• A Cross-Sectional Study Investigating the Relationship Between Alexithymia and Suicide, Violence, and Dual Harm in Male Prisoners

      Hemming, Laura; Shaw, Jennifer; Haddock, Gillian; Carter, Lesley-Anne; Pratt, Daniel; email: daniel.pratt@manchester.ac.uk (Frontiers Media S.A., 2021-04-29)
      Background: Suicide and violence are common within male prisoners. One suggested risk factor for both behaviors is alexithymia. Alexithymia describes a deficit in identifying and describing feelings and is also related to externally oriented thinking. This study aimed to explore the relationship between alexithymia, suicide, violence and dual harm in male prisoners. Methods: Eighty male prisoners were recruited from three prisons. Participants were asked to complete a battery of questionnaires including measures of alexithymia (TAS-20), suicide ideation (ASIQ), suicide behavior, violence ideation (SIV), violence behavior, depression (BDI-II), hopelessness (BHS), impulsivity (DII) and anger (NAS-PI). Regression analyses and ANOVAS were conducted to assess the association between alexithymia (and its subcomponents) with six outcomes; suicide ideation, suicide behavior, violence ideation, violence behavior, dual harm ideation and dual harm behavior. Results: Alexithymia was a univariate predictor of suicide ideation, though was not a significant predictor when considered in a multivariate model. Alexithymia was a significant multivariate predictor of suicide behavior. Alexithymia was not a significant multivariate predictor of violence ideation or behavior. There were no significant differences in alexithymia or subscales between those with suicide ideation/behavior alone, violence ideation/behavior alone and those with dual harm ideation/behavior. Conclusion: In male prisoners, alexithymia appears an important univariate predictor of suicide and violence, though the current study suggests no significant contribution above other well-known correlates of suicide and violence.
    • A Subtle Profile With a Significant Impact: Language and Communication Difficulties for Autistic Females Without Intellectual Disability

      Sturrock, Alexandra; email: Alexandra.sturrock@manchester.ac.uk; Adams, Catherine; Freed, Jenny (Frontiers Media S.A., 2021-08-09)
      The presentation of autism in females is poorly understood, which is thought to contribute to missed or later- age diagnosis, especially for those without intellectual disability. Dedicated research into social and behavioral differences has indicated a specific female phenotype of autism. However, less has been done to explore language and communication profiles, despite known sex/gender differences in typically developing populations. This article provides a synthesis of recent work from this small but emerging field. It focuses on a series of four preliminary and explorative studies conducted by the authors and embeds this within the wider literature. Findings suggest a specific profile of language and communication strengths and weaknesses for autistic females without intellectual disability (compared to autistic males and typically developing females). Furthermore, despite the relatively subtle presentation of difficulties (compared to autistic males), the impact on functionality, social inter-relations and emotional well-being, appears to be equitable and significant. The discussion highlights the need for further empirical research and proposes areas for investigation. Implications for clinical practice include the need for better recognition, testing and provision of interventions dedicated to the language and communication difficulties for autistic females. This has relevance for diagnostic, mental health and speech and language therapy services.
    • A Systematic Review of Glucose Transport Alterations in Alzheimer's Disease

