Nearby Cells Research Articles

Melanoma cells with acquired resistance to vemurafenib have decreased autophagic flux and display enhanced ability to transfer resistance

Over the last years, the incidence of melanoma, the deadliest form of skin cancer, has risen significantly. Nearly half of the melanoma patients exhibit the BRAFV600E mutation. Although the use of BRAF and MEK inhibitors (BRAFi and MEKi) showed an impressive success rate in melanoma patients, durability of response remains an issue because tumor quickly becomes resistant. Here, we generated and characterized Lu1205 and A375 melanoma cells resistant to vemurafenib (BRAFi). Resistant cells (Lu1205R and A375R) exhibit higher IC50 (5–6 fold increase) and phospho-ERK levels and 2–3 times reduced apoptosis than their sensitive parents (Lu1205S and A375S). Moreover, resistant cells are 2–3 times bigger, display a more elongated morphology and have a modulation of migration capacity. Interestingly, pharmacological inhibition of sphingosine kinases, that prevents sphingosine-1-phosphate production, reduces migration of Lu1205R cells by 50 %. In addition, although Lu1205R cells showed increased basal levels of the autophagy markers LC3II and p62, they have decreased autophagosome degradation and autophagy flux. Remarkably, expression of Rab27A and Rab27B, which are involved in the release of extracellular vesicles are dramatically augmented in resistant cells (i.e. 5–7 fold increase). Indeed, conditioned media obtained from Lu1205R cells increased the resistance to vemurafenib of sensitive cells. Hence, these results support that resistance to vemurafenib modulates migration and the autophagic flux and may be transferred to nearby sensitive melanoma cells by factors that are released to the extracellular milieu by resistant cells.

Robust statistical properties of T1 transitions in a multi-phase field model of cell monolayers

Large-scale tissue deformation which is fundamental to tissue development hinges on local cellular rearrangements, such as T1 transitions. In the realm of the multi-phase field model, we analyse the statistical and dynamical properties of T1 transitions in a confluent monolayer. We identify an energy profile that is robust to changes in several model parameters. It is characterized by an asymmetric profile with a fast increase in energy before the T1 transition and a sudden drop after the T1 transition, followed by a slow relaxation. The latter being a signature of the fluidity of the cell monolayer. We show that T1 transitions are sources of localised large deformation of the cells undergoing the neighbour exchange, and they induce other T1 transitions in the nearby cells leading to a chaining of events that propagate local cell deformation to large scale tissue flows.

Redox signaling in impaired cascades of wound healing: promising approach.

In the aging communities, wound healing management is a quite remarkable problem especially in elderly individuals. The optimal level of healing of wounds developed spontaneously or due to surgery is of critical importance in order to prevent the negative effects that may occur due to delayed healing (for example, organ or system damage caused by infections that may develop in the wound area). The deteriorated subcellular redox signaling is considered to be as the main factor in the chronicity of wounds. The pivotal role of mitochondria in redox regulation reveals the importance of modulation of redox signaling pathways in senescent cells. Secretory factors released upon the acquisition of senescence-associated secretory phenotype (SASP) function in a paracrine manner to disseminate impaired tissue redox status by affecting the redox metabolome of nearby cells, which could promote age-related pro-inflammatory pathologies. Evaluating the wound-site redox regulation in impaired redox signaling pathways may help prevent the formation of chronic wounds and the development of long-term complications of the wounds, especially in the elderly. Using the redox modulatory pharmacologically active substances targeting the senescent cells in chronic wound areas hopefully opens a new avenue in wound management. As the signaling mechanisms of wound healing and its relationship with advanced age become more clearly understood, many promising therapeutic approaches and redox modulator substances are coming into clinical view for the management of chronic wounds.

Immunostimulatory DNA Hydrogel Enhances Protective Efficacy of Nanotoxoids against Bacterial Infection.

