• Optimising Large Animal Models of Sustained Atrial Fibrillation: Relevance of the Critical Mass Hypothesis

      Denham, Nathan C.; email: Nathan.denham@manchester.ac.uk; Pearman, Charles M.; Madders, George W. P.; Smith, Charlotte E. R.; Trafford, Andrew W.; Dibb, Katharine M. (Frontiers Media S.A., 2021-06-15)
      Background: Large animal models play an important role in our understanding of the pathophysiology of atrial fibrillation (AF). Our aim was to determine whether prospectively collected baseline variables could predict the development of sustained AF in sheep, thereby reducing the number of animals required in future studies. Our hypothesis was that the relationship between atrial dimensions, refractory periods and conduction velocity (otherwise known as the critical mass hypothesis) could be used for the first time to predict the development of sustained AF. Methods: Healthy adult Welsh mountain sheep underwent a baseline electrophysiology study followed by implantation of a neurostimulator connected via an endocardial pacing lead to the right atrial appendage. The device was programmed to deliver intermittent 50 Hz bursts of 30 s duration over an 8-week period whilst sheep were monitored for AF. Results: Eighteen sheep completed the protocol, of which 28% developed sustained AF. Logistic regression analysis showed only fibrillation number (calculated using the critical mass hypothesis as the left atrial diameter divided by the product of atrial conduction velocity and effective refractory period) was associated with an increased likelihood of developing sustained AF (Ln Odds Ratio 26.1 [95% confidence intervals 0.2–52.0] p = 0.048). A receiver-operator characteristic curve showed this could be used to predict which sheep developed sustained AF (C-statistic 0.82 [95% confidence intervals 0.59–1.04] p = 0.04). Conclusion: The critical mass hypothesis can be used to predict sustained AF in a tachypaced ovine model. These findings can be used to optimise the design of future studies involving large animals.
    • Plant-Morphing Strategies and Plant-Inspired Soft Actuators Fabricated by Biomimetic Four-Dimensional Printing: A Review

      Ren, Luquan; Li, Bingqian; Wang, Kunyang; Zhou, Xueli; Song, Zhengyi; Ren, Lei; email: lei.ren@manchester.ac.uk; Liu, Qingping; email: liuqp@jlu.edu.cn (Frontiers Media S.A., 2021-05-04)
      For prey, seeding, and protection, plants exhibit ingenious adaptive motions that respond autonomously to environmental stimuli by varying cellular organization, anisotropic orientation of cellulose fibers, mechanical instability design, etc. Notably, plants do not leverage muscle and nerves to produce and regulate their motions. In contrast, they harvest energy from the ambient environment and compute through embodied intelligence. These characteristics make them ideal candidates for application in self-morphing devices. Four-dimensional (4D) printing is a bottom-up additive manufacturing method that builds objects with the ability to change shape/properties in a predetermined manner. A versatile motion design catalog is required to predict the morphing processes and final states of the printed parts. This review summarizes the morphing and actuation mechanisms of plants and concludes with the recent development of 4D-printed smart materials inspired by the locomotion and structures of plant systems. We provide analyses of the challenges and our visions of biomimetic 4D printing, hoping to boost its application in soft robotics, smart medical devices, smart parts in aerospace, etc.
    • Quantifying Cooperation Benefits for New Dams in Transboundary Water Systems Without Formal Operating Rules