      Kyrtata, Natalia; Emsley, Hedley C. A.; Sparasci, Oli; Parkes, Laura M.; Dickie, Ben R.; email: ben.dickie@manchester.ac.uk (Frontiers Media S.A., 2021-05-20)
      Introduction: Alzheimer's disease (AD) is characterized by cerebral glucose hypometabolism. Hypometabolism may be partly due to reduced glucose transport at the blood-brain barrier (BBB) and across astrocytic and neuronal cell membranes. Glucose transporters (GLUTs) are integral membrane proteins responsible for moving glucose from the bloodstream to parenchymal cells where it is metabolized, and evidence indicates vascular and non-vascular GLUTs are altered in AD brains, a process which could starve the brain of glucose and accelerate cognitive decline. Here we review the literature on glucose transport alterations in AD from human and rodent studies. Methods: Literature published between 1st January 1946 and 1st November 2020 within EMBASE and MEDLINE databases was searched for the terms “glucose transporters” AND “Alzheimer's disease”. Human and rodent studies were included while reviews, letters, and in-vitro studies were excluded. Results: Forty-three studies fitting the inclusion criteria were identified, covering human (23 studies) and rodent (20 studies). Post-mortem studies showed consistent reductions in GLUT1 and GLUT3 in the hippocampus and cortex of AD brains, areas of the brain closely associated with AD pathology. Tracer studies in rodent models of AD and human AD also exhibit reduced uptake of glucose and glucose-analogs into the brain, supporting these findings. Longitudinal rodent studies clearly indicate that changes in GLUT1 and GLUT3 only occur after amyloid-β pathology is present, and several studies indicate amyloid-β itself may be responsible for GLUT changes. Furthermore, evidence from human and rodent studies suggest GLUT depletion has severe effects on brain function. A small number of studies show GLUT2 and GLUT12 are increased in AD. Anti-diabetic medications improved glucose transport capacity in AD subjects. Conclusions: GLUT1 and GLUT3 are reduced in hippocampal and cortical regions in patients and rodent models of AD, and may be caused by high levels of amyloid-β in these regions. GLUT3 reductions appear to precede the onset of clinical symptoms. GLUT2 and GLUT12 appear to increase and may have a compensatory role. Repurposing anti-diabetic drugs to modify glucose transport shows promising results in human studies of AD.
    • Adolescents' Understanding of What Causes Emotional Distress: A Qualitative Exploration in a Non-clinical Sample Using Ideal-Type Analysis

      O'Neill, Alisha; email: alisha.oneill@Manchester.ac.uk; Stapley, Emily; Stock, Sarah; Merrick, Hannah; Humphrey, Neil (Frontiers Media S.A., 2021-05-24)
      Background: There is increased interest in early intervention and prevention of mental health difficulties during adolescence; thus, we are seeing increased efforts to optimize well-being during this epoch. Positive emotional experiences are a central component of overall well-being. However, research exploring what adolescents perceive to be the cause(s) of their emotional difficulties is lacking. Improving understanding of this issue within non-clinical adolescent groups may provide useful insight into how to develop strategies to support young people as they navigate emotional difficulties. Objectives: The aim of this research was to explore if meaningful categories of perceived cause(s) for emotional distress exist for non-clinical adolescent groups. Methods: The data for this study were drawn from interviews across 6 sites in England conducted as part of the 5-year national evaluation of the HeadStart Learning Programme. The sample comprised of 32 young people aged 11–12 years from the first annual wave of qualitative data collection in 2017. Ideal type analysis—a qualitative form of person-centered analysis—was used to construct a typology of adolescents perceived cause(s) for emotional distress. Findings: We identified five distinct categories of perceived cause: (1) perceived lack of control; (2) unfair treatment; (3) others, their actions and judgements as the catalyst; (4) concerns for self and others; and, (5) self as cause. Conclusions: Our findings illustrate that distinct categories for perceived cause of emotional distress exist among adolescents considered to be “at risk” of developing mental health difficulties, which provides a foundation for future necessary work seeking to investigate the possible link between perceived cause for emotional distress and help-seeking behavior among sub-clinical groups.
    • Autosomal Recessive Cutis Laxa 1C Mutations Disrupt the Structure and Interactions of Latent TGFβ Binding Protein-4

