proteins to the nuclear envelope. Moreover, myogenin is sufficient in fibroblasts for nuclear envelope MTOC (NE-MTOC) formation and centrosome attenuation. Bioinformatics combined with loss- and gain-of-function experiments identified induction of AKAP6 expression as one central mechanism for myogenin-mediated NE-MTOC formation. Promoter studies indicate that myogenin preferentially induces the transcription of muscle- and NE-MTOC-specific isoforms ofAkap6andSyne1, which encodes nesprin-1α, the NE-MTOC anchor protein in muscle cells. Overexpression of AKAP6β and nesprin-1α was sufficient to recruit endogenous MTOC proteins to the nuclear envelope of myoblasts in the absence of myogenin. Taken together, our results illuminate how mammals transcriptionally control the switch from a centrosomal MTOC to an NE-MTOC and identify AKAP6 as a novel NE-MTOC component in muscle cells.
Heavy metal pollutants have additive negative effects on honey bee cognition
Authors: Monchanin Coline , Drujont Erwann , Devaud Jean-Marc , Lihoreau Mathieu , Barron Andrew B.
Published: December 2020

Environmental pollutants can exert sublethal deleterious effects on animals. These include disruption of cognitive functions underlying crucial behaviours. While agrochemicals have been identified as a major threat to pollinators, other compounds, such as heavy metals that are often found in complex mixtures, have largely been overlooked. Here, we assessed the impact of acute exposure to field-realistic concentrations of lead, copper, arsenic, and their combinations, on honey bee learning and memory. All treatments involving single metals slowed down appetitive learning and disrupted memory retrieval at 24 h. Importantly, combinations of these metals induced additive negative effects on both processes, suggesting common pathways of toxicity. Our results highlight the need to further assess the risks of heavy metal pollution on invertebrates and to their associated ecosystem services.

Summary statement

Honey bees displayed reduced learning and memory performances following acute exposure to arsenic, copper or lead. Exposure to combinations of these metals induced additive effects.
Autosomal recessive loci contribute significantly to quantitative variation of male fertility in a dairy cattle population
Authors: Hiltpold Maya , Kadri Naveen Kumar , Janett Fredi , Witschi Ulrich , Schmitz-Hsu Fritz , Pausch Hubert
Published: December 2020

Cattle are ideally suited to investigate the genetics of male fertility. Semen from individual bulls is used for thousands of artificial inseminations for which the fertilization success is monitored. In a cohort of 3881 bulls that had genotypes at 589,791 SNPs, we reveal four novel recessive QTL for male fertility using haplotype-based association testing. We detect either missense or nonsense variants inSPATA16,VWA3A, ENSBTAG00000006717andENSBTAG00000019919that are in linkage disequilibrium with the QTL. A QTL for bull fertility on BTA1 is also associated with sperm head shape anomalies. Using whole-genome sequence and transcriptome data, we prioritise a missense variant (p.Ile193Met) inSPATA16as candidate causal variant underlying this QTL. Our findings in a dairy cattle population provide evidence that recessive variants may contribute substantially to quantitative variation in male fertility in mammals.
Cytoplasmic physical state governs the influence of oxygen onPinus densifloraseed ageing
Authors: Gerna Davide , Ballesteros Daniel , Stöggl Wolfgang , Arc Erwann , Seal Charlotte E. , Na Chae Sun , Kranner Ilse , Roach Thomas
Published: December 2020

During desiccation, the cytoplasm of orthodox seeds solidifies in a glass with highly restricted diffusion and molecular mobility, which extend longevity. Temperature and moisture determine seed cellular physical state, and oxygen can promote deteriorative reactions of seed ageing. However, whether seed physical state affects O2-mediated biochemical reactions during ageing remains unknown. Here, we answered this question using oil-richPinus densifloraseeds aged by controlled deterioration (CD) at 45 °C and distinct relative humidities (RHs), resulting in a glassy (9 and 33% RH) or fluid (64 and 85% RH) cytoplasm. Regardless of CD regimes, the cellular lipid domain remained always fluid. Hypoxia (0.4% O2) prevented seed deterioration only in the glassy state, limiting non-enzymatic lipid peroxidation, consumption of antioxidants (glutathione, tocopherols) and unsaturated fatty acids, accompanied by decreased lipid melt enthalpy and lower concentrations of aldehydes and reactive electrophile species (RES). In contrast, a fluid cytoplasm promoted faster seed deterioration and enabled the resumption of enzymatic activities implicated in glutathione metabolism and RES detoxification, regardless of O2availability. Furthermore, seeds stored under dry/cold seed bank conditions showed biochemical profiles similar to those of CD-aged seeds with glassy cytoplasm under normoxia. These findings are discussed in the context of germplasm management.

