Regenerative Events Research Articles

Accelerating bone defects healing in calvarial defect model using 3D cultured bone marrow-derived mesenchymal stem cells on demineralized bone particle scaffold.

Bone defects are usually difficult to be regenerated due to pathological states or the size of the injury. Researchers are focusing on tissue engineering approaches in order to drive the regenerative events, using stem cells to regenerate bone. The purpose of this study is to evaluate the osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) on biologically derived Gallus gallus domesticus-derived demineralized bone particle (GDD) sponge. The sponges were prepared by freeze-drying method using 1, 2, and 3 wt% GDD and cross-linked with glutaraldehyde. The GDD sponge was characterized using scanning electron microscopy, compressive strength, porosity, and Fourier transform infrared. The potential bioactivity of the sponge was evaluated by osteogenic differentiation of BMSCs using 3(4, dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay and quantifying alkaline phosphatase (ALP) activity. in vivo experiments were evaluated through a micro-computerized tomography (μ-CT) and histological assays. The analysis confirmed that an increase in the concentration of the GDD in the sponge leads to a higher bone formation and deposition in rat calvarial defects. Histological assay results were in line with μ-CT. The results reported in this study demonstrated the potential application of GDD sponges as osteoinductor in bone tissue engineering in pathological or nonunion bone defects.

With a little help from my friends: how intercellular communication shapes neuronal remodeling.

Developmental neuronal remodeling shapes the mature connectivity of the nervous system in both vertebrates and invertebrates. Remodeling often combines degenerative and regenerative events, and defects in its normal progression have been linked to neurological disorders. Here we review recent progress that highlights the roles of cell-cell interactions during remodeling. We propose that these are fundamental to elucidating how spatiotemporal control of remodeling and coordinated circuit remodeling are achieved. We cover examples spanning various neuronal circuits in vertebrates and invertebrates and involving interactions between neurons and different cell types.

The Link between Autotomy and CNS Regeneration: Echinoderms as Non-Model Species for Regenerative Biology.

Achieving regeneration of the central nervous system (CNS) is a major challenge for regenerative medicine. The inability of mammals to regrow a severed CNS contrasts with the amazing regenerative powers of their deuterostome kin, the echinoderms. Rapid CNS regeneration from a specialized autotomy plane in echinoderms presents a highly tractable and suitable non-model system for regenerative biology and evolution. Starfish arm autotomy triggers mass cell migration and local proliferation, facilitating rapid CNS regeneration. Many regeneration events in nature are preceded by autotomy and there are striking parallels between autotomy and regeneration in starfish and lizards. Comparison of these systems holds promise to provide insight into regeneration deficiency in higher vertebrates and to uncover evolutionarily conserved deuterostome-chordate regenerative processes. This will help identify mechanisms that may be present but inactive in higher vertebrates to address the problem of their poor regenerative capacities and the challenge to achieve CNS repair and regrowth.

Late Fuel Post-Injection Influence on the Dynamics and Efficiency of Wall-Flow Particulate Filters Regeneration

Late fuel post-injections are the most usual strategy to reach high exhaust temperature for the active regeneration of diesel particulate filters. However, it is important to optimise these strategies in order to mitigate their negative effect on the engine fuel consumption. This work aims at understanding the influence of the post-injection parameters, such as its start of injection and its fuel quantity, on the duration of the regeneration event and the fuel consumption along it. For this purpose, a set of computational models are employed to figure out in a holistic way the involved phenomena in the interaction between the engine and the exhaust gas aftertreatment system. Firstly, an engine model is implemented to evaluate the effect of the late fuel post-injection pattern on the gas properties at the exhaust aftertreatment system inlet in different steady-state operating conditions. These are selected to provide representative boundary conditions of the exhaust gas flow concerning dwell time, exhaust temperature and O 2 concentration. In this way, the results are later applied to the analysis of the diesel oxidation catalyst and wall-flow particulate filter responses. The dependence of the diesel particulate filter (DPF) inlet temperature is discussed based on the efficiency of each post-injection strategy to increase the exhaust gas temperature. Next, the influence on the dynamics of the regeneration of the post-injection parameters through the change in gas temperature and O 2 concentration is finally studied distinguishing the pre-heating, maximum reactivity and late soot oxidation stages as well as the required fuel consumption to complete the regeneration process.