      Alanazi, Yasmene F.; Lockhart-Cairns, Michael P.; Cain, Stuart A.; Jowitt, Thomas A.; Weiss, Anthony S.; Baldock, Clair; email: clair.baldock@manchester.ac.uk (Frontiers Media S.A., 2021-09-03)
      Latent TGFβ binding protein-4 (LTBP4) is a multi-domain glycoprotein, essential for regulating the extracellular bioavailability of TGFβ and assembly of elastic fibre proteins, fibrillin-1 and tropoelastin. LTBP4 mutations are linked to autosomal recessive cutis laxa type 1C (ARCL1C), a rare congenital disease characterised by high mortality and severely disrupted connective tissues. Despite the importance of LTBP4, the structure and molecular consequences of disease mutations are unknown. Therefore, we analysed the structural and functional consequences of three ARCL1C causing point mutations which effect highly conserved cysteine residues. Our structural and biophysical data show that the LTBP4 N- and C-terminal regions are monomeric in solution and adopt extended conformations with the mutations resulting in subtle changes to their conformation. Similar to LTBP1, the N-terminal region is relatively inflexible, whereas the C-terminal region is flexible. Interaction studies show that one C-terminal mutation slightly decreases binding to fibrillin-1. We also found that the LTBP4 C-terminal region directly interacts with tropoelastin which is perturbed by both C-terminal ARCL1C mutations, whereas an N-terminal mutation increased binding to fibulin-4 but did not affect the interaction with heparan sulphate. Our results suggest that LTBP4 mutations contribute to ARCL1C by disrupting the structure and interactions of LTBP4 which are essential for elastogenesis in a range of mammalian connective tissues.
    • Continuous Magnitude Production of Loudness

      Schlittenlacher, Josef; email: josef.schlittenlacher@manchester.ac.uk; Ellermeier, Wolfgang (Frontiers Media S.A., 2021-05-11)
      Continuous magnitude estimation and continuous cross-modality matching with line length can efficiently track the momentary loudness of time-varying sounds in behavioural experiments. These methods are known to be prone to systematic biases but may be checked for consistency using their counterpart, magnitude production. Thus, in Experiment 1, we performed such an evaluation for time-varying sounds. Twenty participants produced continuous cross-modality matches to assess the momentary loudness of fourteen songs by continuously adjusting the length of a line. In Experiment 2, the resulting temporal line length profile for each excerpt was played back like a video together with the given song and participants were asked to continuously adjust the volume to match the momentary line length. The recorded temporal line length profile, however, was manipulated for segments with durations between 7 to 12 s by eight factors between 0.5 and 2, corresponding to expected differences in adjusted level of −10, −6, −3, −1, 1, 3, 6, and 10 dB according to Stevens’s power law for loudness. The average adjustments 5 s after the onset of the change were −3.3, −2.4, −1.0, −0.2, 0.2, 1.4, 2.4, and 4.4 dB. Smaller adjustments than predicted by the power law are in line with magnitude-production results by Stevens and co-workers due to “regression effects.” Continuous cross-modality matches of line length turned out to be consistent with current loudness models, and by passing the consistency check with cross-modal productions, demonstrate that the method is suited to track the momentary loudness of time-varying sounds.
    • Dance at Home for People With Parkinson's During COVID-19 and Beyond: Participation, Perceptions, and Prospects

      Bek, Judith; email: judith.bek@manchester.ac.uk; Groves, Michelle; Leventhal, David; Poliakoff, Ellen (Frontiers Media S.A., 2021-05-31)
      Emerging evidence shows that dance can provide both physical and non-physical benefits for people living with Parkinson's disease (PD). The suspension of in-person dance classes during the COVID-19 pandemic necessitated a transition to remote provision via live and recorded digital media. An online survey explored accessibility of and engagement with home-based dance programs, as well as potential benefits and processes involved in participation. The survey was co-developed by researchers and dance program providers, with input from people with PD and physiotherapists. Responses were collected from 276 individuals, including 178 current users of home-based programs, the majority of whom were participating at least once per week. Among respondents not currently using digital resources, lack of knowledge and motivation were the primary barriers. Most participants (94.9%) reported that home based practise provided some benefits, including physical (e.g., balance, posture) and non-physical (e.g., mood, confidence) improvements. Participants valued the convenience and flexibility of digital participation, but noted limitations including reductions in social interaction, support from instructors and peers, and motivation. There was a strong preference (70.8%) for continuing with home-based practise alongside in-person classes in the future. The results indicate that at-home dance is accessible and usable for people with PD, and that some of the previously-reported benefits of dance may be replicated in this context. Digital dance programs will likely remain a key element of future provision for people with PD, and the present findings will inform further development of resources and research into mechanisms and outcomes of home-based dance participation.
    • Differences in Characteristics and Ambulance Pathway Adherence Between Strokes and Mimics Presenting to a Large UK Centralized Hyper Acute Stroke Unit (HASU)