Highlight

lipid peroxidation occurred during seed ageing in the glassy state and, like viability loss, could be prevented by hypoxia. Seeds with fluid cytoplasm aged faster and irrespective of oxygen availability.
Osteoprotegerin expression in liver is induced by IL-13 through TGF-β
Authors: Adhyatmika Adhyatmika , Putri Kurnia S. S. , Gore Emilia , Mangnus Keri A. , Reker-Smit Catharina , Schuppan Detlef , Beljaars Leonie , Olinga Peter , Melgert Barbro N.
Published: December 2020

1.

Backgrounds

Osteoprotegerin (OPG) is a profibrotic mediator produced by myofibroblasts under influence of transforming growth factor β (TGFβ). Its expression in experimental models of liver fibrosis correlates well with disease severity and treatment responses. The regulation of OPG in liver tissue is largely unknown and we therefore set out to elucidate which growth factors/interleukins associated with fibrosis induce OPG and through which pathways.

Methods

Precision-cut liver slices of wild type and STAT6-deficient mice and 3T3 fibroblasts were used to investigate the effects of TGFβ, interleukin (IL) 13 (IL13), IL1β, and platelet-derived growth factor BB (PDGF-BB) on expression of OPG.

Results

In addition to TGFβ, only IL13 and not PDGF-BB or IL1β could induce OPG expression in 3T3 fibroblasts and liver slices. This IL13-dependent induction was not shown in liver slices of STAT6-deficient mice and when wild type slices were cotreated with TGFβ receptor 1 kinase inhibitor galunisertib, STAT6 inhibitor AS1517499, or AP1 inhibitor T5224. This suggests that the OPG-inducing effect of IL13 is mediated through IL13 receptor α1-activation and subsequent STAT6-dependent upregulation of IL13 receptor α2, which in turn activates AP1 and induces production of TGFβ and subsequent production of OPG.

Conclusion

We have shown that IL13 induces OPG release by liver tissue through a TGFβ-dependent pathway involving both the α1 and the α2 receptor of IL13 and transcription factors STAT6 and AP1. OPG may therefore be a novel target for the treatment liver fibrosis as it is mechanistically linked to two important regulators of fibrosis in liver, namely IL13 and TGFβ1.
Overexpression ofEiKCSconfers paraquat-tolerance in rice(Oryza sativaL.) by promoting polyamine pathway
Authors: Luo Qiyu , Chen Shu , Zhu Jiazheng , Ye Laihua , Hall Nathan Daniel , Basak Suma , McElroy J. Scott , chen Yong
Published: December 2020

Paraquat is an important bipyridine herbicide by acting on the photosynthetic system of the plants and generating reactive oxygen species leading to cell death, whereas the mechanism of the paraquat resistance remains to be explored. In this study, a putative paraquat-resistant geneEiKCSfrom goosegrass(Eleusine indicaL.) was isolated and overexpressed in a transgenic rice(Oryza sativaL.). This transgenic rice (KCSox) was treated by exogenous spermidine and paraquat and then was analyzed by qualitative and quantitative proteomics. Overexpressing ofEiKCSenhanced paraquat tolerance in KCSox by the accumulation of endogenous polyamines whose dominant presences of polyamines benzoylation derivatizations in rice were C18H20N2O2, C28H31N3O3, and C38H42N4O4. The mechanism underlying the improving tolerance enhanced antioxidant capacity of ROS systems and light-harvesting in photosynthesis in KCSox rice leaves to reducing paraquat toxicity. The protein β-Ketoacyl-CoA Synthase (EiKCS) encoded by theEiKCSgene promoted the synthesis and metabolism of proteins of the polyamine pathway. Three cofactors CERs were identified and positively correlated with the function of EiKCS on very-long-chain fatty acids (VLCFAs) biosynthesis via promoting the polyamine pathway and inhibiting the links with the TCA pathway and fatty acid pathway to responding to the paraquat tolerance in the KCSox rice, which also caused the prolongation of the overproduction of spermine and a transient increase of intracellular malondialdehyde (MDA). These results expanded the polyamines pathway manipulated in cereals using genetic engineering to clarify the mechanism of paraquat-tolerance.

