bluuebunny/crossref_metadata_2025_split huggingface dataset:
Microstructured hydrogels to guide self-assembly and function of lung alveolospheres
Authors: Loebel Claudia , Weiner Aaron I. , Katzen Jeremy B. , Morley Michael P. , Bala Vikram , Cardenas-Diaz Fabian L. , Davidson Matthew D. , Shiraishi Kazushige , Basil Maria C. , Ochs Matthias , Beers Michael F. , Morrisey Edward E. , Vaughan Andrew E. , Burdick Jason A. 
Published: September 2021

AbstractEpithelial cell organoids have increased opportunities to probe questions on tissue development and disease in vitro and for therapeutic cell transplantation. Despite their potential, current protocols to grow these organoids almost exclusively depend on culture within three-dimensional (3D) Matrigel, which limits defined culture conditions, introduces animal components, and results in heterogenous organoids (i.e., shape, size, composition). Here, we describe a method that relies on polymeric hydrogel substrates for the generation and expansion of lung alveolar organoids (alveolospheres). Using synthetic hydrogels with defined chemical and physical properties, human induced pluripotent stem cell (iPSC)-derived alveolar type 2 cells (iAT2s) self-assemble into alveolospheres and propagate in Matrigel-free conditions. By engineering pre-defined microcavities within these hydrogels, the heterogeneity of alveolosphere size and structure was reduced when compared to 3D culture while maintaining alveolar type 2 cell fate of human iAT2 and primary mouse tissue-derived progenitor cells. This hydrogel system is a facile and accessible culture system for the culture of primary and iPSC-derived lung progenitors and the method could be expanded to the culture of other epithelial progenitor and stem cell aggregates.
KMT2D-NOTCH Mediates Coronary Abnormalities in Hypoplastic Left Heart Syndrome
Authors: Yu Zhiyun , Zhou Xin , Liu Ziyi , Pastrana-Gomez Victor , Liu Yu , Guo Minzhe , Tian Lei , Nelson Timothy J. , Wang Nian , Mital Seema , Chitayat David , Wu Joseph C. , Rabinovitch Marlene , Wu Sean M. , Snyder Michael P. , Miao Yifei , Gu Mingxia 
Published: September 2021

AbstractHypoplastic left heart syndrome (HLHS) is a severe form of single ventricle congenital heart disease characterized by the underdevelopment of the left ventricle. Early serial postmortem examinations revealed high rate of coronary artery abnormalities in HLHS fetal hearts, such as thickened wall, kinking arteries and ventriculo-coronary arterial connection. However, it is unclear if there is an intrinsic defect in the HLHS coronary vessels and what the underlying molecular mechanism is.Here, we profiled both human fetal heart with an underdeveloped left ventricle (ULV) and ECs differentiated from induced pluripotent stem cells (iPSCs) derived from HLHS patients at single cell resolution. CD144+/NPR3-vascular ECs were selected and further classified as venous, arterial and late arterial subclusters. To study the arterial EC phenotype, we specifically generated iPSC-arterial ECs (AECs, CD34+CDH5+CXCR4+NT5E-/low) derived from three HLHS patients and three age-matched healthy controls.Gene ontology analysis revealed that ULV late arterial EC subcluster showed specific defects in endothelial development, proliferation, and Notch signaling compared to control. Consistently, HLHS iPSCs exhibited impaired AEC differentiation shown as the reduced CXCR4+NT5E-/low AEC progenitor population. Mature HLHS iPSC-AECs also exhibited increased G0/G1 cell cycle arrest with decreased expression of cell cycle related genes (e.g., Ki67, CCND1/2). Additionally, NOTCH targeted genes (e.g., DLL4, HEY1, GJA5) were found suppressed in both ULV AECs and HLHS iPSC-AECs compared to control. We also found the HLHS de novo mutation gene KMT2D directly regulated the transcription of NOTCH targeted genes participating in arterial differentiation and cell proliferation, contributing to the HLHS AEC dysfunctionalities. Intriguingly, the treatment of NOTCH ligand JAG1 improved cell proliferation of HLHS AECs and upregulated G1/S transition genes downstream of NOTCH pathway.In summary, our results revealed that KMT2D directly regulated transcription activity of NOTCH signaling, contributing to the poor differentiation and low proliferation of HLHS coronary AECs.
Adaptive cognitive maps for curved surfaces in the 3D world
Authors: Kim Misun , Doeller Christian F. 
Published: September 2021