      Gonzalez, Jose M.; Matrosov, Evgenii S.; Obuobie, Emmanuel; Mul, Marloes; Pettinotti, Laetitia; Gebrechorkos, Solomon H.; Sheffield, Justin; Bottacin-Busolin, Andrea; Dalton, James; Smith, D. Mark; et al. (Frontiers Media S.A., 2021-05-07)
      New dams impact downstream ecosystems and water infrastructure; without cooperative and adaptive management, negative impacts can manifest. In large complex transboundary river basins without well codified operating rules and extensive historical data, it can be difficult to assess the benefits of cooperating, in particular in relation to new dams. This constitutes a barrier to harmonious development of river basins and could contribute to water conflict. This study proposes a generalised framework to assess the benefits of cooperation on the management of new dams in water resource systems that do not have formal sharing arrangements. Benefits are estimated via multi-criteria comparison of historical reservoir operations (usually relatively uncooperative) vs. adopting new cooperative rules which would achieve the best results for riparian countries as evaluated by a water resources simulator and its performance metrics. The approach is applied to the Pwalugu Multipurpose Dam (PMD), which is being built in Ghana in the Volta river basin. The PMD could impact downstream ecosystems and infrastructure in Ghana and could itself be impacted by how the existing upstream Bagre Dam is managed in Burkina Faso. Results show that with cooperation Ghana and Burkina Faso could both increase energy production although some ecosystem services loss would need to be mitigated. The study confirms that cooperative rules achieve higher overall benefits compared to seeking benefits only for individual dams or countries.
    • Sleep Disruption and Depression, Stress and Anxiety Levels in Women With Polycystic Ovary Syndrome (PCOS) During the Lockdown Measures for COVID-19 in the UK

      Kite, Chris; Atkinson, Lou; McGregor, Gordon; Clark, Cain C. T.; Brown, James E.; Kyrou, Ioannis; email: kyrouj@gmail.com; Randeva, Harpal S.; email: harpal.randeva@warwick.ac.uk (Frontiers Media S.A., 2021-06-04)
      Background: Lockdown measures have been enforced globally in response to the COVID-19 pandemic. Given the comorbidity burden in women with polycystic ovary syndrome (PCOS), these lockdown measures may have a particularly negative impact on sleep health, quality of life (QoL), and depression/stress levels in this population. The aim of this study was to explore whether such potential problems were present in women with PCOS during the COVID-19 lockdown in the UK. Methods: UK women with PCOS were recruited through social media into a cross-sectional study during the COVID-19 lockdown. The study survey was delivered online, and included demographic and COVID-19 relevant questions, as well as validated questionnaires/scales, namely the Insomnia Severity Index (ISI), Depression Anxiety and Stress Scale (DASS-21), and PCOSQOL questionnaire. Results: Three hundred and thirty-three women with PCOS [median age: 30.0 (9.0) years] were recruited. Participants were dichotomized based on responses regarding the impact of COVID-19 restrictions on their sleep [negative (N = 242) vs. no/positive (N = 91) impact]. No differences were noted between groups regarding age, time since PCOS diagnosis, body mass index, or number of comorbidities. Based on the ISI, 44.2% of participants reporting a negative impact on sleep exhibited at least moderately severe clinical insomnia. Compared to those who reported no/positive effect on sleep, the participants reporting a negative impact on sleep also reported poorer QoL, based on the total PCOSQOL score, with a greater impact of PCOS and poorer mood in the corresponding PCOSQOL domains. Based on the DASS-21, the latter also had statistically higher depression and stress levels compared to the former. Finally, for this cohort significant inverse correlations were noted between the ISI and PCOSQOL scores (total and domain scores), whilst the DASS-21 and ISI scores were positively correlated (all p-values <0.001). Conclusion: The majority of recruited UK women with PCOS reported that the COVID-19 lockdown had a negative impact on their sleep, which was also associated with impaired QoL and higher depression/stress levels. Whilst further research is required, women with PCOS should be considered a vulnerable population that may experience an adverse impact on sleep, QoL and mental health well-being due to lockdown measures during the COVID-19 pandemic.
    • Speed-Related Energy Flow and Joint Function Change During Human Walking