One Sentence Summary

A putative paraquat-resistantEiKCSgene from the goosegrass overexpressing in the rice resulted in the accumulation of polyamines, especially the spermine, and promoted the proteins in polyamine pathways by its EiKCS protein under paraquat stress.
Basal G-protein-gated inwardly rectifying potassium (Kir3/GirK) channels activity governs synaptic plasticity that supports dorsal hippocampus-dependent cognitive functions
Authors: Temprano-Carazo Sara , Djebari Souhail , Iborra-Lázaro Guillermo , Sánchez-Rodríguez Irene , Nava-Mesa Mauricio O. , Múnera Alejandro , Gruart Agnès , Delgado-García José M. , Jiménez-Díaz Lydia , Navarro-López Juan D.
Published: December 2020

G-protein-gated inwardly rectifying potassium (Kir3/GirK) channel is the effector of many G-protein-coupled receptors. Its dysfunction has been linked to the pathophysiology of Down syndrome, Alzheimer’s and Parkinson’s diseases, psychiatric disorders, epilepsy, drug addiction, or alcoholism. GirK channels are constitutively activated in the dorsal hippocampus contributing to resting membrane potential, and their synaptic activation compensates any excitation excess. Here, in order to elucidate the role of GirK channels activity in the maintenance of dorsal hippocampus-dependent cognitive functions, their involvement in controlling neuronal excitability at different levels of complexity was examined. For that purpose, basal GirK activity was pharmacologically modulated by two specific drugs: ML297, a GirK channel opener, and Tertiapin-Q, a GirK channel blocker.Ex vivo,using dorsal hippocampal slices, we studied pharmacological GirK modulation effect on synaptic plasticity processes induced in CA1 by Schaffer collateral stimulation.In vivo, we performed acute intracerebroventricular injections of both GirK modulators to study their contribution to CA3–CA1 synapse electrophysiological properties, synaptic plasticity, and learning and memory capabilities during hippocampal dependent tasks. We found that pharmacological disruption of basal GirK activity in dorsal hippocampus, causing either function gain or loss, induced learning and memory deficits by a mechanism involving neural excitability impairments and alterations in induction and maintenance of long-term synaptic plasticity processes. These results support the contention that an accurate control of GirK activity must take place in the hippocampus to sustain cognitive functions.

Significance Statement

The dorsal hippocampus mostly performs cognitive functions related to contextual/spatial associations. These functions rely on synaptic plasticity processes that are critically ruled by a finely tuned neural excitability. Being the downstream physiological effectors of a variety of G-coupled receptors, activation of G protein-gated inwardly rectifying K+ (GirK) channels induces neurons to hyperpolarize, contributing to neural excitability throughout the control of excitatory excess. Here, we demonstrate that modulation of basal GirK channels activity, causing either function gain or loss, transforms HFS-induced LTP into LTD, inducing deficits in dorsal hippocampus-dependent learning and memory. Together, our data show a crucial GirK activity-mediated mechanism that governs synaptic plasticity direction and modulates subsequent hippocampal-dependent cognitive functions.
Target2DeNovoDrugPropMax : a novel programmatic tool incorporating deep learning andin silicomethods for automatedde novodrug design for any target of interest
Authors: Madaj Rafal , Geoffrey Ben , Sanker Akhil , Valluri Pavan Preetham
Published: December 2020

The past decade has seen a surge in the range of application data science, machine learning, deep learning, and AI methods to drug discovery. The presented work involves an assemblage of a variety of AI methods for drug discovery along with the incorporation of in silico techniques to provide a holistic tool for automated drug discovery. When drug candidates are required to be identified for a particular drug target of interest, the user is required to provide the tool target signatures in the form of an amino acid sequence or its corresponding nucleotide sequence. The tool collects data registered on PubChem required to perform an automated QSAR and with the validated QSAR model, prediction and drug lead generation are carried out. This protocol we call Target2Drug. This is followed by a protocol we call Target2DeNovoDrug wherein novel molecules with likely activity against the target are generated de novo using a generative LSTM model. It is often required in drug discovery that the generated molecules possess certain properties like drug-likeness, and therefore to optimize the generated de novo molecules toward the required drug-like property we use a deep learning model called DeepFMPO, and this protocol we call Target2DeNovoDrugPropMax. This is followed by the fast automated AutoDock-Vina based in silico modeling and profiling of the interaction of optimized drug leads and the drug target. This is followed by an automated execution of the Molecular Dynamics protocol that is also carried out for the complex identified with the best protein-ligand interaction from the AutoDock-Vina based virtual screening. The results are stored in the working folder of the user. The code is maintained, supported, and provide for use in the following GitHub repository

https://github.com/bengeof/Target2DeNovoDrugPropMax
The acute effects of cannabidiol on emotional processing and anxiety: a neurocognitive imaging study
Authors: Bloomfield Michael AP , Yamamori Yumeya , Hindocha Chandni , Jones Augustus PM , Yim Jocelyn LL , Walker Hannah R , Statton Ben , Wall Matthew B , Lees Rachel H , Howes Oliver D , Curran H Valerie , Roiser Jonathan P , Freeman Tom P
Published: December 2020

Background

There is growing interest in the therapeutic potential of cannabidiol (CBD) across a range of psychiatric disorders. CBD has been found to reduce anxiety during experimentally-induced stress in anxious individuals and healthy controls. However, the mechanisms underlying the putative anxiolytic effects of CBD are unknown. We therefore sought to investigate the behavioural and neural effects of a single dose of CBD vs. placebo on a range of emotion-related measures to test cognitive-mechanistic models of its effects on anxiety.