Participation of 5-lipoxygenase and LTB4 in liver regeneration after partial hepatectomy

Regeneration is the unmatched liver ability for recovering its functional mass after tissue lost. Leukotrienes (LT) are a family of eicosanoids with the capacity of signaling to promote proliferation. We analyzed the impact of blocking LT synthesis during liver regeneration after partial hepatectomy (PH). Male Wistar rats were subjected to two-third PH and treated with zileuton, a specific inhibitor of 5-lipoxygenase (5-LOX). Our first find was a significant increment of intrahepatic LTB4 during the first hour after PH together with an increase in 5-LOX expression. Zileuton reduced hepatic LTB4 levels at the moment of hepatectomy and also inhibited the increase in hepatic LTB4. This inhibition produced a delay in liver proliferation as seen by decreased PCNA and cyclin D1 nuclear expression 24 h post-PH. Results also showed that hepatic LTB4 diminution by zileuton was associated with a decrease in NF-ĸB activity. Additionally, decreased hepatic LTB4 levels by zileuton affected the recruitment of neutrophils and macrophages. Non-parenchymal cells (NPCs) from zileuton-treated PH-rats displayed higher apoptosis than NPCs from PH control rats. In conclusion, the present work provides evidences that 5-LOX activation and its product LTB4 are involved in the initial signaling events for liver regeneration after PH and the pharmacological inhibition of this enzyme can delay the initial time course of the phenomenon.

Dynamics of proinflammatory cytokine serum levels in patients with acute inflammatory diseases of pelvic organs in the early stages of conservative treatment

Dynamics of serum proinflammatory cytokines such as interleukins (IL)-1, -2 and -6, tumor necrosis factor alpha (TNFα) was examined in patients of reproductive age suffering from acute inflammatory diseases of the pelvic organs. Our study was carried out with female patients at hospital admission prior to therapy applied with conventional methods of treatment and improved treatment by using vaginal low-frequency laser in a constant continuous magnetic field. The data obtained were compared with serum cytokine level from 20 healthy female volunteers of reproductive age consulted on better contraception methods. It was found that cytokine profile of in patients with acute inflammatory processes in pelvic organs was characterized by a high level of proinflammatory cytokines. It was shown that patients receiving conventional treatment contained decreased level of serum IL-1, IL-2, IL-6 and TNFα displaying slight dynamics, which did not reach it in control group. This may contribute to ongoing inflammatory process, despite the positive clinical dynamics. In turn, imbalance of immune responses leads to a persistently impaired fertility in women and need to perform subsequent comprehensive rehabilitation measures. Moreover, patients applied with intravaginal low-frequency laser radiation in a constant magnetic field were found to contain serum TNFα 100 pg/ml observed in 59.7% of cases, IL-6 level was lower than 20 pg/ml (prevalent in control group) found in 54.2% of cases. Serum IL-2 level was decreased by 3.5-fold compared to baseline, whereas for IL-1β it was higher than 100 pg/ml in as few as 23.6% patients. Such temporal pattern of inflammatory markers with rapid significant decrease of serum proinflammatory cytokines in patients with preformed pathogenic factors can reduce probability of connective tissue formation and activate their own repair as well as regenerative events. The results obtained allow to wider use combined physical interventional factors for therapy of patients with acute inflammatory diseases of the pelvic organs.

Reconstructing the Vascular Developmental Milieu InVitro.

Understanding human development has fascinated scientists for centuries. With advancements in stem cell technologies, this understanding has expanded beyond fascination to application towards informing the design of therapeutics in regenerative medicine. A focus on establishing a better grasp of the physicochemical cues governing differentiation and tissue assembly has continually enhanced engineered systems to an unprecedented level of biomimicry and, in doing so, has allowed the design of novel therapeutics. The vasculature has a critical role during early stages of development and regeneration events, and is responsive to a range of dynamic environmental cues. In this review, we present biomaterials systems capable of spatially and temporally controlling environmental signals that guide vascular fate and assembly, thereby further informing our understanding of differentiation schema.