      Sammut-Powell, Camilla; email: Camilla.sammut-powell@manchester.ac.uk; Ashton, Christopher; Paroutoglou, Kyriaki; Parry-Jones, Adrian (Frontiers Media S.A., 2021-05-10)
      Background: In Greater Manchester (GM), prehospital clinicians use the Face Arm Speech Test (FAST) to identify suspected stroke patients alongside pathway exclusions. Within the centralized stroke service, patients with a suspected stroke are taken directly to a Hyper Acute Stroke Unit (HASU), often bypassing their local emergency department (ED). However, many of these patients are experiencing an illness that looks like a stroke but is not a stroke. The data collected in the prehospital setting is rarely used in research yet could give valuable insights into the performance of the pathway. Aim: To evaluate the presenting symptoms and final diagnoses of prehospital suspected strokes and to evaluate the adherence of prehospital stroke pathway exclusions. Methods: We analyzed data from all patients brought in by ambulance and admitted on the stroke pathway between 01/09/15 and 28/02/17. Patient demographics and all data recorded in the prehospital setting were evaluated to identify differences in stroke, TIA, and mimic patients. Pathway adherence was assessed according to whether the patient was local or out-of-area (OOA) and bypassed their local ED. Results: A total of 4,216 suspected strokes were identified: 2,213 (52.5%) had a final diagnosis of stroke, 492 (11.7%) experienced a transient ischemic attack (TIA), and 1,511 (35.8%) were stroke mimics. There were 714 (16.9%) patients that were identified as having at least one pathway exclusion or were FAST negative, of which 270 (37.8%) experienced a stroke. The proportion of strokes was significantly lower in those with a pathway exclusion (41.8 vs. 53.5%; p < 0.001) and the proportion of breaches tended to be comparable or higher in the local population. Discussion: There are high volumes of stroke mimics but identified differences indicate there is an opportunity to better utilize prehospital data. Ambulance clinicians were able to correctly overrule FAST negative results and the volume of these suggest that FAST alone may be too restrictive.
    • Editorial: Cooperation and Coordination in the Family

      Savage, James L.; email: james.savage@cantab.net; Hinde, Camilla A.; Johnstone, Rufus A. (Frontiers Media S.A., 2020-12-07)
    • Equivalence, Justice, Injustice – Health and Social Care Decision Making in Relation to Prison Populations

      Shepherd, Andrew; email: andrew.shepherd-2@manchester.ac.uk; Hewson, Tom; Hard, Jake; Green, Russell; Shaw, Jennifer (Frontiers Media S.A., 2021-07-14)
      Prisons represent sites of singular healthcare need–characterized by high levels of distress and disorder. In many jurisdictions, practitioners are ethically charged with delivering healthcare that is “equivalent” to that available in the wider community. This claim has been much debated–yet the emergence of a global coronavirus pandemic has highlighted the arguments in a particularly stark manner. In the following conceptual analysis, we explore the emergent discourse of the coronavirus and consider its particular significance for prison healthcare decision making and the concept of equivalence. For example, both the coronavirus pandemic and practice of prison incarceration induce a sense of varied temporality: The discourse of prison is replete in this area–such as the concept of “hard time.” Alongside this, the discourse in relation to coronavirus has highlighted two competing modes of temporal understanding: The political–where the pandemic is conceptualized as has having a discrete “beginning and end”, and the scientific–where the “new normal” reflects the incorporation of the “novel” coronavirus into the wider ecology. The impact of these disparate understandings on the prison population is complex: “Locking down” prisoners–to safeguard the vulnerable against infection–is relatively simple, yet it has traumatic repercussions with respect to liberty and psychosocial health. Easing lockdown, by contrast, is a difficult endeavor and risks collision between the temporalities of prison–where “hard time” is accentuated by separation from the “real world”–the political and the scientific. Whither then the concept of equivalence in relation to a field that is definitively non-equivalent? How can practitioners and policy makers maintain a just ethical stance in relation to the allocation of resources when it comes to a politically marginalized yet manifestly vulnerable population? We argue that further debate and consideration are required in this field–and propose a framework for such discussion.
    • Extrinsic and Existential Mortality Risk in Reproductive Decision-Making: Examining the Effects of COVID-19 Experience and Climate Change Beliefs