Methods

We conducted a randomised, double-blind, placebo-controlled, crossover, acute oral challenge of 600 mg of CBD in 24 healthy participants on emotional processing, with neuroimaging (viewing emotional faces during fMRI) and cognitive (emotional appraisal) measures as well as subjective response to experimentally-induced anxiety.

Results

CBD did not produce effects on BOLD responses to emotional faces, cognitive measures of emotional processing, or modulate experimentally-induced anxiety, relative to placebo.

Conclusions

Given the rising popularity of CBD for its putative medical benefits, further research is warranted to investigate the clinical potential of CBD for the treatment of anxiety disorders.
CEM500K – A large-scale heterogeneous unlabeled cellular electron microscopy image dataset for deep learning
Authors: Conrad Ryan , Narayan Kedar
Published: December 2020

Automated segmentation of cellular electron microscopy (EM) datasets remains a challenge. Supervised deep learning (DL) methods that rely on region-of-interest (ROI) annotations yield models that fail to generalize to unrelated datasets. Newer unsupervised DL algorithms require relevant pre-training images, however, pre-training on currently available EM datasets is computationally expensive and shows little value for unseen biological contexts, as these datasets are large and homogeneous. To address this issue, we present CEM500K, a nimble 25 GB dataset of 0.5 x 106unique cellular EM images curated from nearly 600 three-dimensional (3D) and 10,000 two-dimensional (2D) images from >100 unrelated imaging projects. We show that models pre-trained on CEM500K learn features that are biologically relevant and resilient to meaningful image augmentations. Critically, we evaluate transfer learning from these pre-trained models on six publicly available and one newly derived benchmark segmentation task and report state-of-the-art results on each. We release the CEM500K dataset, pre-trained models and curation pipeline for model building and further expansion by the EM community. Data and code are available athttps://www.ebi.ac.uk/pdbe/emdb/empiar/entry/10592/andhttps://git.io/JLLTz.
A Game-Theoretic Model for Co-Adaptive Brain-Machine Interfaces
Authors: Madduri Maneeshika M. , Burden Samuel A. , Orsborn Amy L.
Published: December 2020

Co-adaptation in brain-machine interfaces (BMIs) can improve performance and facilitate user learning. We propose and analyze a mathematical model for co-adaptation in BMIs. We model the brain and the decoder as strategic agents who seek to minimize their individual cost functions, leading to a game-theoretic formulation of interaction. We frame our BMI model as a potential game to identify stationary points (Nash equilibria) of the brain-decoder interactions, which correspond to points at which both the brain and the decoder stop adapting. Assuming the brain and the decoder adapt using gradientbased schemes, we analytically show how convergence to these equilibria depends on agent learning rates. This theoretical framework presents a basis for simulating co-adaption using dynamic game theory and can be extended to tasks with multiple dimensions and to different decoder models. This framework can ultimately be used to inform adaptive decoder design to shape brain learning and optimize BMI performance.
Cytosplore-Transcriptomics: a scalable inter-active framework for single-cell RNA sequencing data analysis
Authors: Abdelaal Tamim , Eggermont Jeroen , Höllt Thomas , Mahfouz Ahmed , Reinders Marcel J.T. , Lelieveldt Boudewijn P.F.
Published: December 2020

The ever-increasing number of analyzed cells in Single-cell RNA sequencing (scRNA-seq) experiments imposes several challenges on the data analysis. Current analysis methods lack scalability to large datasets hampering interactive visual exploration of the data. We present Cytosplore-Transcriptomics, a framework to analyze scRNA-seq data, including data preprocessing, visualization and downstream analysis. At its core, it uses a hierarchical, manifold preserving representation of the data that allows the inspection and annotation of scRNA-seq data at different levels of detail. Consequently, Cytosplore-Transcriptomics provides interactive analysis of the data using low-dimensional visualizations that scales to millions of cells.

Availability

Cytosplore-Transcriptomics can be freely downloaded fromtranscriptomics.cytosplore.org

Contact

b.p.f.lelieveldt@lumc.nl