Gap junctions in Turing-type periodic feather pattern formation.

Periodic patterning requires coordinated cell-cell interactions at the tissue level. Turing showed, using mathematical modeling, how spatial patterns could arise from the reactions of a diffusive activator-inhibitor pair in an initially homogeneous 2D field. Most activators and inhibitors studied in biological systems are proteins, and the roles of cell-cell interaction, ions, bioelectricity, etc. are only now being identified. Gap junctions (GJs) mediate direct exchanges of ions or small molecules between cells, enabling rapid long-distance communications in a cell collective. They are therefore good candidates for propagating nonprotein-based patterning signals that may act according to the Turing principles. Here, we explore the possible roles of GJs in Turing-type patterning using feather pattern formation as a model. We found 7 of the 12 investigated GJ isoforms are highly dynamically expressed in the developing chicken skin. In ovo functional perturbations of the GJ isoform, connexin 30, by siRNA and the dominant-negative mutant applied before placode development led to disrupted primary feather bud formation. Interestingly, inhibition of gap junctional intercellular communication (GJIC) in the ex vivo skin explant culture allowed the sequential emergence of new feather buds at specific spatial locations relative to the existing primary buds. The results suggest that GJIC may facilitate the propagation of long-distance inhibitory signals. Thus, inhibition of GJs may stimulate Turing-type periodic feather pattern formation during chick skin development, and the removal of GJ activity would enable the emergence of new feather buds if the local environment were competent and the threshold to form buds was reached. We further propose Turing-based computational simulations that can predict the sequential appearance of these ectopic buds. Our models demonstrate how a Turing activator-inhibitor system can continue to generate patterns in the competent morphogenetic field when the level of intercellular communication at the tissue scale is modulated.

A simple and fast method for estimating bat roost locations.

Bats play a pivotal role in pest control, pollination and seed dispersal. Despite their ecological significance, locating bat roosts remains a challenging task for ecologists. Traditional field surveys are time-consuming, expensive and may disturb sensitive bat populations. In this article, we combine data from static audio detectors with a bat movement model to facilitate the detection of bat roosts. Crucially, our technique not only provides a point prediction for the most likely location of a bat roost, but because of the algorithm's speed, it can be applied over an entire landscape, resulting in a likelihood map, which provides optimal searching regions. To illustrate the success of the algorithm and highlight limitations, we apply our technique to greater horseshoe bat (Rhinolophus ferrumequinum) acoustic data acquired from six surveys from four different UK locations and over six different times in the year. Furthermore, we investigate what happens to the accuracy of our predictions in the case that the roost is not contained within the area spanned by the detectors. This innovative approach to searching rural environments holds the potential to greatly reduce the labour required for roost finding, and, hence, enhance the conservation efforts of bat populations and their habitats.

Bat Motion can be Described by Leap Frogging.

We present models of bat motion derived from radio-tracking data collected over 14 nights. The data presents an initial dispersal period and a return to roost period. Although a simple diffusion model fits the initial dispersal motion we show that simple convection cannot provide a description of the bats returning to their roost. By extending our model to include non-autonomous parameters, or a leap frogging form of motion, where bats on the exterior move back first, we find we are able to accurately capture the bat's motion. We discuss ways of distinguishing between the two movement descriptions and, finally, consider how the different motion descriptions would impact a bat's hunting strategy.

Retinal Oxygenation With Conventional 100-ms Versus Short-Pulse Pan-Retinal Laser Photocoagulation.

BACKGROUND AND OBJECTIVE: Conventional (100 ms) pan-retinal photocoagulation (PRP) laser burns are larger than short-pulse (10 ms to 20 ms) PRP burns. This study investigates the effect of PRP burns of different sizes on retinal oxygenation. METHOD: A mathematical model using COMSOL Multiphysics 6 was used to create a three-dimensional abstraction of the coupled biology of the choroid, photoreceptor, and retinal tissues. Laser burn sizes were varied in the model, specifically considering burn diameters of 500 µm, 250 µm, and 125 µm, while keeping the total burn area constant. RESULTS: Total increase in retinal oxygenation was the same for different burn sizes, but the oxygen distribution differed. Smaller burns resulted in a more even lateral oxygen distribution but with reduced penetration into the inner retina. CONCLUSIONS: Conventional and short-pulse PRP may affect retinal oxygenation differently, even when total burn area is the same. Further investigation into optimum burn size and pattern is required. [Ophthalmic Surg Lasers Imaging Retina 2024;55:40-45.].