      Gordon, David S.; email: david.gordon@chester.ac.uk (Frontiers Media S.A., 2021-06-11)
      While the COVID-19 pandemic has presented an immediate risk to human life around the world, climate change poses an arguably greater—although less immediate—threat to our species’ survival. Within the framework of life-history theory (LHT), this pre-registered study investigated whether extrinsic risk (i.e., external factors that pose a risk to an individual’s life, e.g., COVID-19) and existential risk (i.e., risks with outcomes that threaten the existence of humans as a species, e.g., climate change) had similar or different relationships with reproductive decision-making. A UK representative sample of 325 participants between 18 and 35 years of age was asked to indicate their ideal number of children, ideal age to start having children, and whether their desire for a child had recently changed. Participants were asked about their experiences of COVID-19 and given a series of scales with which to assess their beliefs about climate change. In support of LHT, the study found evidence that knowing people who had been hospitalized with or died of COVID-19 was associated with a greater ideal number of children. Conversely, there was no clear evidence of a relationship between climate change beliefs and reproductive decision-making. The repercussions for understanding how we interpret and respond to different forms of mortality risk are discussed.
    • Learning Actions From Natural Language Instructions Using an ON-World Embodied Cognitive Architecture

      Giorgi, Ioanna; email: ioanna.giorgi@manchester.ac.uk; Cangelosi, Angelo; Masala, Giovanni L. (Frontiers Media S.A., 2021-05-13)
      Endowing robots with the ability to view the world the way humans do, to understand natural language and to learn novel semantic meanings when they are deployed in the physical world, is a compelling problem. Another significant aspect is linking language to action, in particular, utterances involving abstract words, in artificial agents. In this work, we propose a novel methodology, using a brain-inspired architecture, to model an appropriate mapping of language with the percept and internal motor representation in humanoid robots. This research presents the first robotic instantiation of a complex architecture based on the Baddeley's Working Memory (WM) model. Our proposed method grants a scalable knowledge representation of verbal and non-verbal signals in the cognitive architecture, which supports incremental open-ended learning. Human spoken utterances about the workspace and the task are combined with the internal knowledge map of the robot to achieve task accomplishment goals. We train the robot to understand instructions involving higher-order (abstract) linguistic concepts of developmental complexity, which cannot be directly hooked in the physical world and are not pre-defined in the robot's static self-representation. Our proposed interactive learning method grants flexible run-time acquisition of novel linguistic forms and real-world information, without training the cognitive model anew. Hence, the robot can adapt to new workspaces that include novel objects and task outcomes. We assess the potential of the proposed methodology in verification experiments with a humanoid robot. The obtained results suggest robust capabilities of the model to link language bi-directionally with the physical environment and solve a variety of manipulation tasks, starting with limited knowledge and gradually learning from the run-time interaction with the tutor, past the pre-trained stage.
    • Like Father Like Son: Cultural and Genetic Contributions to Song Inheritance in an Estrildid Finch