AbstractTerrains in a 3D world can be undulating. Yet, most prior research has exclusively investigated spatial representations on a flat surface, leaving a 2D cognitive map as the dominant model in the field. Here, we investigated whether humans represent a curved surface by building a dimension-reduced flattened 2D map or a full 3D map. Participants learned the location of objects positioned on a flat and curved surface in a virtual environment by driving on the concave side of the surface (Experiment 1), driving and looking vertically (Experiment 2), or flying (Experiment 3). Subsequently, they were asked to retrieve either the path distance or the 3D Euclidean distance between the objects. Path distance estimation was good overall, but we found a significant underestimation bias for the path distance on the curve, suggesting an influence of potential 3D shortcuts, even though participants were only driving on the surface. Euclidean distance estimation was better when participants were exposed more to the global 3D structure of the environment by looking and flying. These results suggest that the representation of the 2D manifold, embedded in a 3D world, is neither purely 2D nor 3D. Rather, it is flexible and dependent on the behavioral experience and demand.
Effective and Efficient Neural Networks for Spike Inference fromIn VivoCalcium Imaging
Authors: Zhou Zhanhong , Yip Hei Matthew , Tsimring Katya , Sur Mriganka , Kan Ip Jacque Pak , Tin Chung 
Published: September 2021

ABSTRACTCalcium imaging technique provides the advantages in monitoring large population of neuronal activities simultaneously. However, it lacks the signal quality provided by neural spike recording in traditional electrophysiology. To address this issue, we developed a supervised data-driven approach to extract spike information from calcium signals. We propose the ENS2(effective and efficientneuralnetworks for spike inference from calcium signals) system for spike-rate and spike-event predictions using raw calcium inputs based on U-Net deep neural network. When testing on a large, ground truth public database, it consistently outperformed state-of-the-arts algorithms in both spike-rate and spike-event predictions with reduced computational load. We further demonstrated that ENS2can be applied to analyses of orientation selectivity in primary visual cortex neurons. We concluded that it would be a versatile inference system that benefits diverse neuroscience studies.
Disentangling the flow of signals between populations of neurons
Authors: Gokcen Evren , Jasper Anna I. , Semedo João D. , Zandvakili Amin , Kohn Adam , Machens Christian K. , Yu Byron M. 
Published: September 2021

AbstractTechnological advances now allow us to record from large populations of neurons across multiple brain areas. These recordings may illuminate how communication between areas contributes to brain function, yet a substantial barrier remains: How do we disentangle the concurrent, bidirectional flow of signals between populations of neurons? We therefore propose here a novel dimensionality reduction framework: Delayed Latents Across Groups (DLAG). DLAG disentangles signals relayed in each direction, identifies how these signals are represented by each population, and characterizes how they evolve within and across trials. We demonstrate that DLAG performs well on synthetic datasets similar in scale to current neurophysiological recordings. Then we study simultaneously recorded populations in primate visual areas V1 and V2, where DLAG reveals signatures of bidirectional yet selective communication. Our framework lays a foundation for dissecting the intricate flow of signals across populations of neurons, and how this signaling contributes to cortical computation.
Synaptotagmin 13 orchestrates pancreatic endocrine cell egression and islet morphogenesis
Authors: Bakhti Mostafa , Bastidas-Ponce Aimée , Tritschler Sophie , Tarquis-Medina Marta , Nedvedova Eva , Scheibner Katharina , Jaki Jessica , Cota Perla , Salinno Ciro , Boldt Karsten , Willmann Stefanie J. , Horn Nicola , Ueffing Marius , Burtscher Ingo , Theis Fabian J. , Coskun Ünal , Lickert Heiko 
Published: September 2021