Unravelling the Clinical Co-Morbidity and Risk Factors Associated with Agenesis of the Corpus Callosum.

Agenesis of the Corpus Callosum (ACC) can result in multiple neurological deficits including social and behavioural issues. However, the underlying aetiology, clinical co-morbidity and the contributing risk factors remain elusive, resulting in inaccurate prognosis and delayed therapy. The main objective of this study was to comprehensively describe the epidemiology and clinical co-morbidity associated with patients diagnosed with ACC. The secondary objective was to identify the factors that contribute towards increased risk for ACC. For this, we analysed 22 years (1998-2020) of clinical data across the whole of Wales, UK collected through the Congenital Anomaly Register & Information Service (CARIS) and Public Health Wales (PHW). Our results demonstrate that complete ACC (84.1%) was the prevalent subtype, in comparison to partial ACC. Further, ventriculomegaly/hydrocephalus (26.37%) and ventricular septal defect (21.92%) were identified to be the most prevalent neural malformation (NM) and congenital heart disorder (CHD) in our cohort. Although 12.7% of subjects with ACC had both an NM and CHD, we found no significant association between them (χ2 (1, n = 220) = 3.84, p = 0.33). We found socioeconomic deprivation and increased maternal age contributed towards an increased risk for ACC. To the best of our knowledge, this study for the first time defines the clinical phenotypes and the factors that contribute to ACC within the Welsh population. These findings will be of value to both patients and healthcare professionals, who may take preventative or remedial measures.

Gap junctions in Turing-type periodic feather pattern formation.

Periodic patterning requires coordinated cell-cell interactions at the tissue level. Turing showed, using mathematical modeling, how spatial patterns could arise from the reactions of a diffusive activator-inhibitor pair in an initially homogenous two-dimensional field. Most activators and inhibitors studied in biological systems are proteins, and the roles of cell-cell interaction, ions, bioelectricity, etc. are only now being identified. Gap junctions (GJs) mediate direct exchanges of ions or small molecules between cells, enabling rapid long-distance communications in a cell collective. They are therefore good candidates for propagating non-protein-based patterning signals that may act according to the Turing principles. Here, we explore the possible roles of GJs in Turing-type patterning using feather pattern formation as a model. We found seven of the twelve investigated GJ isoforms are highly dynamically expressed in the developing chicken skin. In ovo functional perturbations of the GJ isoform, connexin 30, by siRNA and the dominant-negative mutant applied before placode development led to disrupted primary feather bud formation, including patches of smooth skin and buds of irregular sizes. Later, after the primary feather arrays were laid out, inhibition of gap junctional intercellular communication in the ex vivo skin explant culture allowed the emergence of new feather buds in temporal waves at specific spatial locations relative to the existing primary buds. The results suggest that gap junctional communication may facilitate the propagation of long-distance inhibitory signals. Thus, the removal of GJ activity would enable the emergence of new feather buds if the local environment is competent and the threshold to form buds is reached. We propose Turing-based computational simulations that can predict the appearance of these ectopic bud waves. Our models demonstrate how a Turing activator-inhibitor system can continue to generate patterns in the competent morphogenetic field when the level of intercellular communication at the tissue scale is modulated.

The developmental basis of fingerprint pattern formation and variation.

Fingerprints are complex and individually unique patterns in the skin. Established prenatally, the molecular and cellular mechanisms that guide fingerprint ridge formation and their intricate arrangements are unknown. Here we show that fingerprint ridges are epithelial structures that undergo a truncated hair follicle developmental program and fail to recruit a mesenchymal condensate. Their spatial pattern is established by a Turing reaction-diffusion system, based on signaling between EDAR, WNT, and antagonistic BMP pathways. These signals resolve epithelial growth into bands of focalized proliferation under a precociously differentiated suprabasal layer. Ridge formation occurs as a set of waves spreading from variable initiation sites defined by the local signaling environments and anatomical intricacies of the digit, with the propagation and meeting of these waves determining the type of pattern that forms. Relying on a dynamic patterning system triggered at spatially distinct sites generates the characteristic types and unending variation of human fingerprint patterns.

