bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single-cell analyses reveal a continuum of cell state and composition changes in the malignant transformation of polyps to colorectal cancer
Authors: Becker Winston R. , Nevins Stephanie A. , Chen Derek C. , Chiu Roxanne , Horning Aaron , Laquindanum Rozelle , Mills Meredith , Chaib Hassan , Ladabaum Uri , Longacre Teri , Shen Jeanne , Esplin Edward D. , Kundaje Anshul , Ford James M. , Curtis Christina , Snyder Michael P. , Greenleaf William J. 
Published: March 2021

ABSTRACTTo chart cell composition and cell state changes that occur during the transformation of healthy colon to precancerous adenomas to colorectal cancer (CRC), we generated 451,886 single-cell chromatin accessibility profiles and 208,557 single-cell transcriptomes from 48 polyps, 27 normal tissues, and 6 CRCs collected from patients with and without germline APC mutations. A large fraction of polyp and CRC cells exhibit a stem-like phenotype, and we define a continuum of epigenetic and transcriptional changes occurring in these stem-like cells as they progress from normal to CRC. Advanced polyps contain increasing numbers of stem-like cells, regulatory T-cells, and a subtype of FOX-regulated pre-cancer associated fibroblasts. In the cancerous state, we observe T-cell exhaustion, RUNX1-regulated cancer associated fibroblasts, and increasing accessibility associated with HNF4A motifs in epithelia. Methylation changes in sporadic CRC are strongly anti-correlated with accessibility changes along this continuum, further identifying regulatory markers for molecular staging of polyps.
A stochastic oscillator model simulates the entrainment of vertebrate cellular clocks by light
Authors: Kumpošt Vojtěch , Vallone Daniela , Gondi Srinivas Babu , Foulkes Nicholas S. , Mikut Ralf , Hilbert Lennart 
Published: March 2021

AbstractThe circadian clock is a cellular mechanism that synchronizes various biological processes with respect to the time of the day. While much progress has been made characterizing the molecular mechanisms underlying this clock, it is less clear how external light cues influence the dynamics of the core clock mechanism and thereby entrain it with the light-dark cycle. Zebrafish-derived cell cultures possess clocks that are directly light-entrainable, thus providing an attractive laboratory model for circadian entrainment. Here, we have developed a stochastic oscillator model of the zebrafish circadian clock, which accounts for the core clock negative feedback loop, light input, and the proliferation of single-cell oscillator noise into population-level luminescence recordings. The model accurately predicts the entrainment dynamics observed in bioluminescent clock reporter assays upon exposure to a wide range of lighting conditions. Furthermore, we have applied the model to obtain refitted parameter sets for cell cultures exposed to a variety of pharmacological treatments and predict changes in single-cell oscillator parameters. Our work paves the way for model-based, large-scale screens for genetic or pharmacologically-induced modifications to the entrainment of circadian clock function.Author summaryThe circadian clock is a key, cell-autonomous timing mechanism that is encountered in most organisms. It is entrained by environmental lighting conditions and in turn temporally coordinates most aspects of physiology according to the time of day. Cell lines derived from zebrafish are attractive experimental models for studying how clocks are entrained by light since they possess clocks that respond directly to light stimuli. Here we describe a mathematical model for the behavior of the circadian clock in zebrafish cell lines during exposure to a range of lighting conditions. Using this model, we can determine how different pharmacological treatments may affect the entrainment dynamics of the clock and the degree of synchronization of individual cells’ circadian clocks in bioluminescent clock reporter assays. Our current model is mathematically simple and thus easy to apply and extend in future studies.
A computational probe into the behavioral and neural markers of atypical facial emotion processing in autism
Authors: Kar Kohitij 
Published: March 2021