While vaccines have been highly successful in protecting against various infections, there are still many high-priority pathogens for which there are no clinically approved formulations. To overcome this challenge, researchers have explored the use of nanoparticulate strategies for more effective antigen delivery to the immune system. Along these lines, nanotoxoids are a promising biomimetic platform that leverages cell membrane coating technology to safely deliver otherwise toxic bacterial antigens in their native form for antivirulence vaccination. Here, in order to further boost their immunogenicity, nanotoxoids formulated against staphylococcal α-hemolysin are embedded into a DNA-based hydrogel with immunostimulatory CpG motifs. The resulting nanoparticle-hydrogel composite is injectable and improves the in vivo delivery of vaccine antigens while simultaneously stimulating nearby immune cells. This leads to elevated antibody production and stronger antigen-specific cellular immune responses. In murine models of pneumonia and skin infection caused by methicillin-resistant Staphylococcus aureus, mice vaccinated with the hybrid vaccine formulation are well-protected. This work highlights the benefits of combining nanoparticulate antigen delivery systems with immunostimulatory hydrogels into a single platform, and the approach can be readily generalized to a wide range of infectious diseases.

Astrocytic uptake of neuronal corpses promotes cell-to-cell spreading of tau pathology

Tau deposits in astrocytes are frequently found in Alzheimer’s disease (AD) and other tauopathies. Since astrocytes do not express tau, the inclusions have been suggested to be of neuronal origin. However, the mechanisms behind their appearance and their relevance for disease progression remain unknown. Here we demonstrate, using a battery of experimental techniques that human astrocytes serve as an intermediator, promoting cell-to-cell spreading of pathological tau. Human astrocytes engulf and process, but fail to fully degrade dead neurons with tau pathology, as well as synthetic tau fibrils and tau aggregates isolated from AD brain tissue. Instead, the pathogenic tau is spread to nearby cells via secretion and tunneling nanotube mediated transfer. By performing co-culture experiments we could show that tau-containing astrocytes induce tau pathology in healthy human neurons directly. Furthermore, our results from a FRET based seeding assay, demonstrated that the tau proteoforms secreted by astrocytes have an exceptional seeding capacity, compared to the original tau species engulfed by the cells. Taken together, our study establishes a central role for astrocytes in mediating tau pathology, which could be of relevance for identifying novel treatment targets for AD and other tauopathies.

Extracellular vesicles: pathogenic messengers and potential therapy for neonatal lung diseases.

Extracellular vesicles (EVs) are a heterogeneous group of nano-sized membranous structures increasingly recognized as mediators of intercellular and inter-organ communication. EVs contain a cargo of proteins, lipids and nucleic acids, and their cargo composition is highly dependent on the biological function of the parental cells. Their cargo is protected from the extracellular environment by the phospholipid membrane, thus allowing for safe transport and delivery of their intact cargo to nearby or distant target cells, resulting in modification of the target cell's gene expression, signaling pathways and overall function. The highly selective, sophisticated network through which EVs facilitate cell signaling and modulate cellular processes make studying EVs a major focus of interest in understanding various biological functions and mechanisms of disease. Tracheal aspirate EV-miRNA profiling has been suggested as a potential biomarker for respiratory outcome in preterm infants and there is strong preclinical evidence showing that EVs released from stem cells protect the developing lung from the deleterious effects of hyperoxia and infection. This article will review the role of EVs as pathogenic messengers, biomarkers, and potential therapies for neonatal lung diseases.

Fractal dimension to characterize interactions between blood and lymphatic endothelial cells

Spatial patterning of different cell types is crucial for tissue engineering and is characterized by the formation of sharp boundary between segregated groups of cells of different lineages. The cell−cell boundary layers, depending on the relative adhesion forces, can result in kinks in the border, similar to fingering patterns between two viscous partially miscible fluids which can be characterized by its fractal dimension. This suggests that mathematical models used to analyze the fingering patterns can be applied to cell migration data as a metric for intercellular adhesion forces. In this study, we develop a novel computational analysis method to characterize the interactions between blood endothelial cells (BECs) and lymphatic endothelial cells (LECs), which form segregated vasculature by recognizing each other through podoplanin. We observed indiscriminate mixing with LEC−LEC and BEC−BEC pairs and a sharp boundary between LEC−BEC pair, and fingering-like patterns with pseudo-LEC−BEC pairs. We found that the box counting method yields fractal dimension between 1 for sharp boundaries and 1.3 for indiscriminate mixing, and intermediate values for fingering-like boundaries. We further verify that these results are due to differential affinity by performing random walk simulations with differential attraction to nearby cells and generate similar migration pattern, confirming that higher differential attraction between different cell types result in lower fractal dimensions. We estimate the characteristic velocity and interfacial tension for our simulated and experimental data to show that the fractal dimension negatively correlates with capillary number (Ca), further indicating that the mathematical models used to study viscous fingering pattern can be used to characterize cell−cell mixing. Taken together, these results indicate that the fractal analysis of segregation boundaries can be used as a simple metric to estimate relative cell−cell adhesion forces between different cell types.