An Exploration of the Multiplicative Effect of "Other People" and Other Environmental Effects on Violence in the Night-Time Environment.

BACKGROUND: The characteristics of night-time environments (NTEs) in which alcohol is consumed and that contribute to violence are poorly described. We explore competing explanations for violence in the NTE, with a particular focus on the number of patrons and its association with assault-related visits to a hospital emergency department. Other environmental features including the weather and notable events were also considered. The primary aim was to stimulate debate around the causal mechanisms responsible for violence. METHODS: Assault-related ED visits occurring between 8 pm and 4 am were recorded at the University Hospital of Wales, the single Emergency Department (ED) serving Cardiff, Wales, United Kingdom. Footfall was derived from the total number of unique MAC addresses recorded per hour collected from ten wireless fidelity monitoring tools located in the city centre. A narrative review of the literature concerning alcohol and violence informed exploratory analyses into the association between night-time footfall, sporting events, the weather, and other potential predictors of assault-related visits to the ED. We developed analytic methods from formal accounts of queueing. RESULTS: International rugby matches at home, the weather (temperature), national holidays, the day of the week, and number of patrons in the NTE predicted assault-related injury (R2 = 0.70), with footfall yielding a positive non-linear exponential association consistent with predictions derived from mathematical models of queueing. DISCUSSION: Assault-related visits to the ED have a non-linear association with the number of people socialising in the night-time environment and are further influenced by the weather and notable events. Opportunities for further research that might inform policy and interventions aimed at better managing NTEs are discussed.

Boundary Conditions Cause Different Generic Bifurcation Structures in Turing Systems.

Turing's theory of morphogenesis is a generic mechanism to produce spatial patterning from near homogeneity. Although widely studied, we are still able to generate new results by returning to common dogmas. One such widely reported belief is that the Turing bifurcation occurs through a pitchfork bifurcation, which is true under zero-flux boundary conditions. However, under fixed boundary conditions, the Turing bifurcation becomes generically transcritical. We derive these algebraic results through weakly nonlinear analysis and apply them to the Schnakenberg kinetics. We observe that the combination of kinetics and boundary conditions produce their own uncommon boundary complexities that we explore numerically. Overall, this work demonstrates that it is not enough to only consider parameter perturbations in a sensitivity analysis of a specific application. Variations in boundary conditions should also be considered.

Challenging molecular dogmas in human sepsis using mathematical reasoning.

Sepsis is defined as a dysregulated host-response to infection, across all ages and pathogens. What defines a dysregulated state remains intensively researched but incompletely understood. Here, we dissect the meaning of this definition and its importance for the diagnosis and management of sepsis. We deliberate on pathophysiological features and dogmas that range from cytokine storms and immune paralysis to dormancy and altered homeostasis setpoints. Mathematical reasoning, used to test for plausibility, reveals three interlinked cardinal rules governing host-response trajectories in sepsis. Rule one highlights that the amplitude of the immune response while important is not sufficient and is strictly dependent on rule two, specifying bioenergetic capacity and are together dynamically driven by rule three, delineating stability and alterations in setpoints. We consider these rules and associated pathophysiological parameters for guiding data-science and artificial intelligence mining of multi-omics and big-data for improving the precision of diagnostic and therapeutic approaches to sepsis. FUNDING: PG funded by the European Regional Development Fund and Welsh Government (Ser Cymru programme - Project Sepsis).

The association of neurodevelopmental abnormalities, congenital heart and renal defects in a tuberous sclerosis complex patient cohort.