AbstractDespite ample behavioral evidence of atypical facial emotion processing in individuals with autism (IwA), the neural underpinnings of such behavioral heterogeneities remain unclear. Here, I have used brain-tissue mapped artificial neural network (ANN) models of primate vision to probe candidate neural and behavior markers of atypical facial emotion recognition in IwA at an image-by-image level. Interestingly, the ANNs’ image-level behavioral patterns better matched the neurotypical subjects’ behavior than those measured in IwA. This behavioral mismatch was most remarkable when the ANN behavior was decoded from units that correspond to the primate inferior temporal (IT) cortex. ANN-IT responses also explained a significant fraction of the image-level behavioral predictivity associated with neural activity in the human amygdala — strongly suggesting that the previously reported facial emotion intensity encodes in the human amygdala could be primarily driven by projections from the IT cortex. Furthermore, in silico experiments revealed how learning under noisy sensory representations could lead to atypical facial emotion processing that better matches the image-level behavior observed in IwA. In sum, these results identify primate IT activity as a candidate neural marker and demonstrate how ANN models of vision can be used to generate neural circuit-level hypotheses and guide future human and non-human primate studies in autism.
Fuzzy-Discernibility Matrix-based Efficient Feature Selection Techniques for Improved Motor-Imagery EEG Signal Classification
Authors: Chatterjee Rajdeep , Sanyal Debarshi Kumar , Chatterjee Ankita 
Published: March 2021

AbstractBrain activities, calledbrain rhythms, are the micro-level electrical signals (that is, Electroencephalogram or EEG) generated in our brain while we are performing a task. Even when we imagine a limb movement, it generates the same EEG signals called motor-imagery. Motor-imagery based Brain-computer Interface (BCI) provides a non-muscular means to connect the human brain with limbs through computer-based interpretations. The main aim of this paper is to find a suitable feature-set and a classifier to efficiently classify EEG signals into distinct motor-imagery brain-states. We propose to use sliding temporal window-based approaches for feature extraction from EEG and a mix-bagging classifier which is essentially a bagging-based ensemble of multiple types of learners for motor imagery EEG classification. We observe that mix-bagging with overlapping sliding window-based feature extraction achieves an accuracy of 91.43% on the BCI Competition II Dataset III. To reduce the feature size further, we use a fuzzy discernibility matrix that selects the most discriminative features instead of all the features. This additional feature selection strategy improves the classification accuracy to 92.14% and sets a new state-of-the art result on this dataset.
An open-source and wearable system for measuring 3D human motion in real-time
Authors: Slade Patrick , Habib Ayman , Hicks Jennifer L. , Delp Scott L. 
Published: March 2021

AbstractAnalyzing human motion is essential for diagnosing movement disorders and guiding rehabilitation interventions for conditions such as osteoarthritis, stroke, and Parkinson’s disease. Optical motion capture systems are the current standard for estimating kinematics but require expensive equipment located in a predefined space. While wearable sensor systems can estimate kinematics in any environment, existing systems are generally less accurate than optical motion capture. Further, many wearable sensor systems require a computer in close proximity and rely on proprietary software, making it difficult for researchers to reproduce experimental findings. Here, we present OpenSenseRT, an open-source and wearable system that estimates upper and lower extremity kinematics in real time by using inertial measurement units and a portable microcontroller. We compared the OpenSenseRT system to optical motion capture and found an average RMSE of 4.4 degrees across 5 lower-limb joint angles during three minutes of walking (n= 5) and an average RMSE of 5.6 degrees across 8 upper extremity joint angles during a Fugl-Meyer task (n= 5). The open-source software and hardware are scalable, tracking between 1 and 14 body segments, with one sensor per segment. Kinematics are estimated in real-time using a musculoskeletal model and inverse kinematics solver. The computation frequency, depends on the number of tracked segments, but is sufficient for real-time measurement for many tasks of interest; for example, the system can track up to 7 segments at 30 Hz in real-time. The system uses off-the-shelf parts costing approximately $100 USD plus $20 for each tracked segment. The OpenSenseRT system is accurate, low-cost, and simple to replicate, enabling movement analysis in labs, clinics, homes, and free-living settings.
Transthyretin promotes axon growth via regulation of microtubule dynamics and tubulin acetylation
Authors: Eira Jessica , Magalhães Joana , Macedo Nídia , Pero Maria Elena , Misgeld Thomas , Sousa Mónica M , Bartolini Francesca , Liz Márcia A 
Published: March 2021

