bluuebunny/crossref_metadata_2025 huggingface dataset:
Regional patterns ofδ13C andδ15N for European common cuttlefish (Sepia officinalis) throughout the Northeast Atlantic Ocean and Mediterranean Sea
Authors: David Wells R. J. , Rooker Jay R. , Addis Piero , Arrizabalaga Haritz , Baptista Miguel , Bearzi Giovanni , Fraile Igaratza , Lacoue-Labarthe Thomas , Meese Emily N. , Megalofonou Persefoni , Rosa Rui , Sobrino Ignacio , Sykes Antonio V. , Villanueva Roger
Published: September 2021

Stable isotope compositions of carbon and nitrogen (expressed asδ13C andδ15N) from the European common cuttlefish (Sepia officinalis) were measured in order to evaluate the utility of using these natural tracers throughout the Northeast Atlantic Ocean and Mediterranean Sea (NEAO-MS). Mantle tissue was obtained fromS. officinaliscollected from 11 sampling locations spanning a wide geographical coverage in the NEAO-MS. Significant differences of bothδ13C andδ15N values were found amongS. officinalissamples relative to sampling location.δ13C values did not show any discernable spatial trends; however, a distinct pattern of lowerδ15N values in the Mediterranean Sea relative to the NEAO existed. Meanδ15N values ofS. officinalisin the Mediterranean Sea averaged 2.5‰ lower than conspecifics collected in the NEAO and showed a decreasing eastward trend within the Mediterranean Sea with the lowest values in the most eastern sampling locations. Results suggestδ15N may serve as a useful natural tracer for studies on the population structure ofS. officinalisas well as other marine organisms throughout the NEAO-MS.
Pre-combustion gas separation by ZIF-8-polybenzimidazole mixed matrix membranes in the form of hollow fibres—long-term experimental study
Authors: Perea-Cachero Adelaida , Etxeberría-Benavides Miren , David Oana , Deacon Adam , Johnson Timothy , Malankowska Magdalena , Téllez Carlos , Coronas Joaquín
Published: September 2021

Polybenzimidazole (PBI) is a promising and suitable membrane polymer for the separation of the H2/CO2pre-combustion gas mixture due to its high performance in terms of chemical and thermal stability and intrinsic H2/CO2selectivity. However, there is a lack of long-term separation studies with this polymer, particularly when it is conformed as hollow fibre membrane. This work reports the continuous measurement of the H2/CO2separation properties of PBI hollow fibres, prepared as mixed matrix membranes with metal-organic framework (MOF) ZIF-8 as filler. To enhance the scope of the experimental approach, ZIF-8 was synthesized from the transformation of ZIF-L upon up-scaling the MOF synthesis into a 1 kg batch. The effects of membrane healing with poly(dimethylsiloxane), to avoid cracks and non-selective gaps, and operation conditions (use of sweep gas or not) were also examined at 200°C during approximately 51 days. In these conditions, for all the membrane samples studied, the H2permeance was in the 22–47 GPU range corresponding to 22–32 H2/CO2selectivity values. Finally, this work continues our previous report on this type of application (Etxeberria-Benavideset al. 2020Sep. Purif. Technol.237, 116347 (doi:10.1016/j.seppur.2019.116347)) with important novelties dealing with the use of ZIF-8 for the mixed matrix membrane coming from a green methodology, the long-term gas separation testing for more than 50 days and the study on the membrane operation under more realistic conditions (e.g. without the use of sweep gas).
On the equilibrium bifurcation of axially deformable holonomic systems: solution of a long-standing enigma
Authors: Fraldi M. , Palumbo S. , Cutolo A. , Carotenuto A. R. , Guarracino F.
Published: September 2021

The stability of equilibrium is a fundamental topic in mechanics and applied sciences. Apart from its central role in most engineering fields, it also arises in many natural systems at any scale, from folding/unfolding processes of macromolecules and growth-induced wrinkling in biological tissues to meteorology and celestial mechanics. As such, a few key models represent essential benchmarks in order to gain significant insights into more complex physical phenomena. Among these models, a cornerstone is represented by a structure made of two straight axially deformable bars, connected by an elastic hinge and simply supported at the ends, which are capable of buckling under a compressive axial force. This classical example has been proposed and analysed in some depth by Feodosyev but the attention is here focused on an apparently paradoxical result given by this model, i.e. the existence of a lower bound for the axial-to-flexural stiffness ratio in order for the bifurcation to take place. This enigma is solved theoretically by showing that, differently from other classical stability problems, constitutive and geometric nonlinearities cannot be
a priori
disconnected and an ideal linearized axial constitutive law cannot be employed in this case. The theory is validated with an experiment, and post-buckling and energy extrema of the proposed solution are discussed as well, highlighting possible snap-back and snap-through phenomena. Finally, the results are extended to the complementary case of tensile buckling.
Attitude and Behavior of People Towards Visiting the Hospital During the Pandemic
Authors: shamsundar Manaswi , Choudhary Shaista
Published: September 2021