BACKGROUND: Tuberous sclerosis complex (TSC) is a rare multi-system genetic disorder characterised by the presence of benign tumours throughout multiple organs including the brain, kidneys, heart, liver, eyes, lungs and skin, in addition to neurological and neuropsychiatric complications. Intracardiac tumour (rhabdomyoma), neurodevelopmental disorders (NDDs) and kidney disorders (KD) are common manifestations of TSC and have been linked with TSC1 and TSC2 loss-of-function mutations independently, but the dynamic relationship between these organ manifestations remains unexplored. Therefore, this study aims to characterise the nature of the relationship specifically between these three organs' manifestations in TSC1 and TSC2 mutation patients. METHODS: Clinical data gathered from TSC patients across South Wales registered with Cardiff and Vale University Health Board (CAV UHB) between 1990 and 2020 were analysed retrospectively to evaluate abnormalities in the heart, brain and kidney development. TSC-related abnormalities such as tumour prevalence, location and size were analysed for each organ in addition to neuropsychiatric involvement and were compared between TSC1 and TSC2 mutant genotypes. Lastly, statistical co-occurrence between organ manifestations co-morbidity was quantified, and trajectories of disease progression throughout organs were modelled. RESULTS: This study found a significantly greater mutational frequency at the TSC2 locus in the cohort in comparison to TSC1. An equal proportion of male and female patients were observed in this group and by meta-analysis of previous studies. No significant difference in characterisation of heart involvement was observed between TSC1 and TSC2 patients. Brain involvement was seen with increased severity in TSC2 patients, characterised by a greater prevalence of cortical tubers and communication disorders. Renal pathology was further enhanced in TSC2 patients, marked by increased bilateral angiomyolipoma prevalence. Furthermore, co-occurrence of NDDs and KDs was the most positively correlated out of investigated manifestations, regardless of genotype. Analysis of disease trajectories revealed a more diverse clinical outcome for TSC2 patients: however, a chronological association of rhabdomyoma, NDD and KD was most frequently observed for TSC1 patients. CONCLUSIONS: This study marks the first empirical investigation of the co-morbidity between congenital heart defects (CHD), NDDs, and KDs in TSC1 and TSC2 patients. This remains a unique first step towards the characterisation of the dynamic role between genetics, heart function, brain function and kidney function during the early development in the context of TSC.

Accounting for dimensional differences in stochastic domain invasion with applications to precancerous cell removal.

We consider a specific form of domain invasion that is an abstraction of pancreatic tissue eliminating precancerous mutant cells through juxtacrine signalling. The model is explored discretely, continuously, stochastically and deterministically, highlighting unforeseen nonlinear dependencies on the dimension of the solution domain. Specifically, stochastically simulated populations invade with a dimension dependent wave speed that can be over twice as fast as their deterministic analogues. Although the wave speed can be analytically derived in the cases of small domains, the probabilistic state space grows exponentially and, thus, we use numeric simulation and curve fitting to predict limiting dynamics.

Pannexin 1 Regulates Skeletal Muscle Regeneration by Promoting Bleb-Based Myoblast Migration and Fusion Through a Novel Lipid Based Signaling Mechanism.

Adult skeletal muscle has robust regenerative capabilities due to the presence of a resident stem cell population called satellite cells. Muscle injury leads to these normally quiescent cells becoming molecularly and metabolically activated and embarking on a program of proliferation, migration, differentiation, and fusion culminating in the repair of damaged tissue. These processes are highly coordinated by paracrine signaling events that drive cytoskeletal rearrangement and cell-cell communication. Pannexins are a family of transmembrane channel proteins that mediate paracrine signaling by ATP release. It is known that Pannexin1 (Panx1) is expressed in skeletal muscle, however, the role of Panx1 during skeletal muscle development and regeneration remains poorly understood. Here we show that Panx1 is expressed on the surface of myoblasts and its expression is rapidly increased upon induction of differentiation and that Panx1-/- mice exhibit impaired muscle regeneration after injury. Panx1-/- myoblasts activate the myogenic differentiation program normally, but display marked deficits in migration and fusion. Mechanistically, we show that Panx1 activates P2 class purinergic receptors, which in turn mediate a lipid signaling cascade in myoblasts. This signaling induces bleb-driven amoeboid movement that in turn supports myoblast migration and fusion. Finally, we show that Panx1 is involved in the regulation of cell-matrix interaction through the induction of ADAMTS (Disintegrin-like and Metalloprotease domain with Thrombospondin-type 5) proteins that help remodel the extracellular matrix. These studies reveal a novel role for lipid-based signaling pathways activated by Panx1 in the coordination of myoblast activities essential for skeletal muscle regeneration.