AbstractTransthyretin (TTR), a plasma and cerebrospinal fluid protein, increases axon growth and organelle transport in sensory neurons. These TTR functions were suggested to underlie its activity in promoting nerve regeneration. While neurons extend their axons, the microtubule (MT) cytoskeleton is crucial for the segregation of functional compartments and axonal outgrowth. Herein, we investigated the hypothesis that TTR promotes axon elongation and regeneration by modulating MT dynamics. Indeed, we found that TTR KO mice have an intrinsic increase in dynamic MTs and reduced levels of acetylated α-tubulin in uninjured peripheral axons, and fail to modulate microtubule dynamics in response to sciatic nerve injury. Importantly, restoring acetylated α-tubulin levels of TTR KO DRG neurons using an HDAC6 inhibitor was sufficient to completely revert defective MT dynamics and neurite outgrowth. In summary, our results revealed a new role for TTR in the modulation of MT dynamics by regulating α-tubulin acetylation and support that this activity underlies TTR neuritogenic function.
Analysing and simulating energy-based models in biology using BondGraphTools
Authors: Cudmore Peter , Pan Michael , Gawthrop Peter J. , Crampin Edmund J. 
Published: March 2021

AbstractLike all physical systems, biological systems are constrained by the laws of physics. However, mathematical models of biochemistry frequently neglect the conservation of energy, leading to unrealistic behaviour. Energy-based models that are consistent with conservation of mass, charge and energy have the potential to aid the understanding of complex interactions between biological components, and are becoming easier to develop with recent advances in experimental measurements and databases. In this paper, we motivate the use of bond graphs (a modelling tool from engineering) for energy-based modelling and introduce,BondGraphTools, a Python library for constructing and analysing bond graph models. We use examples from biochemistry to illustrate howBondGraphToolscan be used to automate model construction in systems biology while maintaining consistency with the laws of physics.
Modular Dynamic Biomolecular Modelling with Bond Graphs: The Unification of Stoichiometry, Thermodynamics, Kinetics and Data
Authors: Gawthrop Peter J. , Pan Michael , Crampin Edmund J. 
Published: March 2021

AbstractRenewed interest in dynamic simulation models of biomolecular systems has arisen from advances in genome-wide measurement and applications of such models in biotechnology and synthetic biology. In particular, genome-scale models of cellular metabolism beyond the steady state are required in order to represent transient and dynamic regulatory properties of the system. Development of such whole-cell models requires new modelling approaches. Here we propose the energy-based bond graph methodology, which integrates stoichiometric models with thermo-dynamic principles and kinetic modelling. We demonstrate how the bond graph approach intrinsically enforces thermodynamic constraints, provides a modular approach to modelling, and gives a basis for estimation of model parameters leading to dynamic models of biomolecular systems. The approach is illustrated using a well-established stoichiometric model ofEscherichia coli(E. coli) and published experimental data.
Directed differentiation of hPSCs through lateral plate mesoderm for generation of articular cartilage progenitors
Authors: Smith Christopher A , Humphreys Paul A , Naven Mark A , Mancini Fabrizio E , Kimber Susan J 
Published: March 2021

AbstractDevelopmentally the articular joints are derived from lateral plate (LP) mesoderm. However, no study has produced LP derived prechondrocytes or preosteoblasts from human pluripotent stem cells (hPSC) in a chemically defined manner. Differentiation of hPSCs through the authentic route, via an LP-osteochondral progenitor (OCP), may aid understanding of human cartilage development and the generation of effective cell therapies for osteoarthritis. We refined our existing chondrogenic protocol, incorporating knowledge from development and other studies to produce a LP-OCP from which prechondrocytes- and preosteoblast-like cells can be produced. Results show the formation of an OCP, which can be further driven to prechondrocytes and preosteoblasts. Prechondrocytes cultured in pellets produced cartilage like matrix with lacunae and superficial flattened cells expressing lubricin. Additionally, preosteoblasts were able to generate a mineralised structure. This protocol can therefore be used to further investigate cartilage development and in the development of joint cartilage for potential treatments.
The Arabidopsis F-box protein FBW2 degrades AGO1 to avoid spurious loading of illegitimate small RNA
Authors: Hacquard Thibaut , Clavel Marion , Baldrich Patricia , Lechner Esther , Pérez-Salamó Imma , Schepetilnikov Mikhail , Derrien Benoît , Dubois Marieke , Hammann Philippe , Kuhn Lauriane , Brun Danaé , Bouteiller Nathalie , Vaucheret Hervé , Meyers Blake C. , Genschik Pascal 
Published: March 2021