Modeling the thermal and soot oxidation dynamics inside a ceria-coated gasoline particulate filter

Gasoline particulate filters (GPFs) are practically adoptable devices to mitigate particulate matter emissions from vehicles using gasoline direct ignition engines. This paper presents a newly developed control-oriented model to characterize the thermal and soot oxidation dynamics in a ceria-coated GPF. The model utilizes the GPF inlet exhaust gas temperature, exhaust gas mass flow rate, the initial GPF soot loading density, and air–fuel ratio to predict the internal GPF temperature and the amount of soot oxidized during regeneration events. The reaction kinetics incorporated in the model involve the rates of both oxygen- and ceria-initiated soot oxidation reactions. Volumetric model parameters are calculated from the geometric information of the coated GPF, while the air–fuel ratio is used to determine the volume fractions of the exhaust gas constituents. The exhaust gas properties are evaluated using the volume fractions and thermodynamic tables, while the cordierite specific heat capacity is identified using a clean experimental data set. The enthalpies of the regeneration reactions are calculated using thermochemical tables. Physical insights from the proposed model are thus enhanced by limiting the number of parameters obtained from fitting to only those which cannot be directly measured from experiments. The parameters of the model are identified using the particle swarm optimization algorithm and a cost function designed to simultaneously predict both thermal and soot oxidation dynamics. Parameter identification and model validation are performed using independent data sets from laboratory experiments conducted on a ceria-coated GPF. This work demonstrates that the proposed model can be successfully implemented to predict ceria-coated GPF dynamics under different soot loading and temperature conditions.

Early skeletal muscle pathology and disease progress in the dy3K/dy3K mouse model of congenital muscular dystrophy with laminin \u03b12 chain-deficiency

Deficiency of laminin α2 chain leads to a severe form of congenital muscular dystrophy (LAMA2-CMD), and dystrophic symptoms progress rapidly in early childhood. Currently, there is no treatment for this detrimental disorder. Development of therapies is largely hindered by lack of understanding of mechanisms involved in the disease initiation and progress, both in patients but also in mouse models that are commonly used in the preclinical setup. Here, we unveil the first pathogenic events and characterise the disease development in a mouse model for LAMA2-CMD (dy3K/dy3K), by analysing muscles at perinatal, neonatal and postnatal stages. We found that apoptotic muscle fibres were present as early as postnatal day 1. Other typical dystrophic hallmarks (muscle degeneration, inflammation, and extensive production of the extracellular matrix proteins) were clearly evident already at postnatal day 4, and the highest degree of muscle deterioration was reached by day 7. Interestingly, the severe phenotype of limb muscles partially recovered on days 14 and 21, despite worsening of the general condition of the dy3K/dy3K mouse by that age. We found that masticatory muscles were severely affected in dy3K/dy3K mice and this may be an underlying cause of their malnutrition, which contributes to death around day 21. We also showed that several signalling pathways were affected already in 1-day-old dy3K/dy3K muscle. Therapeutic tests in the dy3K/dy3K mouse model should therefore be initiated shortly after birth, but should also take into account timing and correlation between regenerative and pathogenic events.

Live cell imaging of cell movement and transdifferentiation during regeneration of an amputated multicellular body of the social amoeba Dictyostelium discoideum