Vitrifying multiple embryos in different arrangements does not alter the cooling rate.

Vitrification is the most common method of cryopreservation of gametes in fertility clinics due to its improved survival rates compared to slow freezing techniques. For the Open Cryotop® vitrification device, the number of oocytes, or embryos, mounted onto a single device can vary. In this work, a mathematical model is developed for the cooling of oocytes and embryos (samples). The model is solved computationally, to investigate whether varying the number of samples mounted onto the Open Cryotop® affects the cooling rates, and consequently the survival rates, of vitrified samples. Several realistic spatial arrangements of samples are examined, determining their temperature over time. In this way we quantify the effect of spatial arrangement on the cooling rate. Our results indicate that neither the spatial arrangement nor the number of mounted samples has a large effect on cooling rates, so long as the volume of the cryoprotectant remains minimal. The time taken for cooling is found to be on the order of half a second, or less, regardless of the spatial arrangement or number of mounted samples. Hence, rapid cooling can be achieved for any number or arrangement of samples, as long as device manufacturer guidelines are adhered to.

Further development of spinal cord retreatment dose estimation: including radiotherapy with protons and light ions.

PURPOSE: A graphical user interface (GUI) was developed to aid in the assessment of changes in the radiation tolerance of spinal cord/similar central nervous system tissues with time between two individual treatment courses. METHODS: The GUI allows any combination of photons, protons (or ions) to be used as the initial, or retreatment, radiotherapy courses. Allowances for clinical circumstances, of reduced tolerance, can also be made. The radiobiological model was published previously and has been incorporated with additional checks and safety features, to be as safe to use as possible. The proton option includes use of a fixed RBE of 1.1 (set as the default), or a variable RBE, the latter depending on the proton linear energy transfer (LET) for organs at risk. This second LET-based approach can also be used for ions, by changing the LET parameters. RESULTS: GUI screenshots are used to show the input and output parameters for different clinical situations used in worked examples. The results from the GUI are in agreement with manual calculations, but the results are now rapidly available without tedious and error-prone manual computations. The software outputs provide a maximum dose limit boundary, which should not be exceeded. Clinicians may also choose to further lower the number of treatment fractions, whilst using the same dose per fraction (or conversely a lower dose per fraction but with the same number of fractions) in order to achieve the intended clinical benefit as safely as possible. CONCLUSIONS: The new GUI will allow scientific-based estimations of time related radiation tolerance changes in the spinal cord and similar central nervous tissues (optic chiasm, brainstem), which can be used to guide the choice of retreatment dose fractionation schedules, with either photons, protons or ions.

The embryonic trunk neural crest microenvironment regulates the plasticity and invasion of human neuroblastoma via TrkB signaling.

Mistakes in trunk neural crest (NC) cell migration may lead to birth defects of the sympathetic nervous system (SNS) and neuroblastoma (NB) cancer. Receptor tyrosine kinase B (TrkB) and its ligand BDNF critically regulate NC cell migration during normal SNS development and elevated expression of TrkB is correlated with high-risk NB patients. However, in the absence of a model with in vivo interrogation of human NB cell and gene expression dynamics, the mechanistic role of TrkB in NB disease progression remains unclear. Here, we study the functional relationship between TrkB, cell invasion and plasticity of human NB cells by taking advantage of our validated in vivo chick embryo transplant model. We find that LAN5 (high TrkB) and SHSY5Y (moderate TrkB) human NB cells aggressively invade host embryos and populate typical NC targets, however loss of TrkB function significantly reduces cell invasion. In contrast, NB1643 (low TrkB) cells remain near the transplant site, but over-expression of TrkB leads to significant cell invasion. Invasive NB cells show enhanced expression of genes indicative of the most invasive host NC cells. In contrast, transplanted human NB cells down-regulate known NB tumor initiating and stem cell markers. Human NB cells that remain within the dorsal neural tube transplant also show enhanced expression of cell differentiation genes, resulting in an improved disease outcome as predicted by a computational algorithm. These in vivo data support TrkB as an important biomarker and target to control NB aggressiveness and identify the chick embryonic trunk neural crest microenvironment as a source of signals to drive NB to a less aggressive state, likely acting at the dorsal neural tube.