AbstractRNA silencing is a conserved mechanism in eukaryotes and is involved in development, heterochromatin maintenance and defense against viruses. In plants, ARGONAUTE1 (AGO1) protein plays a central role in both microRNA (miRNA) and small interfering RNA (siRNA)-directed silencing and its expression is regulated at multiple levels. Here, we report that the F-box protein FBW2 targets proteolysis of AGO1 by a CDC48-mediated mechanism. We found that FBW2 assembles an SCF complex that recognizes the MID-PIWI domain of AGO1 and requires its C-terminal domain containing a GW motif for AGO1 turnover. We showed that FBW2 prefers the unloaded and some mutated forms of AGO1 protein. WhileFBW2loss of function does not lead to strong growth or developmental defects, it significantly increases RNA silencing activity. Interestingly, under conditions in which small RNA production or accumulation is affected, the failure to degrade AGO1 infbw2mutants becomes more deleterious for the plant. Hence, the non-degradable AGO1 protein assembles high molecular weight complexes and binds illegitimate small RNA leading to the cleavage of new target genes that belong to stress responses and cellular metabolic processes. Therefore, the control of AGO1 homeostasis by ubiquitin ligases plays an important role in quality control to avoid off-target cleavage.
Phosphorylation-dependent mitotic SUMOylation drives nuclear envelope-chromatin interactions
Authors: Ptak Christopher , Saik Natasha O. , Premashankar Ashwini , Lapetina Diego L. , Aitchison John D. , Montpetit Ben , Wozniak Richard W. 
Published: March 2021

AbstractIn eukaryotes, chromatin binding to the inner nuclear membrane (INM) and nuclear pore complexes (NPCs) contributes to spatial organization of the genome and epigenetic programs important for gene expression. In mitosis, chromatin-nuclear envelope (NE) interactions are lost and then formed again as sister chromosomes segregate to post-mitotic nuclei. Investigating these processes inS. cerevisiae, we identified temporally and spatially controlled phosphorylation-dependent SUMOylation events that positively regulate post-metaphase chromatin association with the NE. Our work establishes a phosphorylation-mediated targeting mechanism of the SUMO ligase Siz2 to the INM during anaphase, where Siz2 binds to and SUMOylates the VAP protein Scs2. The recruitment of Siz2 through Scs2 is further responsible for a wave of SUMOylation along the INM that supports the assembly and anchorage of subtelomeric chromatin at the INM and localization of an active gene (INO1) to NPCs during the later stages of mitosis and into G1-phase.
Arginine Methylation Regulates SARS-CoV-2 Nucleocapsid Protein Function and Viral Replication
Authors: Cai Ting , Yu Zhenbao , Wang Zhen , Liang Chen , Richard Stéphane 
Published: March 2021

AbstractViral proteins are known to be methylated by host protein arginine methyltransferases (PRMTs) playing critical roles during viral infections. Herein, we show that PRMT1 methylates SARS-CoV-2 nucleocapsid (N) protein at residues R95 and R177 within RGG/RG sequences. Arginine methylation of N protein was confirmed by immunoblotting viral proteins extracted from SARS-CoV-2 virions isolated by cell culture. We demonstrate that arginine methylation of N protein is required for its RNA binding capacity, since treatment with a type I PRMT inhibitor (MS023) or substitution of R95K or R177K inhibited interaction with the 5’-UTR of the SARS-CoV-2 genomic RNA. We defined the N interactome in HEK293 cells with or without MS023 treatment and identified PRMT1 and many of its RGG/RG substrates including the known interactor, G3BP1, and other components of stress granules (SG). Methylation of N protein at R95 regulates another function namely its property to suppress the formation of SGs. MS023 treatment or R95K substitution blocked N-mediated suppression of SGs. Also, the co-expression of methylarginine reader TDRD3 quenched N-mediated suppression of SGs in a dose-dependent manner. Finally, pre-treatment of VeroE6 cells with MS023 significantly reduced SARS-CoV-2 replication. With type I PRMT inhibitors being in clinical trials for cancer treatment, inhibiting arginine methylation to target the later stages of the viral life cycle such as viral genome packaging and assembly of virions may be an additional therapeutic application of these drugs.
Analytical solutions of the chemical master equation with bursty production and isomerization reactions
Authors: Gorin Gennady , Pachter Lior 
Published: March 2021