      Lewis, Rebecca N.; email: rebecca.lewis-3@manchester.ac.uk; Soma, Masayo; de Kort, Selvino R.; Gilman, R. Tucker (Frontiers Media S.A., 2021-06-04)
      Social learning of vocalizations is integral to song inheritance in oscine passerines. However, other factors, such as genetic inheritance and the developmental environment, can also influence song phenotype. The relative contributions of these factors can have a strong influence on song evolution and may affect important evolutionary processes such as speciation. However, relative contributions are well-described only for a few species and are likely to vary with taxonomy. Using archived song data, we examined patterns of song inheritance in a domestic population of Java sparrows (Lonchura oryzivora), some of which had been cross-fostered. Six-hundred and seventy-six songs from 73 birds were segmented and classified into notes and note subtypes (N = 22,972), for which a range of acoustic features were measured. Overall, we found strong evidence for cultural inheritance of song structure and of the acoustic characteristics of notes; sons’ song syntax and note composition were similar to that of their social fathers and were not influenced by genetic relatedness. For vocal consistency of note subtypes, a measure of vocal performance, there was no apparent evidence of social or genetic inheritance, but both age and developmental environment influenced consistency. These findings suggest that high learning fidelity of song material, i.e., song structure and note characteristics, could allow novel variants to be preserved and accumulate over generations, with implications for evolution and conservation. However, differences in vocal performance do not show strong links to cultural inheritance, instead potentially serving as condition dependent signals.
    • Mechanisms and Therapeutic Prospects of Diabetic Cardiomyopathy Through the Inflammatory Response

      Kaur, Namrita; Guan, Yingshu; Raja, Rida; Ruiz-Velasco, Andrea; Liu, Wei; email: wei.liu@manchester.ac.uk (Frontiers Media S.A., 2021-06-21)
      The incidence of heart failure (HF) continues to increase rapidly in patients with diabetes. It is marked by myocardial remodeling, including fibrosis, hypertrophy, and cell death, leading to diastolic dysfunction with or without systolic dysfunction. Diabetic cardiomyopathy (DCM) is a distinct myocardial disease in the absence of coronary artery disease. DCM is partially induced by chronic systemic inflammation, underpinned by a hostile environment due to hyperglycemia, hyperlipidemia, hyperinsulinemia, and insulin resistance. The detrimental role of leukocytes, cytokines, and chemokines is evident in the diabetic heart, yet the precise role of inflammation as a cause or consequence of DCM remains incompletely understood. Here, we provide a concise review of the inflammatory signaling mechanisms contributing to the clinical complications of diabetes-associated HF. Overall, the impact of inflammation on the onset and development of DCM suggests the potential benefits of targeting inflammatory cascades to prevent DCM. This review is tailored to outline the known effects of the current anti-diabetic drugs, anti-inflammatory therapies, and natural compounds on inflammation, which mitigate HF progression in diabetic populations.
    • Microbial Degradation of Citric Acid in Low Level Radioactive Waste Disposal: Impact on Biomineralization Reactions