The regeneration of lost body parts is a fascinating phenomenon exhibited by some multicellular organisms. In social amoebae, such as Dictyostelium discoideum, the pseudoplasmodium is a temporary migratory multicellular structure with high regeneration ability. It consists of future stalk cells (prestalk cells) at the anterior end and future spore cells (prespore cells) at the posterior end, and if amputated, the remaining cells can rapidly regenerate the lost portion within several hours. Details of this regeneration event have been extensively documented; however, little is known about the behavior of individual cells involved in this process. In this study, we performed live cell imaging of cell behavior during regeneration of the excised anterior prestalk region. We used cells that specifically express GFP in the prestalk cell lineage to examine how the prestalk region is regenerated after this region is excised. The current model of prestalk regeneration suggests that the progenitors of prestalk cells, known as anterior-like cells (ALCs), which are sparsely distributed in the prespore region, are redistributed to form the new prestalk region. However, we found that the regenerated prestalk region was formed mainly by the transdifferentiation of prespore cells surrounding the excised anterior end, with little clustering of pre-existing ALCs. Furthermore, the movement of randomly distributed labeled cells during regeneration revealed that although the posterior end was deformed and rounded in shape, the relative position of cells along the anterior-posterior axis remained largely unchanged. These results suggest that the original anterior-posterior axis is maintained in posterior bodies and that prespore cells at the anterior side transdifferentiate and regenerate the prestalk region.

Compensation for the differences in LHV of diesel-OME blends by using injector nozzles with different number of holes: Emissions and combustion

The reduction of particulate matter (PM) emissions has become a major topic in the development of compression ignition (CI) engines. The aftertreatment of exhaust gases by means of particulate traps (DPF) has given promising results in terms of effectiveness. However, the backpressure and necessity to regenerate causes an increase in fuel consumption and operational cost. A possible strategy to reduce this cost is the abatement of PM levels of engine out exhaust gases by employing oxygenated fuels. This solution reduces the backpressure in the exhaust as well as fuel expensive regeneration events. In the present work the performances, in terms of combustion and emissions, of two different blends composed of diesel and a mixture of polyoxymethylene dimethyl ether (OME, POMDME or PODE) were investigated in a single-cylinder, direct injection, 4-stroke, heavy duty diesel engine. In order to minimize the influence on combustion characteristics (i.e. ignition delay, premixed and diffusion combustion portion, etc.), the compensation for the smaller caloric value of the blends in comparison to diesel was performed with an increased number of injector nozzles holes. This strategy was chosen to avoid effects on emissions caused by a prolonged duration of injection, increased fuel pressure or increased nozzle diameter. In total three different number of nozzle holes were tested with a reference diesel case (7-hole) and two with according blends (8-hole, ca. 22% OME; 9-hole, ca. 42% OME). The results show an acceleration of the diffusion combustion rate and the resulting improvements in the indicated specific fuel consumption (−5.7%) with increasing OME portion. In addition, mainly due to a reduction of up to 90% of the soot emissions, the NOx-soot trade-off improved as well. The NOx emissions showed decreased values for the less oxygenated, and increased values for the stronger oxygenated blend. This behaviour is attributed to the faster combustion, which, on the one hand reduces the residence time to form NOx and on the other hand increases the temperature, which enhances NOx formation again. The investigation of the trade-off between shorter residence time and higher temperature can only be performed with constant injection parameters (injected energy, fuel pressure and duration of injection) among the different fuels.

Sequential drug delivery for liver diseases.

The liver performs critical physiological functions such as metabolism/detoxification and blood homeostasis/biliary excretion. A high degree of blood access means that a drug's resident time in any cell is relatively short. This short drug exposure to cells requires local sequential delivery of multiple drugs for optimal efficacy, potency, and safety. The high metabolism and excretion of drugs also impose both technical challenges and opportunities to sequential drug delivery. This review provides an overview of the sequential events in liver regeneration and the related liver diseases. Using selected examples of liver cancer, hepatitis B viral infection, fatty liver diseases, and drug-induced liver injury, we highlight efforts made for the sequential delivery of small and macromolecular drugs through different biomaterials, cells, and microdevice-based delivery platforms that allow fast delivery kinetics and rapid drug switching. As this is a nascent area of development, we extrapolate and compare the results with other sequential drug delivery studies to suggest possible application in liver diseases, wherever appropriate.

M2 Macrophages Enhance the Cementoblastic Differentiation of Periodontal Ligament Stem Cells via the Akt and JNK Pathways.