High-LET-Radiation-Induced Persistent DNA Damage Response Signaling and Gastrointestinal Cancer Development.

Ionizing radiation (IR) dose, dose rate, and linear energy transfer (LET) determine cellular DNA damage quality and quantity. High-LET heavy ions are prevalent in the deep space environment and can deposit a much greater fraction of total energy in a shorter distance within a cell, causing extensive DNA damage relative to the same dose of low-LET photon radiation. Based on the DNA damage tolerance of a cell, cellular responses are initiated for recovery, cell death, senescence, or proliferation, which are determined through a concerted action of signaling networks classified as DNA damage response (DDR) signaling. The IR-induced DDR initiates cell cycle arrest to repair damaged DNA. When DNA damage is beyond the cellular repair capacity, the DDR for cell death is initiated. An alternative DDR-associated anti-proliferative pathway is the onset of cellular senescence with persistent cell cycle arrest, which is primarily a defense mechanism against oncogenesis. Ongoing DNA damage accumulation below the cell death threshold but above the senescence threshold, along with persistent SASP signaling after chronic exposure to space radiation, pose an increased risk of tumorigenesis in the proliferative gastrointestinal (GI) epithelium, where a subset of IR-induced senescent cells can acquire a senescence-associated secretory phenotype (SASP) and potentially drive oncogenic signaling in nearby bystander cells. Moreover, DDR alterations could result in both somatic gene mutations as well as activation of the pro-inflammatory, pro-oncogenic SASP signaling known to accelerate adenoma-to-carcinoma progression during radiation-induced GI cancer development. In this review, we describe the complex interplay between persistent DNA damage, DDR, cellular senescence, and SASP-associated pro-inflammatory oncogenic signaling in the context of GI carcinogenesis.

Cell tracking with multifeature fusion

Cell tracking is currently a powerful tool in a variety of biomedical research topics. Most cell tracking algorithms follow the tracking by detection paradigm. Detection is critical for subsequent tracking. Unfortunately, very accurate detection is not easy due to many factors like densely populated, low contrast, and possible impurities included. Keeping tracking multiple cells across frames suffers many difficulties, as cells may have similar appearance, they may change their shapes, and nearby cells may interact each other. In this paper, we propose a unified tracking-by-detection framework, where a powerful detector AttentionUnet++, a multimodal extension of the Efficient Convolution Operators algorithm, and an effective data association algorithm are included. Experiments show that the proposed algorithm can outperform many existing cell tracking algorithms.

Ribosomal protein mutations and cell competition: autonomous and nonautonomous effects on a stress response.

Ribosomal proteins (Rps) are essential for viability. Genetic mutations affecting Rp genes were first discovered in Drosophila, where they represent a major class of haploinsufficient mutations. One mutant copy gives rise to the dominant "Minute" phenotype, characterized by slow growth and small, thin bristles. Wild-type (WT) and Minute cells compete in mosaics, that is, Rp+/- are preferentially lost when their neighbors are of the wild-type genotype. Many features of Rp gene haploinsufficiency (i.e. Rp+/- phenotypes) are mediated by a transcriptional program. In Drosophila, reduced translation and slow growth are under the control of Xrp1, a bZip-domain transcription factor induced in Rp mutant cells that leads ultimately to the phosphorylation of eIF2α and consequently inhibition of most translation. Rp mutant phenotypes are also mediated transcriptionally in yeast and in mammals. In mammals, the Impaired Ribosome Biogenesis Checkpoint activates p53. Recent findings link Rp mutant phenotypes to other cellular stresses, including the DNA damage response and endoplasmic reticulum stress. We suggest that cell competition results from nonautonomous inputs to stress responses, bringing decisions between adaptive and apoptotic outcomes under the influence of nearby cells. In Drosophila, cell competition eliminates aneuploid cells in which loss of chromosome leads to Rp gene haploinsufficiency. The effects of Rp gene mutations on the whole organism, in Minute flies or in humans with Diamond-Blackfan Anemia, may be inevitable consequences of pathways that are useful in eliminating individual cells from mosaics. Alternatively, apparently deleterious whole organism phenotypes might be adaptive, preventing even more detrimental outcomes. In mammals, for example, p53 activation appears to suppress oncogenic effects of Rp gene haploinsufficiency.