Introduction

Visiting the hospital is important as a part of check-up in avoiding the major risks of unknown and serious diseases irrespective of any pandemic. Our study aims to understand the attitude and behaviour of common people towards visiting the hospital during COVID-19 pandemic in two major hotspot states of India namely Maharashtra and Karnataka.

Methodology

A cross-sectional study was conducted between July-august 2021 among the population of two states. A total of 636 respondents completed the survey and returned electronically. Data were analysed using suitable statistical tools to achieve the objective of the study.

Results

74.8% of the respondents were not ready to visit the hospitals during the COVID-19 pandemic unless the symptoms were serious. On the other hand, 25.2% of the of respondents were willing to go to the hospitals. The top three reasons for the reduction in visits are fear of getting infected in the hospitals by COVID-19 patients (72.6%), fear of stepping out of home (31.1%) and fear of COVID-19 infection by the lab equipment (24.5%).

Conclusion

Overall the study revealed that there was a reduction in number of visits to the hospitals for common diseases in people after the pandemic started. But the people were still willing to go to the hospitals if they noticed any major symptoms or symptoms related to COVID-19. Our findings may be useful to develop strategies to address concerns in order to ensure that people don’t get any serious illness because of the fear of COVID-19.
Elucidation of Master Allostery Essential for Circadian Clock Oscillation in Cyanobacteria
Authors: Furuike Y. , Mukaiyama A. , Ouyang D. , Ito-Miwa K. , Simon D. , Yamashita E. , Kondo T. , Akiyama S.
Published: September 2021

Spatio-temporal allostery is the source of complex but ordered biological phenomena. To identify the structural basis for allostery that drives the cyanobacterial circadian clock, we crystallized the clock protein KaiC in four distinct states, which cover a whole cycle of phosphor–transfer events at Ser431 and Thr432. The minimal set of allosteric events required for oscillatory nature is a bidirectional coupling between the coil-to-helix transition of the Ser431-dependent phospho-switch in the C-terminal domain of KaiC and ADP release from its N-terminal domain during ATPase cycle. An engineered KaiC–protein oscillator consisting of a minimal set of the identified master allosteric events exhibited mono-phosphorylation cycle of Ser431 with a temperature-compensated circadian period, providing design principles for simple post-translational biochemical circadian oscillators.

One Sentence Summary

Coupling between a phospho-switch and KaiC ATPase-dependent nucleotide exchange drives the cyanobacterial circadian clock.
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

Epithelial 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

Hypoplastic 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

Terrains 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

Calcium 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

Technological 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

Epithelial 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

The 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

Here, 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

The 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

The 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

We 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

Transcranial 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

In 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

Purpose

To 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.

Methods

Twenty-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.

Results

Only 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.

Conclusion

Lower 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

Robotic 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.
Programmable RNA base editing with a single gRNA-free enzyme
Authors: Han Wenjian , Huang Wendi , Mao Miaowei , Wei Tong , Ye Yanwen , Wang Zefeng
Published: September 2021

Programmable RNA editing enables rewriting gene expression without changing genome sequences. Current tools for specific RNA editing dependent on the assembly of guide RNA into an RNA/protein complex, causing delivery barrier and low editing efficiency. We report a new gRNA-free system, RNA editing with individual RNA-binding enzyme (REWIRE), to perform precise base editing with a single engineered protein. This artificial enzyme contains a human-originated programmable PUF domain to specifically recognize RNAs and different deaminase domains to achieve efficient A-to-I or C-to-U editing, which achieved 60-80% editing rate in human cells, with a few non-specific editing sites in the targeted region and a low level off-target effect globally. The RNA-binding domain in REWIREs was further optimized to improve editing efficiency and minimize off-target effects. We applied the REWIREs to correct disease-associated mutations and achieve both types of base editing in mice. As a single-component system originated from human proteins, REWIRE presents a precise and efficient RNA editing platform with broad applicability.
Age differences in aperiodic neural activity measured with resting EEG
Authors: Merkin Ashley , Sghirripa Sabrina , Graetz Lynton , Smith Ashleigh E. , Hordacre Brenton , Harris Richard , Pitcher Julia , Semmler John , Rogasch Nigel C. , Goldsworthy Mitchell
Published: September 2021