Although macrophage (Mφ) polarization has been demonstrated to play crucial roles in cellular osteogenesis across the cascade of events in periodontal regeneration, how polarized Mφ phenotypes influence the cementoblastic differentiation of periodontal ligament stem cells (PDLSCs) remains unknown. In the present study, human monocyte leukemic cells (THP-1) were induced into M0, M1, and M2 subsets, and the influences of these polarized Mφs on the cementoblastic differentiation of PDLSCs were assessed in both conditioned medium-based and Transwell-based coculture systems. Furthermore, the potential pathways and cyto-/chemokines involved in Mφ-mediated cementoblastic differentiation were screened and identified. In both systems, M2 subsets increased cementoblastic differentiation-related gene/protein expression levels in cocultured PDLSCs, induced more PDLSCs to differentiate into polygonal and square cells, and enhanced alkaline phosphatase activity in PDLSCs. Furthermore, Akt and c-Jun N-terminal Kinase (JNK) signaling was identified as a potential pathway involved in M2 Mφ-enhanced PDLSC cementoblastic differentiation, and cyto-/chemokines (interleukin (IL)-10 and vascular endothelial growth factor [VEGF]) secreted by M2 Mφs were found to be key players that promoted cell cementoblastic differentiation by activating Akt signaling. Our data indicate for the first time that Mφs are key modulators during PDLSC cementoblastic differentiation and are hence very important for the regeneration of multiple periodontal tissues, including the cementum. Although the Akt and JNK pathways are involved in M2 Mφ-enhanced cementoblastic differentiation, only the Akt pathway can be activated via a cyto-/chemokine-associated mechanism, suggesting that players other than cyto-/chemokines also participate in the M2-mediated cementoblastic differentiation of PDLSCs. Stem Cells 2019;37:1567-1580.

Impact of Particulate Size During Deep Loading on DPF Management

Wall-flow particulate filters are a required emission control device to abate diesel emission in order to comply with current regulations. DPFs (diesel particulate filters) are characterized by high filtration efficiency—but in order to avoid deterioration of power and performance, they are required to cause low values of backpressure. The periodical oxidation of collected particle allows for the reestablishment of the ideal flow conditions. Studies highlighted that the regeneration event has an important impact on engine emission, since it is responsible for the emission of a large number of smaller particles. From these considerations, the importance of optimizing the DPF management for what concerns both filtration and regeneration mechanisms arises. The present paper focuses on the loading process of the filter. A filtration model was implemented, based on the ‘unit-collector’ and fluid-dynamic approaches, known as valid modelling techniques. The model was used to predict trapped mass and filter backpressure evolution with time during loading processes, in which soot particle sizes varied, with the aim to analyze how particulate size affects the filter pressure drop rise. A wall-flow filter was investigated, and the behavior of clean material was evaluated by a parametric analysis in which particle diameter varies in the filed 20–1000 nm, that is the typical range of soot sizes in diesel engine exhaust. The results demonstrate that soot size has a great influence on the initial deep bed loading process. Moreover, it defines the value from which the linear pressure drop shape during cake filtration starts, not only when the initial loaded is completed, but also each time the regeneration event is concluded. This outcome provides an important guideline to define the most appropriate strategy for the initial DPF loading in order to establish the regeneration event based on the estimation of trapped mass accounting for the filter backpressure and on the time interval between two successive regeneration.

Interpreting in vivo calcium signals from neuronal cell bodies, axons, and dendrites: a review.

.Calcium imaging is emerging as a popular technique in neuroscience. A major reason is that intracellular calcium transients are reflections of electrical events in neurons. For example, calcium influx in the soma and axonal boutons accompanies spiking activity, whereas elevations in dendrites and dendritic spines are associated with synaptic inputs and local regenerative events. However, calcium transients have complex spatiotemporal dynamics, and since most optical methods visualize only one of the somatic, axonal, and dendritic compartments, a straightforward inference of the underlying electrical event is typically challenging. We highlight experiments that have directly calibrated in vivo calcium signals recorded using fluorescent indicators against electrophysiological events. We address commonly asked questions such as: Can calcium imaging be used to characterize neurons with high firing rates? Can the fluorescent signal report a decrease in spiking activity? What is the evidence that calcium transients in subcellular compartments correspond to distinct presynaptic axonal and postsynaptic dendritic events? By reviewing the empirical evidence and limitations, we suggest that, despite some caveats, calcium imaging is a versatile method to characterize a variety of neuronal events in vivo.