      Byrd, Natalie; Lloyd, Jonathan R.; Small, Joe S.; Taylor, Frank; Bagshaw, Heath; Boothman, Christopher; Morris, Katherine; email: katherine.morris@manchester.ac.uk (Frontiers Media S.A., 2021-04-28)
      Organic complexants are present in some radioactive wastes and can challenge waste disposal as they may enhance subsurface mobility of radionuclides and contaminant species via chelation. The principal sources of organic complexing agents in low level radioactive wastes (LLW) originate from chemical decontamination activities. Polycarboxylic organic decontaminants such as citric and oxalic acid are of interest as currently there is a paucity of data on their biodegradation at high pH and under disposal conditions. This work explores the biogeochemical fate of citric acid, a model decontaminant, under high pH anaerobic conditions relevant to disposal of LLW in cementitious disposal environments. Anaerobic microcosm experiments were set up, using a high pH adapted microbial inoculum from a well characterized environmental site, to explore biodegradation of citrate under representative repository conditions. Experiments were initiated at three different pH values (10, 11, and 12) and citrate was supplied as the electron donor and carbon source, under fermentative, nitrate-, Fe(III)- and sulfate- reducing conditions. Results showed that citrate was oxidized using nitrate or Fe(III) as the electron acceptor at > pH 11. Citrate was fully degraded and removed from solution in the nitrate reducing system at pH 10 and pH 11. Here, the microcosm pH decreased as protons were generated during citrate oxidation. In the Fe(III)-reducing systems, the citrate removal rate was slower than in the nitrate reducing systems. This was presumably as Fe(III)-reduction consumes fewer moles of citrate than nitrate reduction for the same molar concentrations of electron acceptor. The pH did not change significantly in the Fe(III)-reducing systems. Sulfate reduction only occurred in a single microcosm at pH 10. Here, citrate was fully removed from solution, alongside ingrowth of acetate and formate, likely fermentation products. The acetate and lactate were subsequently used as electron donors during sulfate-reduction and there was an associated decrease in solution pH. Interestingly, in the Fe(III) reducing experiments, Fe(II) ingrowth was observed at pH values recorded up to 11.7. Here, TEM analysis of the resultant solid Fe-phase indicated that nanocrystalline magnetite formed as an end product of Fe(III)-reduction under these extreme conditions. PCR-based high-throughput 16S rRNA gene sequencing revealed that bacteria capable of nitrate Fe(III) and sulfate reduction became enriched in the relevant, biologically active systems. In addition, some fermentative organisms were identified in the Fe(III)- and sulfate-reducing systems. The microbial communities present were consistent with expectations based on the geochemical data. These results are important to improve long-term environmental safety case development for cementitious LLW waste disposal.
    • Mitochondrial Arrest on the Microtubule Highway—A Feature of Heart Failure and Diabetic Cardiomyopathy?

      Kassab, Sarah; Albalawi, Zainab; Daghistani, Hussam; Kitmitto, Ashraf; email: ashraf.kitmitto@manchester.ac.uk (Frontiers Media S.A., 2021-07-02)
      A pathophysiological consequence of both type 1 and 2 diabetes is remodelling of the myocardium leading to the loss of left ventricular pump function and ultimately heart failure (HF). Abnormal cardiac bioenergetics associated with mitochondrial dysfunction occurs in the early stages of HF. Key factors influencing mitochondrial function are the shape, size and organisation of mitochondria within cardiomyocytes, with reports identifying small, fragmented mitochondria in the myocardium of diabetic patients. Cardiac mitochondria are now known to be dynamic organelles (with various functions beyond energy production); however, the mechanisms that underpin their dynamism are complex and links to motility are yet to be fully understood, particularly within the context of HF. This review will consider how the outer mitochondrial membrane protein Miro1 (Rhot1) mediates mitochondrial movement along microtubules via crosstalk with kinesin motors and explore the evidence for molecular level changes in the setting of diabetic cardiomyopathy. As HF and diabetes are recognised inflammatory conditions, with reports of enhanced activation of the NLRP3 inflammasome, we will also consider evidence linking microtubule organisation, inflammation and the association to mitochondrial motility. Diabetes is a global pandemic but with limited treatment options for diabetic cardiomyopathy, therefore we also discuss potential therapeutic approaches to target the mitochondrial-microtubule-inflammatory axis.
    • Myogenic Cell Transplantation in Genetic and Acquired Diseases of Skeletal Muscle