      Hu, Zheqi; Ren, Lei; email: lei.ren@manchester.ac.uk; Hu, Dan; Gao, Yilei; Wei, Guowu; Qian, Zhihui; Wang, Kunyang; email: kywang@jlu.edu.cn (Frontiers Media S.A., 2021-05-31)
      During human walking, mechanical energy transfers between segments via joints. Joint mechanics of the human body are coordinated with each other to adapt to speed change. The aim of this study is to analyze the functional behaviors of major joints during walking, and how joints and segments alter walking speed during different periods (collision, rebound, preload, and push-off) of stance phase. In this study, gait experiment was performed with three different self-selected speeds. Mechanical works of joints and segments were determined with collected data. Joint function indices were calculated based on net joint work. The results show that the primary functional behaviors of joints would not change with altering walking speed, but the function indices might be changed slightly (e.g., strut functions decrease with increasing walking speed). Waist acts as strut during stance phase and contributes to keep stability during collision when walking faster. Knee of stance leg does not contribute to altering walking speed. Hip and ankle absorb more mechanical energy to buffer the strike during collision with increasing walking speed. What is more, hip and ankle generate more energy during push-off with greater motion to push distal segments forward with increasing walking speed. Ankle also produces more mechanical energy during push-off to compensate the increased heel-strike collision of contralateral leg during faster walking. Thus, human may utilize the cooperation of hip and ankle during collision and push-off to alter walking speed. These findings indicate that speed change in walking leads to fundamental changes to joint mechanics.
    • The Drosophila Larval Locomotor Circuit Provides a Model to Understand Neural Circuit Development and Function

      Hunter, Iain; email: Iain.hunter-2@manchester.ac.uk; Coulson, Bramwell; Zarin, Aref Arzan; Baines, Richard A. (Frontiers Media S.A., 2021-07-01)
      It is difficult to answer important questions in neuroscience, such as: “how do neural circuits generate behaviour?,” because research is limited by the complexity and inaccessibility of the mammalian nervous system. Invertebrate model organisms offer simpler networks that are easier to manipulate. As a result, much of what we know about the development of neural circuits is derived from work in crustaceans, nematode worms and arguably most of all, the fruit fly, Drosophila melanogaster. This review aims to demonstrate the utility of the Drosophila larval locomotor network as a model circuit, to those who do not usually use the fly in their work. This utility is explored first by discussion of the relatively complete connectome associated with one identified interneuron of the locomotor circuit, A27h, and relating it to similar circuits in mammals. Next, it is developed by examining its application to study two important areas of neuroscience research: critical periods of development and interindividual variability in neural circuits. In summary, this article highlights the potential to use the larval locomotor network as a “generic” model circuit, to provide insight into mammalian circuit development and function.
    • The Functional Role of Hyperpolarization Activated Current ( I f ) on Cardiac Pacemaking in Human vs. in the Rabbit Sinoatrial Node: A Simulation and Theoretical Study

      Bai, Xiangyun; Wang, Kuanquan; Boyett, Mark R.; Hancox, Jules C.; Zhang, Henggui; email: henggui.zhang@manchester.ac.uk (Frontiers Media S.A., 2021-08-19)
      The cardiac hyperpolarization-activated “funny” current (If), which contributes to sinoatrial node (SAN) pacemaking, has a more negative half-maximal activation voltage and smaller fully-activated macroscopic conductance in human than in rabbit SAN cells. The consequences of these differences for the relative roles of If in the two species, and for their responses to the specific bradycardic agent ivabradine at clinical doses have not been systematically explored. This study aims to address these issues, through incorporating rabbit and human If formulations developed by Fabbri et al. into the Severi et al. model of rabbit SAN cells. A theory was developed to correlate the effect of If reduction with the total inward depolarising current (Itotal) during diastolic depolarization. Replacing the rabbit If formulation with the human one increased the pacemaking cycle length (CL) from 355 to 1,139 ms. With up to 20% If reduction (a level close to the inhibition of If by ivabradine at clinical concentrations), a modest increase (~5%) in the pacemaking CL was observed with the rabbit If formulation; however, the effect was doubled (~12.4%) for the human If formulation, even though the latter has smaller If density. When the action of acetylcholine (ACh, 0.1 nM) was considered, a 20% If reduction markedly increased the pacemaking CL by 37.5% (~27.3% reduction in the pacing rate), which is similar to the ivabradine effect at clinical concentrations. Theoretical analysis showed that the resultant increase of the pacemaking CL is inversely proportional to the magnitude of Itotal during diastolic depolarization phase: a smaller If in the model resulted in a smaller Itotal amplitude, resulting in a slower pacemaking rate; and the same reduction in If resulted in a more significant change of CL in the cell model with a smaller Itotal. This explained the mechanism by which a low dose of ivabradine slows pacemaking rate more in humans than in the rabbit. Similar results were seen in the Fabbri et al. model of human SAN cells, suggesting our observations are model-independent. Collectively, the results of study explain why low dose ivabradine at clinically relevant concentrations acts as an effective bradycardic agent in modulating human SAN pacemaking.
    • The Long-Term Effects of Developmental Hypoxia on Cardiac Mitochondrial Function in Snapping Turtles