AbstractEpithelial cell egression is important for organ development, but also drives cancer metastasis. Better understandings of pancreatic epithelial morphogenetic programs generating islets of Langerhans aid to diabetes therapy. Here we identify the Ca2+-independent atypical Synaptotagmin 13 (Syt13) as a key driver of endocrine cell egression and islet formation. We detected upregulation of Syt13 in endocrine precursors that correlates with increased expression of unique cytoskeletal components. High-resolution imaging reveals a previously unidentified apical-basal to front-rear repolarization during endocrine cell egression. Strikingly, Syt13 interacts with acetylated tubulin and phosphatidylinositol phospholipids and localizes to the leading-edge of egressing cells. Knockout of Syt13 impairs endocrine cell egression and skews the α- to-β-cell ratio. Mechanistically, Syt13 regulates endocytosis to remodel the basement membrane and cell-matrix adhesion at the leading-edge of egressing endocrine cells. Altogether, these findings implicate an unexpected role of Syt13 in regulating cell polarity to orchestrate endocrine cell egression and islet morphogenesis.
The effect of non-linear competitive interactions on quantifying niche and fitness differences
Authors: Spaak Jurg , Millet Remi , Ke Po-Ju , Letten Andrew D. , De Laender Frederik 
Published: September 2021

AbstractThe niche and fitness differences of modern coexistence theory separate mechanisms into stabilizing and equalizing components. Although this decomposition can help us predict and understand species coexistence, the extent to which mechanistic inference is sensitive to the method used to partition niche and fitness differences remains unclear. We apply two alternative methods to assess niche and fitness differences to four well known community models. We show that because standard methods based on linear approximations do not capture the full community dynamics, they can sometimes lead to incorrect predictions of coexistence and misleading interpretations of stabilizing and equalizing mechanisms. Conversely, a more recently developed method to decompose niche and fitness differences, that accounts for the full nonlinear dynamics of competition, consistently identifies the correct contribution of stabilizing and equalizing components. This approach further reveals that when the true complexity of the system is taken into account, essentially all mechanisms comprise both stabilizing and equalizing components. Amidst growing interest in the role of non-additive and higher-order interactions in regulating species coexistence, we propose that the effective decomposition of niche and fitness differences will become increasingly reliant on methods that account for the inherent non-linearity of community dynamics.
NEURON-SPECIFIC CHROMOSOMAL MEGADOMAIN ORGANIZATION IS ADAPTIVE TO RECENT RETROTRANSPOSON EXPANSIONS
Authors: Chandrasekaran Sandhya , Espeso-Gil Sergio , Loh Yong-Hwee Eddie , Javidfar Behnam , Kassim Bibi , Dong Yuhao , Zhu Yueyan , Bicks Lucy K. , Rajarajan Prashanth , Peter Cyril J. , Agullo-Pascual Esperanza , Iskhakova Marina , Estill Molly , Shen Li , Jiang Yan , Akbarian Schahram 
Published: September 2021

ABSTRACTHere, we mapped cell-type specific chromatin domain organization in adult mouse cerebral cortex and report strong enrichment of Endogenous Retrovirus 2 (ERV2) repeat sequences in the neuron-specific heterochromatic ‘B2NeuN+’ megabase-scaling subcompartment. Comparative chromosomal conformation mapping in Mus spretus and Mus musculus revealed neuron-specific reconfigurations tracking recent ERV2 retrotransposon expansions in the murine germline, with significantly higher B2 megadomain contact frequencies at sites with ongoing ERV2 insertions in Mus musculus. Ablation of the retrotransposon silencer Kmt1e/Setdb1 triggered B2 megadomain disintegration and rewiring with open chromatin domains enriched for cellular stress response genes, along with severe neuroinflammation and proviral assembly of ERV2/Intracisternal-A-Particles (IAPs) infiltrating dendrites and spines. We conclude that neuronal megadomain architectures include evolutionarily adaptive heterochromatic organization which, upon perturbation, unleashes ERV proviruses with strong tropism within mature neurons.
Altered interaction between RBD and ACE2 receptor contributes towards the increased transmissibility of SARS CoV-2 delta, kappa, beta, and gamma strains with RBD double mutations
Authors: Sinha Siddharth , Tam Benjamin , Wang San Ming 
Published: September 2021