Symmetry breaking of tissue mechanics in wound induced hair follicle regeneration of laboratory and spiny mice.

Tissue regeneration is a process that recapitulates and restores organ structure and function. Although previous studies have demonstrated wound-induced hair neogenesis (WIHN) in laboratory mice (Mus), the regeneration is limited to the center of the wound unlike those observed in African spiny (Acomys) mice. Tissue mechanics have been implicated as an integral part of tissue morphogenesis. Here, we use the WIHN model to investigate the mechanical and molecular responses of laboratory and African spiny mice, and report these models demonstrate opposing trends in spatiotemporal morphogenetic field formation with association to wound stiffness landscapes. Transcriptome analysis and K14-Cre-Twist1 transgenic mice show the Twist1 pathway acts as a mediator for both epidermal-dermal interactions and a competence factor for periodic patterning, differing from those used in development. We propose a Turing model based on tissue stiffness that supports a two-scale tissue mechanics process: (1) establishing a morphogenetic field within the wound bed (mm scale) and (2) symmetry breaking of the epidermis and forming periodically arranged hair primordia within the morphogenetic field (µm scale). Thus, we delineate distinct chemo-mechanical events in building a Turing morphogenesis-competent field during WIHN of laboratory and African spiny mice and identify its evo-devo advantages with perspectives for regenerative medicine.

EPHA2-dependent outcompetition of KRASG12D mutant cells by wild-type neighbors in the adult pancreas.

As we age, our tissues are repeatedly challenged by mutational insult, yet cancer occurrence is a relatively rare event. Cells carrying cancer-causing genetic mutations compete with normal neighbors for space and survival in tissues. However, the mechanisms underlying mutant-normal competition in adult tissues and the relevance of this process to cancer remain incompletely understood. Here, we investigate how the adult pancreas maintains tissue health in vivo following sporadic expression of oncogenic Kras (KrasG12D), the key driver mutation in human pancreatic cancer. We find that when present in tissues in low numbers, KrasG12D mutant cells are outcompeted and cleared from exocrine and endocrine compartments in vivo. Using quantitative 3D tissue imaging, we show that before being cleared, KrasG12D cells lose cell volume, pack into round clusters, and E-cadherin-based cell-cell adhesions decrease at boundaries with normal neighbors. We identify EphA2 receptor as an essential signal in the clearance of KrasG12D cells from exocrine and endocrine tissues in vivo. In the absence of functional EphA2, KrasG12D cells do not alter cell volume or shape, E-cadherin-based cell-cell adhesions increase and KrasG12D cells are retained in tissues. The retention of KRasG12D cells leads to the early appearance of premalignant pancreatic intraepithelial neoplasia (PanINs) in tissues. Our data show that adult pancreas tissues remodel to clear KrasG12D cells and maintain tissue health. This study provides evidence to support a conserved functional role of EphA2 in Ras-driven cell competition in epithelial tissues and suggests that EphA2 is a novel tumor suppressor in pancreatic cancer.

Covid-19 transmission modelling of students returning home from university.

We provide an open-source model to estimate the number of secondary Covid-19 infections caused by potentially infectious students returning from university to private homes with other occupants. Using a Monte-Carlo method and data derived from UK sources, we predict that an infectious student would, on average, infect 0.94 other household members. Or, as a rule of thumb, each infected student would generate (just less than) one secondary within-household infection. The total number of secondary cases for all returning students is dependent on the virus prevalence within each student population at the time of their departure from campus back home. Although the proposed estimation method is general and robust, the results are sensitive to the input data. We provide Matlab code and a helpful online app (http://bit.ly/Secondary_infections_app) that can be used to estimate numbers of secondary infections based on local parameter values. This can be used worldwide to support policy making.