      Galli, Gina L. J.; email: gina.galli@manchester.ac.uk; Ruhr, Ilan M.; Crossley, Janna; Crossley, Dane A., II (Frontiers Media S.A., 2021-06-28)
      It is well established that adult vertebrates acclimatizing to hypoxic environments undergo mitochondrial remodeling to enhance oxygen delivery, maintain ATP, and limit oxidative stress. However, many vertebrates also encounter oxygen deprivation during embryonic development. The effects of developmental hypoxia on mitochondrial function are likely to be more profound, because environmental stress during early life can permanently alter cellular physiology and morphology. To this end, we investigated the long-term effects of developmental hypoxia on mitochondrial function in a species that regularly encounters hypoxia during development—the common snapping turtle (Chelydra serpentina). Turtle eggs were incubated in 21% or 10% oxygen from 20% of embryonic development until hatching, and both cohorts were subsequently reared in 21% oxygen for 8 months. Ventricular mitochondria were isolated, and mitochondrial respiration and reactive oxygen species (ROS) production were measured with a microrespirometer. Compared to normoxic controls, juvenile turtles from hypoxic incubations had lower Leak respiration, higher P:O ratios, and reduced rates of ROS production. Interestingly, these same attributes occur in adult vertebrates that acclimatize to hypoxia. We speculate that these adjustments might improve mitochondrial hypoxia tolerance, which would be beneficial for turtles during breath-hold diving and overwintering in anoxic environments.
    • The Role of the European Society of Human Genetics in Delivering Genomic Education

      Tobias, Edward S.; Avram, Elena; Calapod, Patricia; Cordier, Christophe; den Dunnen, Johan T.; Ding, Can; Dolzan, Vita; Houge, Sofia Douzgou; Lynch, Sally Ann; O’Byrne, James; et al. (Frontiers Media S.A., 2021-09-03)
      The European Society of Human Genetics (ESHG) was founded in 1967 as a professional organisation for members working in genetics in clinical practice, research and education. The Society seeks the integration of scientific research and its implementation into clinical practice and the education of specialists and the public in all areas of medical and human genetics. The Society works to do this through many approaches, including educational sessions at the annual conference; training courses in general and specialist areas of genetics; an online resource of educational materials (EuroGEMS); and a mentorship scheme. The ESHG Education Committee is implementing new approaches to expand the reach of its educational activities and portfolio. With changes in technology, appreciation of the utility of genomics in healthcare and the public’s and patients’ increased awareness of the role of genomics, this review will summarise how the ESHG is adapting to deliver innovative educational activity.
    • Thermodynamic Origin of Differential Excipient-Lysozyme Interactions