ABSTRACTThe COVID-19 pandemics by SARS-CoV-2 causes catastrophic damage for global human health. The initial step of SARS-CoV-2 infection is the binding of the receptor-binding domain (RBD) in its spike protein to ACE2 receptor in host cell membrane. The evolving of SARS-CoV-2 constantly generates new mutations across its genome including RBD. Besides the well-known single mutation in RBD, the recent new mutation strains with RBD “double mutation” is causing new outbreaks globally, as represented by the delta strain containing RBD L452R/T478K. Although it is considered that the increased transmissibility of the double mutated strains could be attributed to the alteration of mutated RBD to ACE2 receptor, the molecular details remains to be unclear. Using the methods of molecular dynamics simulation, superimposed structural comparison, free binding energy estimation and antibody escaping, we investigated the relationship between ACE2 receptor and the RBD double mutant L452R/T478K (delta), L452R/E484Q (kappa) and E484K/N501Y (beta, gamma). The results demonstrated that each of the three RBD double mutants altered RBD structure, led to enhanced binding affinity of mutated RBD to ACE2 receptor, leading to increased transmissibility of SARS-CoV-2 to the host cells.
Modelling the collective mechanical regulation of the structure and morphology of epithelial cell layers
Authors: Khataee Hamid , Fraser Madeleine , Neufeld Zoltan 
Published: September 2021

AbstractThe morphology and function of epithelial sheets play an important role in healthy tissue development and cancer progression. The maintenance of structure of closely packed epithelial layers requires the coordination of various mechanical forces within the cells and others resulting from interactions with other cells and other tissues or substrates. However, a general model for the combination of mechanical properties which determine the cell shape and the overall structure of epithelial layers remains elusive. Here, we propose a computational model, based on the Cellular Potts Model, to study the interplay between mechanical properties of cells and dynamical transitions in epithelial structures and cell shapes. We map out phase diagrams as functions of cellular properties and the orientation of cell division. Monolayers of squamous, cuboidal, and columnar cells are found when the axis of cell proliferation is perpendicular to the substrate. Monolayer-to-multilayer transition is promoted via cell extrusion, depending on the mechanical properties of cells and the orientation of cell division. The results and model predictions are discussed in the context of experimental observations.
PERCOVID: A Model to Describe COVID Percolation on a Network of Social Relationships
Authors: Mathiot Jean-François , Gerbaud Laurent , Breton Vincent 
Published: September 2021

AbstractWe develop a site-bond percolation model, called PERCOVID, in order to describe the time evolution of COVID epidemics and more generally all epidemics propagating through respiratory tract in human populations. This model is based on a network of social relationships representing interconnected households experiencing governmental non-pharmaceutical interventions. The model successfully accounts for the COVID-19 epidemiological data in metropolitan France from December 2019 up to July 2021. Our model shows the impact of lockdowns and curfews, as well as the influence of the progressive vaccination campaign in order to keep COVID-19 pandemic under the percolation threshold. We illustrate the role played by the social interactions by comparing a typical scenario for the epidemic evolution in France, Germany and Italy during the first wave from January to May 2020. We investigate finally the role played by the α and δ variants in the evolution of the epidemic in France till autumn 2021, paying particular attention to the essential role played by the vaccination. Our model predicts that the rise of the epidemic observed in July 2021 will not result in a fourth major epidemic wave in France.
Mimicking and mitigating the cutaneous response to transcranial electrical stimulation using interferential and combinatorial techniques
Authors: Howell Bryan , McIntyre Cameron C. 
Published: September 2021

ABSTRACTTranscranial electrical stimulation (tES) is a promising adjunct treatment for neurological impairment and mental health disorders. The modulatory effects of tES are small to moderate, and accrue over days to weeks with repeated administration, but these effects are also inconsistent across individuals, which poses a challenge for its clinical administration. Some of the variability in tES may stem from uncontrolled behavioral factors, and inadequate dosing of current across individuals, so new strategies are needed to address these issues. We evaluated the biophysics of emerging techniques for tES and provided new testable hypotheses for the tolerability of interferentail and combinatorial waveforms. Millisecond pulsatile currents may serve as suitable alternatives to alternating currents in modulating neural spike timing from tES. Pulsatile currents limit spike generation in nerves and may be tolerated above the standard limit of 2 mA when combined with a direct current to block nerve activation. Additionally, we posit that combinations of kilohertz interferential currents can mimic the nerve response of different tES waveforms but with minimal modulation of cortical neurons, providing a new strategy for active placebo stimulation. These results will help guide design of interferential tES strategies for better blinding and provide a testable model for evaluating the tolerability of new combinatorial strategies.
Exploring the kinetic selectivity of drugs targeting the β1-adrenoceptor
Authors: Sykes David A. , Jiménez-Rosés Mireia , Reilly John , Fairhurst Robin A. , Charlton Steven J. , Veprintsev Dmitry B. 
Published: September 2021