      collab: Aldearee, H.; collab: Bisson, A.; collab: Bragg, L.; collab: Bridoux, V.; collab: Duelen, R.; collab: Farini, A.; collab: Gazzero, E.; collab: Giarratana, N.; collab: Giverne, C.; collab: Meggiolaro, L.; et al. (Frontiers Media S.A., 2021-08-02)
      This article will review myogenic cell transplantation for congenital and acquired diseases of skeletal muscle. There are already a number of excellent reviews on this topic, but they are mostly focused on a specific disease, muscular dystrophies and in particular Duchenne Muscular Dystrophy. There are also recent reviews on cell transplantation for inflammatory myopathies, volumetric muscle loss (VML) (this usually with biomaterials), sarcopenia and sphincter incontinence, mainly urinary but also fecal. We believe it would be useful at this stage, to compare the same strategy as adopted in all these different diseases, in order to outline similarities and differences in cell source, pre-clinical models, administration route, and outcome measures. This in turn may help to understand which common or disease-specific problems have so far limited clinical success of cell transplantation in this area, especially when compared to other fields, such as epithelial cell transplantation. We also hope that this may be useful to people outside the field to get a comprehensive view in a single review. As for any cell transplantation procedure, the choice between autologous and heterologous cells is dictated by a number of criteria, such as cell availability, possibility of in vitro expansion to reach the number required, need for genetic correction for many but not necessarily all muscular dystrophies, and immune reaction, mainly to a heterologous, even if HLA-matched cells and, to a minor extent, to the therapeutic gene product, a possible antigen for the patient. Finally, induced pluripotent stem cell derivatives, that have entered clinical experimentation for other diseases, may in the future offer a bank of immune-privileged cells, available for all patients and after a genetic correction for muscular dystrophies and other myopathies.
    • “No Way Out Except From External Intervention”: First-Hand Accounts of Autistic Inertia

      Buckle, Karen Leneh; email: karenleneh.buckle@manchester.ac.uk; Leadbitter, Kathy; Poliakoff, Ellen; Gowen, Emma (Frontiers Media S.A., 2021-07-13)
      This study, called for by autistic people and led by an autistic researcher, is the first to explore ‘autistic inertia,’ a widespread and often debilitating difficulty acting on their intentions. Previous research has considered initiation only in the context of social interaction or experimental conditions. This study is unique in considering difficulty initiating tasks of any type in real life settings, and by gathering qualitative data directly from autistic people. Four face-to-face and 2 online (text) focus groups were conducted with 32 autistic adults (19 female, 8 male, and 5 other), aged 23–64 who were able to express their internal experiences in words. They articulate in detail the actions they have difficulty with, what makes it easier or harder to act, and the impact on their lives. Thematic analysis of the transcripts found four overarching themes: descriptions of inertia, scaffolding to support action, the influence of wellbeing, and the impact on day-to-day activities. Participants described difficulty starting, stopping and changing activities that was not within their conscious control. While difficulty with planning was common, a subset of participants described a profound impairment in initiating even simple actions more suggestive of a movement disorder. Prompting and compatible activity in the environment promoted action, while mental health difficulties and stress exacerbated difficulties. Inertia had pervasive effects on participants’ day-to-day activities and wellbeing. This overdue research opens the door to many areas of further investigation to better understand autistic inertia and effective support strategies.
    • Notch Signalling in Breast Development and Cancer

      Edwards, Abigail; Brennan, Keith; email: keith.brennan@manchester.ac.uk (Frontiers Media S.A., 2021-07-06)
      The Notch signalling pathway is a highly conserved developmental signalling pathway, with vital roles in determining cell fate during embryonic development and tissue homeostasis. Aberrant Notch signalling has been implicated in many disease pathologies, including cancer. In this review, we will outline the mechanism and regulation of the Notch signalling pathway. We will also outline the role Notch signalling plays in normal mammary gland development and how Notch signalling is implicated in breast cancer tumorigenesis and progression. We will cover how Notch signalling controls several different hallmarks of cancer within epithelial cells with sections focussed on its roles in proliferation, apoptosis, invasion, and metastasis. We will provide evidence for Notch signalling in the breast cancer stem cell phenotype, which also has implications for therapy resistance and disease relapse in breast cancer patients. Finally, we will summarise the developments in therapeutic targeting of Notch signalling, and the pros and cons of this approach for the treatment of breast cancer.
    • 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.