AbstractSplicing cascades that alter gene products post-transcriptionally also affect expression dynamics. We study a class of processes and associated distributions that emerge from a bursty promoter model coupled to a path graph of downstream mRNA splicing, and more generally examine the behavior of finite-activity jump drivers coupled to a directed acyclic graph of splicing with one or more roots. These solutions provide full time-dependent joint distributions for an arbitrary number of species, offering qualitative and quantitative insights about how splicing can regulate expression dynamics. Finally, we derive a set of quantitative constraints on the minimum complexity necessary to reproduce gene co-expression patterns using synchronized burst models. We validate these findings by analyzing long-read sequencing data, where we find evidence of expression patterns largely consistent with these constraints.
Brain virtual histology with X-ray phase-contrast tomography Part I: whole-brain myelin mapping in white-matter injury models
Authors: Chourrout Matthieu , Rositi Hugo , Ong Elodie , Hubert Violaine , Paccalet Alexandre , Foucault Louis , Autret Awen , Fayard Barbara , Olivier Cécile , Bolbos Radu , Peyrin Françoise , Crola-da-Silva Claire , Meyronet David , Raineteau Olivier , Elleaume Hélène , Brun Emmanuel , Chauveau Fabien , Wiart Marlène 
Published: March 2021

AbstractWhite-matter injury leads to severe functional loss in many neurological diseases. Myelin staining on histological samples is the most common technique to investigate white-matter fibers. However, tissue processing and sectioning may affect the reliability of 3D volumetric assessments. The purpose of this study was to propose an approach that enables myelin fibers to be mapped in the whole rodent brain with microscopic resolution and without the need for strenuous staining. With this aim, we coupled inline (propagation-based) X-ray phase-contrast tomography (XPCT) to ethanol-induced brain sample dehydration. We here provide the proof-of-concept that this approach enhances myelinated axons in rodent and human brain tissue. In addition, we demonstrated that white-matter injuries could be detected and quantified with this approach, using three animal models: ischemic stroke, premature birth and multiple sclerosis. Furthermore, in analogy to diffusion tensor imaging (DTI), we retrieved fiber directions and DTI-like diffusion metrics from our XPCT data to quantitatively characterize white-matter microstructure. Finally, we showed that this non-destructive approach was compatible with subsequent complementary brain sample analysis by conventional histology. In-line XPCT might thus become a novel gold-standard for investigating white-matter injury in the intact brain. This is Part I of a series of two articles reporting the value of in-line XPCT for virtual histology of the brain; Part II shows how in-line XPCT enables the whole-brain 3D morphometric analysis of amyloid-β (Aβ) plaques.HighlightsX-ray phase-contrast tomography (XPCT) enables myelin mapping of the whole brainXPCT detects and quantifies white-matter injuries in a range of diseasesFiber directions and anisotropy metrics can be retrieved from XPCT dataXPCT is compatible with subsequent conventional histology of brain samplesXPCT is a powerful virtual histology tool that requires minimal sample preparationGraphical Abstract
A Pilot Study Using Two Novel fMRI Tasks: Understanding Theory of Mind and Emotion Recognition Among Children With ASD
Authors: Han Yu , Prelock Patricia A. , Coderre Emily L. , Orr Joseph M. 
Published: March 2021

AbstractChildren with autism spectrum disorder (ASD) struggle with social interactions due to deficits in theory of mind (ToM). In this study, we collected behavioral and neuroimaging data from 9 children with ASD and 19 neurotypical children between the age of 7 and 14 years old, particularly in the area of emotion recognition to better understand those skills needed for meaningful social interaction. The results suggest impaired abilities in multiple ToM metrics and brain deficits associated with ToM-related emotion recognition and processing among children with ASD. Findings from this study are expected to establish connections between behavior and brain activities surrounding ToM in ASD, which may assist the development of neuroanatomical diagnostic criteria and provide a way to measure intervention outcomes.