      Kalayan, Jas; email: jas.kalayan@manchester.ac.uk; Curtis, Robin A.; Warwicker, Jim; Henchman, Richard H. (Frontiers Media S.A., 2021-06-11)
      Understanding the intricate interplay of interactions between proteins, excipients, ions and water is important to achieve the effective purification and stable formulation of protein therapeutics. The free energy of lysozyme interacting with two kinds of polyanionic excipients, citrate and tripolyphosphate, together with sodium chloride and TRIS-buffer, are analysed in multiple-walker metadynamics simulations to understand why tripolyphosphate causes lysozyme to precipitate but citrate does not. The resulting multiscale decomposition of energy and entropy components for water, sodium chloride, excipients and lysozyme reveals that lysozyme is more stabilised by the interaction of tripolyphosphate with basic residues. This is accompanied by more sodium ions being released into solution from tripolyphosphate than for citrate, whilst the latter instead has more water molecules released into solution. Even though lysozyme aggregation is not directly probed in this study, these different mechanisms are suspected to drive the cross-linking between lysozyme molecules with vacant basic residues, ultimately leading to precipitation.
    • Toward ‘Vaccine Internationalism’: The Need for an Equitable and Coordinated Global Vaccination Approach to Effectively Combat COVID-19

      Wong, Brian L. H.; email: b.wong@ucl.ac.uk; Green, Manfred S.; reid, John; Martin-Moreno, Jose M.; Davidovitch, Nadav; Chambaud, Laurent; Leighton, Lore; Sheek-Hussein, Mohamud; Dhonkal, Ranjeet; Otok, Robert; et al. (Frontiers Media S.A., 2021-04-14)
    • Toward ‘Vaccine Internationalism’: The Need for an Equitable and Coordinated Global Vaccination Approach to Effectively Combat COVID-19

      Wong, Brian L. H.; email: b.wong@ucl.ac.uk; Green, Manfred S.; Reid, John; Martin-Moreno, Jose M.; Davidovitch, Nadav; Chambaud, Laurent; Leighton, Lore; Sheek-Hussein, Mohamud; Dhonkal, Ranjeet; Otok, Robert; et al. (Frontiers Media S.A., 2021-04-14)
    • Towards a Bio-Inspired Real-Time Neuromorphic Cerebellum

      Bogdan, Petruţ A.; email: petrut.bogdan@manchester.ac.uk; Marcinnò, Beatrice; Casellato, Claudia; Casali, Stefano; Rowley, Andrew G.D.; Hopkins, Michael; Leporati, Francesco; D'Angelo, Egidio; Rhodes, Oliver (Frontiers Media S.A., 2021-05-31)
      This work presents the first simulation of a large-scale, bio-physically constrained cerebellum model performed on neuromorphic hardware. A model containing 97,000 neurons and 4.2 million synapses is simulated on the SpiNNaker neuromorphic system. Results are validated against a baseline simulation of the same model executed with NEST, a popular spiking neural network simulator using generic computational resources and double precision floating point arithmetic. Individual cell and network-level spiking activity is validated in terms of average spike rates, relative lead or lag of spike times, and membrane potential dynamics of individual neurons, and SpiNNaker is shown to produce results in agreement with NEST. Once validated, the model is used to investigate how to accelerate the simulation speed of the network on the SpiNNaker system, with the future goal of creating a real-time neuromorphic cerebellum. Through detailed communication profiling, peak network activity is identified as one of the main challenges for simulation speed-up. Propagation of spiking activity through the network is measured, and will inform the future development of accelerated execution strategies for cerebellum models on neuromorphic hardware. The large ratio of granule cells to other cell types in the model results in high levels of activity converging onto few cells, with those cells having relatively larger time costs associated with the processing of communication. Organizing cells on SpiNNaker in accordance with their spatial position is shown to reduce the peak communication load by 41%. It is hoped that these insights, together with alternative parallelization strategies, will pave the way for real-time execution of large-scale, bio-physically constrained cerebellum models on SpiNNaker. This in turn will enable exploration of cerebellum-inspired controllers for neurorobotic applications, and execution of extended duration simulations over timescales that would currently be prohibitive using conventional computational platforms.
    • Views of Practitioners and Researchers on the Use of Virtual Reality in Treatments for Substance Use Disorders