Previous research using electroencephalography (EEG) and magnetoencephalography (MEG) has shown that neural oscillatory activity within the alpha band (8-12 Hz) becomes slower and lower in amplitude with advanced age. However, most studies have focused on quantifying age-related differences in periodic oscillatory activity with little consideration of the influence of aperiodic activity on these measures. The aim of this study was to investigate age differences in aperiodic activity inherent in the resting EEG signal. We assessed aperiodic activity in 85 healthy younger adults (mean age: 22.2 years, SD: 3.9, age range: 18–35, 37 male) and 92 healthy older adults (mean age: 66.1 years, SD: 8.2, age range 50–86, 53 male) by fitting the 1/f-like background activity evident in EEG power spectra using the fitting oscillations & one over f (FOOOF) toolbox. Across the scalp, the aperiodic exponent and offset were smaller in older compared to younger participants, reflecting a flatter 1/f-like slope and a downward broadband shift in the power spectra with age. Before correcting for aperiodic activity, older adults showed slower peak alpha frequency and reduced peak alpha power relative to younger adults. After correcting for aperiodic activity, peak alpha frequency remained slower in older adults; however, peak alpha power no longer differed statistically between age groups. The large sample size utilized in this study, as well as the depth of analysis, provides further evidence that the aperiodic component of the resting EEG signal is altered with aging and should be considered when investigating neural oscillatory activity.
HCN1 channels mediate mu opioid receptor long-term depression at insular cortex inputs to the dorsal striatum
Authors: Munoz Braulio , Fritz Brandon M. , Yin Fuqin , Atwood Brady K.
Published: September 2021

Mu opioid receptors (MORs) are expressed in the dorsal striatum, a brain region that mediates goal-directed (via the dorsomedial striatum), and habitual (via the dorsolateral striatum, DLS) behaviors. Our previous work indicates that glutamate transmission is depressed when MORs are activated in the dorsal striatum, inducing MOR-mediated long-term synaptic depression (MOR-LTD) or short-term depression (MOR-STD), depending on the input. In the DLS, MOR-LTD is produced by MORs on anterior insular cortex (AIC) inputs and MOR-STD occurs at thalamic inputs, suggesting input-specific MOR plasticity mechanisms. Here, we evaluated the mechanisms of induction of MOR-LTD and MOR-STD in the DLS using pharmacology and optogenetics combined with patch clamp electrophysiology. We found that cAMP/PKA signaling and protein synthesis are necessary for MOR-LTD expression, similar to previous studies of cannabinoid-mediated LTD in DLS. MOR-STD does not utilize these same mechanisms. We also demonstrated that cannabinoid-LTD occurs at AIC inputs to DLS. However, while cannabinoid-LTD requires mTOR signaling in DLS, MOR-LTD does not. We characterized the role of presynaptic HCN1 channels in MOR-LTD induction as HCN1 channels expressed in AIC are necessary for MOR-LTD expression in the DLS. These results suggest a mechanism in which MOR activation requires HCN1 to induce MOR-LTD, suggesting a new target for pharmacological modulation of synaptic plasticity, providing new opportunities to develop novel drugs to treat alcohol and opioid use disorders.

Key Points

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Mu opioid receptor-mediated long-term depression at anterior insular cortex inputs to dorsolateral striatum involves presynaptic cAMP/PKA signaling and protein translation, similar to known mechanisms of cannabinoid long-term depression.

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Dorsal striatal cannabinoid long-term depression also occurs at anterior insular cortex inputs to dorsolateral striatum. Dorsal striatal cannabinoid long-term depression requires mTOR signaling, similar to hippocampal cannabinoid long-term depression, but dorsal striatal mu opioid long-term depression does not require mTOR signaling.