Modulation of Metamorphic and Regenerative Events by Cold Atmospheric Pressure Plasma Exposure in Tadpoles, Xenopus laevis

Atmospheric pressure plasma has found wide clinical applications including wound healing, tissue regeneration, sterilization, and cancer treatment. Here, we have investigated its effect on developmental processes like metamorphosis and tail regeneration in tadpoles. Plasma exposure hastens the process of tail regeneration but delays metamorphic development. The observed differences in these two developmental processes following plasma exposure are indicative of physiological costs associated with developmental plasticity for their survival. Ultrastructural changes in epidermis and mitochondria in response to the stress of tail amputation and plasma exposure show characteristics of cellular hypoxia and oxidative stress. Mitochondria show morphological changes such as swelling with wide and fewer cristae and seem to undergo processes such as fission and fusion. Complex interactions between calcium, peroxisomes, mitochondria and their pore transition pathways are responsible for changes in mitochondrial structure and function, suggesting the subcellular site of action of plasma in this system.

Cancer Drug Repositioning by Comparison of Gene Expression in Humans and Axolotl (Ambystoma mexicanum) During Wound Healing.

Urodele amphibians such as the axolotl (Ambystoma mexicanum) display a large capacity for tissue regeneration and remarkable resistance to cancer. As a model organism, axolotl thus offers a unique opportunity for cancer research and anticancer drug discovery, not to mention the discerning mechanisms that underpin controlled cellular growth and regeneration versus cancer. To the best of our knowledge, little is known on comparative gene expression changes during regeneration events such as wound healing in axolotl and humans. Using publicly available transcriptomics data and bioinformatics analyses, we examined the differential gene expression signatures in skin wound samples from axolotl and humans after skin biopsy punch injury, in comparison with intact (uninjured) control skin samples. We identified 95 genes exhibiting a reversal expression pattern between humans and axolotl during the wound healing/regeneration period. These genes were significantly associated with collagen biosynthesis, extracellular matrix organization, PI3K-Akt signaling pathway, immune system response, and apoptotic process. Furthermore, this new gene set exhibited high prognostic performance in discriminating the survival risk in skin-related cancers, including melanoma (hazard ratio [HR] = 8.14, p < 10-30), oral cancer (HR >100, p < 10-12), and head and neck carcinoma (HR = 5.29, p < 10-30). Moreover, considering these gene signatures, we repositioned 11 small molecules as potential anticancer drug candidates indicating reversal effects on upregulated human genes and downregulated axolotl genes or mimicking downregulated human genes and upregulated axolotl genes. We anticipate that this study offers new insights on gene signatures bridging regeneration mechanisms with tumorigenesis and cancer drug repositioning.

Corneal nerve healing after in situ laser nerve transection.

PurposeWe have previously reported that lamellar dissection of the cornea transects stromal nerves, and that regenerating neurites form a dense net along the surgical plane. In these experiments, we have disrupted the stromal nerve trunks in situ, without incising the cornea, to determine the regeneration events in the absence of a surgical plane.MethodsThy1-YFP mice were anesthetized and in vivo images of the corneal nerves were obtained with a wide-field stereofluorescent microscope. A far infrared XYRCOS Laser attached to 20X objective of an upright microscope was used to perform in situ transection of the stromal nerves. 3 types of laser transections were performed (n = 5/group): (i) point transection (a single cut); (ii) segmental transection (two cuts enclosing a segment of nerve trunk); and (iii) annular transection (cuts on all nerve trunks crossing the perimeter of a 0.8 mm diameter circular area centered on the corneal apex). Mice were imaged sequentially for 4 weeks thereafter to assess nerve degeneration (disappearance or weakening of original fluorescence intensity) or regeneration (appearance of new fluorescent fronds). Beta-3-tubulin immunostaining was performed on corneal whole-mounts to demonstrate nerve disruption.ResultsThe pattern of stromal nerves in corneas of the same mouse and in corneas of littermates was dissimilar. Two distinct patterns were observed, often within the same cornea: (i) interconnected trunks that spanned limbus to limbus; or (ii) dichotomously branching trunks that terminate at the corneal apex. Point transections did not cause degeneration of proximal or distal segment in interconnected trunks, but resulted in degeneration of distal segment of branching trunks. In segmental transections, the nerve segment enclosed within the two laser cuts degenerated. Lack of beta-3 tubulin staining at transection site confirmed nerve transection. In interconnected trunks, at 4 weeks, a hyperfluorescent plaque filled the gap created by the transection. In annular transections, some nerve trunks degenerated, while others regained or retained fluorescence.ConclusionsInterconnected stromal nerves in murine corneas do not degenerate after in situ point transection and show evidence of healing at the site of disruption. Presence or absence of a surgical plane influences corneal nerve regeneration after transection.