      Skeva, Rigina; email: rigina.skeva@manchester.ac.uk; Gregg, Lynsey; Jay, Caroline; Pettifer, Steve (Frontiers Media S.A., 2021-05-21)
      Virtual Reality Therapy (VRT) has been shown to be effective in treating anxiety disorders and phobias, but has not yet been widely tested for Substance Use Disorders (SUDs) and it is not known whether health care practitioners working with SUDs would use VRT if it were available. We report the results of an interview study exploring practitioners’ and researchers’ views on the utility of VRT for SUD treatment. Practitioners and researchers with at least two years’ experience delivering or researching and designing SUD treatments were recruited (n = 14). Interviews were thematically analyzed, resulting in themes relating to the safety and realism of VRT, and the opportunity for the additional insight it could offer to during SUD treatment. Participants were positive about employing VRT as an additional treatment for SUD. VRT was thought suitable for treating adults and people with mental health issues or trauma, provided that risks were appropriately managed. Subsequent relapse, trauma and over-confidence in the success of treatment were identified as risks. The opportunity VRT offered to include other actors in therapy (via avatar use), and observe reactions, were benefits that could not currently be achieved with other forms of therapy. Overall, VRT was thought to offer the potential for safe, realistic, personalized and insightful exposure to diverse triggering scenarios, and to be acceptable for integration into a wide range of SUD treatments.
    • Visual Sensory Experiences From the Viewpoint of Autistic Adults

      Parmar, Ketan R.; email: ketan.parmar@manchester.ac.uk; Porter, Catherine S.; Dickinson, Christine M.; Pelham, James; Baimbridge, Peter; Gowen, Emma (Frontiers Media S.A., 2021-06-08)
      Although previous research has investigated altered sensory reactivity in autistic individuals, there has been no specific focus on visual sensory experiences, particularly in adults. Using qualitative methods, this study aimed to characterize autistic visual sensory symptoms, contextualize their impact and document any associated coping strategies. A total of 18 autistic adults took part in four focus groups which involved questions around visual experiences, the impact of these on daily life, and strategies for their reduction. Transcripts of each session were thematically analyzed allocating six key themes. Participants described a range of visual hypersensitivities, including to light, motion, patterns and particular colors, which contributed to distraction and were frequently part of a wider multisensory issue. Such experiences had significant negative impacts on personal wellbeing and daily life with participants describing fatigue, stress and hindrances on day-to-day activities (e.g., travel and social activities). However, the degree of understanding that participants had about their visual experiences influenced their emotional response, with greater understanding reducing concern. Participants employed a variety of coping strategies to overcome visual sensory experiences but with varied success. Discussions also highlighted that there may be a poor public understanding of sensory issues in autism affecting how well autistic individuals are able manage their sensory symptoms. In summary, autistic adults expressed significant concern about their visual experiences and there is a need to improve understanding of visual experiences on a personal and public level as well as for developing potential support.
    • Volatile Liquid Detection by Terahertz Technologies

      Baxter, Harry W; Worrall, Adam A; Pang, Jie; Chen, Riqing; email: riqing.chen@fafu.edu.cn; Yang, Bin; email: b.yang@chester.ac.uk (Frontiers Media S.A., 2021-04-08)
      The prospect of being able to move through security without the inconvenience of separating liquids from bags is an exciting one for passengers, and there are important operational benefits for airports as well. Here, two terahertz (THz) systems, 100 GHz sub-THz line scanner and attenuation total reflection-based THz time domain spectroscopy (TDS), have been used to demonstrate the capability of identifying different liquid samples. Liquid samples’ THz complex permittivities are measured and their differences have contributed to the variation of 100 GHz 2D images of volatile liquids with different volumes inside of cannister bottles. The acquired attenuation images at 100 GHz can easily be used to distinguish highly absorbed liquids (Water, Ethanol, Fuel Treatment Chemicals) and low loss liquids (Petrol, Diesel, Kerosene and Universal Bottle Cleaner). The results give a promising feasibility for mm-wave imager and THz spectroscopy to efficiently identify different volatile liquids.