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Mu opioid long-term depression requires presynaptic HCN1 channels at anterior insular cortex inputs to dorsolateral striatum.
Genome-wide identification of sexual-reproduction genes in fission yeast via transposon-insertion sequencing
Authors: Billmyre R. Blake , Eickbush Michael T. , Craig Caroline J. , Lange Jeffrey J. , Wood Christopher , Helston Rachel M. , Zanders Sarah E.
Published: September 2021

Many genes required for sexual reproduction remain to be identified. Moreover, many of the genes that are known have been characterized in distinct experiments using different conditions, which complicates understanding the relative contributions of genes to sex. To address these challenges, we developed an assay inSchizosaccharomyces pombe that couples transposon mutagenesis with high-throughput sequencing (TN-seq) to quantitatively measure the fitness contribution of nonessential genes across the genome to sexual reproduction. This approach identified 532 genes that contribute to sex, including more than 200 that were not previously annotated to be involved in the process, of which more than 150 have orthologs in vertebrates. Among our verified hits was an uncharacterized gene,ifs1(importantforsex), that is required for spore viability. In two other hits,plb1andalg9, we observed a novel mutant phenotype of poor spore health wherein viable spores are produced, but the spores exhibit low fitness and are rapidly outcompeted by wildtype. Finally, we fortuitously discovered that a gene previously thought to be essential,sdg1(socialdistancinggene), is instead required for growth at low cell densities. Our assay will be valuable in further studies of sexual reproduction inS. pombeand identifies multiple candidate genes that could contribute to sexual reproduction in other eukaryotes, including humans.
Biomarkers of Cardiovascular Toxicity of Benzene Inhalation in Mice
Authors: Malovichko Marina V. , Abplanalp Wesley T. , McFall Samantha A. , Taylor Breandon S. , Wickramasinghe Nalinie S. , Sithu Israel D. , Zelko Igor N. , Uchida Shizuka , Sutaria Saurin R. , Nantz Michael H. , Bhatnagar Aruni , Conklin Daniel J. , O’Toole Timothy E. , Srivastava Sanjay
Published: September 2021

Benzene is a ubiquitous environmental pollutant. Recent population-based studies suggest that benzene exposure is associated with an increased risk for cardiovascular disease. However, it is unclear whether benzene exposure is sufficient to induce cardiovascular toxicity. We examined the effects of benzene inhalation (50 ppm, 6 h/day, 5 days/week, 6 weeks) or HEPA-filtered air exposure on the biomarkers of cardiovascular toxicity in male C57BL/6J mice. Benzene inhalation significantly increased the biomarkers of endothelial activation and injury including endothelial microparticles, activated endothelial microparticles, endothelial progenitor cell microparticles, lung endothelial microparticles, and activated lung and endothelial microparticles while having no effect on circulating levels of endothelial adhesion molecules, endothelial selectins, and biomarkers of angiogenesis. To understand how benzene may induce endothelial injury, we exposed human aortic endothelial cells to benzene metabolites. Of metabolites tested, trans,trans-mucondialdehyde (10 μM, 18h) was most toxic. It induced caspases-3, −7 and −9 (intrinsic pathway) activation, and enhanced microparticle formation by 2.4-fold. Levels of plateletleukocyte aggregates, platelet macroparticles, and proportion of CD4+ and CD8+ T-cells were also significantly elevated in the blood of the benzene-exposed mice. We also found that benzene exposure increased the transcription of genes associated with endothelial cell and platelet activation in the liver; and induced inflammatory genes and suppressed cytochrome P450s in the lungs and the liver. Together, these data suggest that benzene exposure induces endothelial injury, enhances platelet activation and inflammatory processes; and circulatory levels of endothelial cell and platelet-derived microparticles and platelet-leukocyte aggregates are excellent biomarkers of cardiovascular toxicity of benzene.

Highlights

Inhaled benzene exposure increases the levels of blood endothelial microparticles.

In vitro, benzene metabolite trans, trans-mucondialdehyde induces endothelial cell apoptosis and microparticles formation.

Inhaled benzene exposure decreases the levels of hematopoietic progenitor cells in the bone marrow.

Inhaled benzene exposure augments the circulating levels of platelet-leukocyte adducts.
Effect of Vinyl Chloride Exposure on Cardiometabolic Toxicity
Authors: Zelko Igor N. , Taylor Breandon S. , Das Trinath P. , Watson Walter H. , Sithu Israel D. , Wahlang Banrida , Malovichko Marina V. , Cave Matthew C. , Srivastava Sanjay
Published: September 2021