Learning to belong? ‘Culture’ and ‘place making’ among children and young people in Hull, UK City of Culture 2017

ABSTRACTDespite the rise of ‘child-friendly cities’ internationally, and a growing interest in youth engagement in urban planning, the role of children and young people in culture-led regeneration and ‘place making’ schemes, remains under-researched. Notwithstanding the wealth of research into childhood and youth cultures, little is known about the ways in which the abstract (and perhaps predominantly ‘adult’) notions of ‘culture’ and ‘place’ are negotiated by younger citizens. Drawing on participative research with schools across Hull, the UK City of Culture 2017, this contribution explores children’s and young people’s understandings of culture and place within this cultural regeneration event. Although our findings suggest that the City of Culture designation has brought benefits to children and young people in a marginalised city, there is still much to be learned from their often personal and informal interpretations of ‘place’ and ‘culture’, as well as the role played by schools in this context.

Morphogenesis as Bayesian inference: A variational approach to pattern formation and control in complex biological systems.

Recent advances in molecular biology such as gene editing [1], bioelectric recording and manipulation [2] and live cell microscopy using fluorescent reporters [3], [4] - especially with the advent of light-controlled protein activation through optogenetics [5] - have provided the tools to measure and manipulate molecular signaling pathways with unprecedented spatiotemporal precision. This has produced ever increasing detail about the molecular mechanisms underlying development and regeneration in biological organisms. However, an overarching concept - that can predict the emergence of form and the robust maintenance of complex anatomy - is largely missing in the field. Classic (i.e., dynamic systems and analytical mechanics) approaches such as least action principles are difficult to use when characterizing open, far-from equilibrium systems that predominate in Biology. Similar issues arise in neuroscience when trying to understand neuronal dynamics from first principles. In this (neurobiology) setting, a variational free energy principle has emerged based upon a formulation of self-organization in terms of (active) Bayesian inference. The free energy principle has recently been applied to biological self-organization beyond the neurosciences [6], [7]. For biological processes that underwrite development or regeneration, the Bayesian inference framework treats cells as information processing agents, where the driving force behind morphogenesis is the maximization of a cell's model evidence. This is realized by the appropriate expression of receptors and other signals that correspond to the cell's internal (i.e., generative) model of what type of receptors and other signals it should express. The emerging field of the free energy principle in pattern formation provides an essential quantitative formalism for understanding cellular decision-making in the context of embryogenesis, regeneration, and cancer suppression. In this paper, we derive the mathematics behind Bayesian inference - as understood in this framework - and use simulations to show that the formalism can reproduce experimental, top-down manipulations of complex morphogenesis. First, we illustrate this 'first principle' approach to morphogenesis through simulated alterations of anterior-posterior axial polarity (i.e., the induction of two heads or two tails) as in planarian regeneration. Then, we consider aberrant signaling and functional behavior of a single cell within a cellular ensemble - as a first step in carcinogenesis as false 'beliefs' about what a cell should 'sense' and 'do'. We further show that simple modifications of the inference process can cause - and rescue - mis-patterning of developmental and regenerative events without changing the implicit generative model of a cell as specified, for example, by its DNA. This formalism offers a new road map for understanding developmental change in evolution and for designing new interventions in regenerative medicine settings.