AbstractIn this study, we report the β1-adrenoceptor binding kinetics of several clinically relevant β1/2-adrenoceptor (β1/2AR) agonists and antagonists. We demonstrate that the physicochemical properties of a molecule directly affect its kinetic association rate (kon) and affinity for the target. In contrast to our findings at the β2-adrenoceptor, a drug’s immobilized artificial membrane partition coefficient (KIAM), reflecting both hydrophobic and electrostatic interactions of the drug with the charged surface of biological membranes, was no better predictor than simple hydrophobicity measurements such as log P or logD7.4, characterized by a distribution between water and a non-aqueous organic phase (e.g. n-octanol) at predicting association rate. Overall, this suggests that hydrophobic interactions rather than a combination of polar and hydrophobic interactions play a more prominent role in dictating the binding of these ligands to the β1-adrenoceptor.Using a combination of kinetic data, detailed structural and physicochemical information we rationalize the above findings and speculate that the association of positively charged ligands at the β1AR is curtailed somewhat by its predominantly neutral/positive charged extracellular surface. Consequently, hydrophobic interactions in the ligand binding pocket dominate the kinetics of ligand binding. In comparison at the β2AR, a combination of hydrophobicity and negative charge attracts basic, positively charged ligands to the receptor’s surface promoting the kinetics of ligand binding. Additionally, we reveal the potential role kinetics plays in the on-target and off-target pharmacology of clinically used β-blockers.
Dynamic analysis of lower leg muscles response to whole body vibration stimulation at different frequencies and postures: implications for training
Authors: Rigoni Isotta , Bonci Tecla , Bifulco Paolo , Fratini Antonio 
Published: September 2021

AbstractPurposeTo characterise the mechanical and neuromuscular response of lower limb muscles in subjects undergoing Whole Body Vibration (WBV) at different frequencies while holding two static postures.MethodsTwenty-five participants underwent WBV at 15, 20, 25 and 30 Hz while holding a static ‘hack squat’ and on ‘fore feet’ posture. Surface electromyography (sEMG) and soft tissue accelerations were collected from Gastrocnemius Lateralis (GL), Soleus (SOL) and Tibialis Anterior (TA) muscles.ResultsOnly specific WBV settings led to a significant increase in muscle contraction. Specifically, the WBV-induced activation of SOL and GL was maximal in fore-feet and in response to higher frequencies. Estimated displacement at muscle bellies revealed a resonant pattern never highlighted before. After stimulation starts, muscle oscillation reaches a peak followed by a drop and a further stabilisation (few seconds after the peak) that suggests the occurrence of a neuromuscular activation to reduce the vibration-induced oscillation.ConclusionLower leg muscles need a response time to tune to a vibratory stimulation, which discourages the use of dynamic exercises on vibrating platforms. To maximize calf muscle response to WBVs, a stimulation frequency in the range of 25-30 Hz and an ‘on fore feet’ posture are recommended.
Predictive Simulations of Gait with Exoskeletons that Alter Energetics
Authors: Koelewijn Anne D. , Selinger Jessica C. 
Published: September 2021

AbstractRobotic exoskeletons, designed to augment human locomotion, have the potential to restore function in those with mobility impairments and enhance it in able-bodied individuals. However, optimally controlling these devices, to work in concert with complex and diverse human users, is a challenge. Accurate model simulations of the interaction between exoskeletons and walking humans may expedite the design process and improve control. Here, we use predictive gait simulations to investigate the effect of an exoskeleton that alters the energetic consequences of walking. To validate our approach, we re-created an past experimental paradigm where robotic exoskeletons were used to shift people’s energetically optimal step frequency to frequencies higher and lower than normally preferred. To match the experimental controller, we modelled a knee-worn exoskeleton that applied resistive torques that were either proportional or inversely proportional to step frequency—decreasing or increasing the energy optimal step frequency, respectively. We were able to replicate the experiment, finding higher and lower optimal step frequencies than in natural walking under each respective condition. Our simulated resistive torques and objective landscapes resembled the measured experimental resistive torque and energy landscapes. Individual muscle energetics revealed distinct coordination strategies consistent with each exoskeleton controller condition. Predicted step frequency and energetic outcomes were best achieved by increasing the number of virtual participants (varying whole-body anthropometrics), rather than number of muscle parameter sets (varying muscle anthropometrics). In future, our approach can be used to design controllers in advance of human testing, to help identify reasonable solution spaces or tailor design to individual users.