Vinyl chloride is an organochlorine mainly used to manufacture its polymer polyvinyl chloride, which is extensively used in the manufacturing of consumer products. Recent studies suggest that chronic low dose vinyl chloride exposure affects glucose homeostasis in high fat diet-fed mice. Our data suggest that even in the absence of high fat diet, exposure to vinyl chloride (0.8 ppm, 6h/day, 5day/week, for 12 weeks) induces glucose intolerance (1.0 g/kg, i.p) in male C57BL/6 mice. This was accompanied with the depletion of hepatic glutathione and a modest increase in lung interstitial macrophages. Vinyl chloride exposure did not affect the levels of circulating immune cells, endothelial progenitor cells, platelet-immune cell aggregates, and cytokines and chemokines. The acute challenge of vinyl chloride-exposed mice with LPS did not affect lung immune cell composition or plasma IL-6. To examine the effect of vinyl chloride exposure on vascular inflammation and atherosclerosis, LDL receptor-KO mice on C57BL/6 background maintained on western diet were exposed to vinyl chloride for 12 weeks (0.8 ppm, 6h/day, 5day/week). Unlike the WT C57BL/6 mice, vinyl chloride exposure did not affect glucose tolerance in the LDL receptor-KO mice. Plasma cytokines, lesion area in the aortic valve, and markers of lesional inflammation in vinyl chloride-exposed LDL receptor-KO mice were comparable with the air-exposed controls. Collectively, despite impaired glucose tolerance and modest pulmonary inflammation, chronic low dose vinyl chloride exposure does not affect surrogate markers of cardiovascular injury, LPS-induced acute inflammation in C57BL/6 mice, and chronic inflammation and atherosclerosis in the LDL receptor-KO mice.
Chronic Benzene Exposure Aggravates Pressure Overload-Induced Cardiac Dysfunction
Authors: Zelko Igor N. , Dassanayaka Sujith , Malovichko Marina V. , Howard Caitlin M. , Garrett Lauren F. , Shizuka Uchida , Brittian Kenneth R. , Conklin Daniel J. , Jones Steven P. , Srivastava Sanjay
Published: September 2021

Benzene is a ubiquitous environmental pollutant abundant in household products, petrochemicals and cigarette smoke. Benzene is a well-known carcinogen in humans and experimental animals; however, little is known about the cardiovascular toxicity of benzene. Recent population-based studies indicate that benzene exposure is associated with an increased risk for heart failure. Nonetheless, it is unclear whether benzene exposure is sufficient to induce and/or exacerbate heart failure. We examined the effects of benzene (50 ppm, 6 h/day, 5 days/week, 6 weeks) or HEPA-filtered air exposure on transverse aortic constriction (TAC)-induced pressure overload in male C57BL/6J mice. Our data show that benzene exposure had no effect on cardiac function in the Sham group; however, it significantly compromised cardiac function as depicted by a significant decrease in fractional shortening and ejection fraction, as compared with TAC/Air-exposed mice. RNA-seq analysis of the cardiac tissue from the TAC/benzene-exposed mice showed a significant increase in several genes associated with adhesion molecules, cell-cell adhesion, inflammation, and stress response. In particular, neutrophils were implicated in our unbiased analyses. Indeed, immunofluorescence studies showed that TAC/benzene exposure promotes infiltration of CD11b+/S100A8+/myeloperoxidase+-positive neutrophils in the hearts by 3-fold. In vitro, the benzene metabolites, hydroquinone and catechol, induced the expression of P-selectin in cardiac microvascular endothelial cells by 5-fold and increased the adhesion of neutrophils to these endothelial cells by 1.5-2.0-fold. Benzene metabolite-induced adhesion of neutrophils to the endothelial cells was attenuated by anti-P-selectin antibody. Together, these data suggest that benzene exacerbates heart failure by promoting endothelial activation and neutrophil recruitment.
Imaging erythrocyte sedimentation in whole blood
Authors: Darras Alexis , Breunig Hans Georg , John Thomas , Zhao Renping , Koch Johannes , Kummerow Carsten , König Karsten , Wagner Christian , Kaestner Lars
Published: September 2021

The erythrocyte sedimentation rate (ESR) is one of the oldest medical diagnostic tools. However, currently there is some debate on the structure formed by the cells during the sedimentation process. While the conventional view is that erythrocytes sediment as separate aggregates, others have suggested that they form a percolating gel, similar to other colloidal suspensions. A direct probing of the structures formed by erythrocytes in blood at stasis is then required to settle these discrepancies. Here, we report observations performed with three different optical imaging techniques: direct light transmission through thin samples, two-photon microscopy and light-sheet microscopy. All techniques revealed a dynamic structure of a channeling gel but with differences in the resolved details. A quantitative analysis of the erythrocyte related processes and interactions during the sedimentation need a further refinement of the experimental set-ups.