Study on the mechanism of CXCR3 expression in paracancer and tumor tissues of colon cancer patients.

e15506 Background: Colorectal cancer (CRC) is one of the most common types of malignant tumors, and its incidence is increasing year by year.Chemokines are small cytokines or signaling proteins secreted by cells. They have the ability to induce directional chemotactic migration of nearby responding cells and can mediate intracellular signal transduction by binding to 18 G protein-coupled receptor families.C-X-C motif chemokine receptor 3 (CXCR3) is activated by three Interferon-γ inducible ligands CXCL9, CXCL10 and CXCL11 and encodes 368 amino acids. Its molecular weight was about 41KDa and the cDNA was 1104bp in length.In recent years, a large number of studies have confirmed that the expression of CXCR3 and its ligands in the body is closely related to tumor immunity, tumorigenesis and metastasis.Therefore, the aim of this study is to investigate the expression of CXCR3 in tumor and adjacent intestinal tissues of patients with colorectal cancer and the effects of related gene detection on tumor proliferation, migration, invasion and recurrence in patients with colorectal cancer. Methods: Flow cytometry was used to detect 40 colon cancer patients who had not received neoadjuvant therapy in the Department of General Surgery of the Affiliated Cancer Hospital of Zhengzhou University. The expression of CXCR3, PD-1, CD4+, CD45+ and CD8+T cells in tumor and para-tumor specimens (taken > 2cm from the edge of the cancer) was detected, and the expression characteristics of CXCR3 in colon cancer patients and its correlation with general clinical data were analyzed. The correlation between KRAS, MSS, MSI-H gene mutations and colon cancer was analyzed under the condition of different lymphocyte expression. Results: 1.CXCR3+CD8+T cells were significantly different, and CXCR3+CD4+T cells were significantly different. These results suggest that CXCR3 expression with different lymphocytes may play an important role in tumor cell growth.2.The difference of CD45+T cells was statistically significant. This suggests that the expression of CD45+T cells may also affect tumor growth.3.CXCR3+CD4+T cells may play a role in promoting tumor metastasis. Conclusions: The expression of CXCR3+CD8+T cells, CXCR3+CD4+T cells and CD45+T lymphocytes in tumor tissues of colon cancer patients is correlated with the expression of adjacent tissues. The expression of PD-1+CD8+ lymphocytes in tumor tissues is less than that in adjacent tissues, indicating that they are related to tumor metastasis and proliferation. CXCR3 may play an important role in lymph node metastasis, and PD-1 expression may also be related to patient gender. Therefore, the expression of CXCR3 and T lymphocytes in tumor tissues and adjacent tissues of patients is helpful for the diagnosis and treatment of colon cancer, and has important value in clinical application.

Extracellular Vesicles and Intercellular Communication: Challenges for In Vivo Molecular Imaging and Tracking.

Extracellular vesicles (EVs) are a heterogeneous class of cell-derived membrane vesicles released by various cell types that serve as mediators of intercellular signaling. When released into circulation, EVs may convey their cargo and serve as intermediaries for intracellular communication, reaching nearby cells and possibly also distant organs. In cardiovascular biology, EVs released by activated or apoptotic endothelial cells (EC-EVs) disseminate biological information at short and long distances, contributing to the development and progression of cardiovascular disease and related disorders. The significance of EC-EVs as mediators of cell-cell communication has advanced, but a thorough knowledge of the role that intercommunication plays in healthy and vascular disease is still lacking. Most data on EVs derive from in vitro studies, but there are still little reliable data available on biodistribution and specific homing EVs in vivo tissues. Molecular imaging techniques for EVs are crucial to monitoring in vivo biodistribution and the homing of EVs and their communication networks both in basal and pathological circumstances. This narrative review provides an overview of EC-EVs, trying to highlight their role as messengers of cell-cell interaction in vascular homeostasis and disease, and describes emerging applications of various imaging modalities for EVs visualization in vivo.

An information theoretic approach to detecting spatially varying genes

A key step in spatial transcriptomics is identifying genes with spatially varying expression patterns. We adopt an information theoretic perspective to this problem by equating the degree of spatial coherence with the Jensen-Shannon divergence between pairs of nearby cells and pairs of distant cells. To avoid the notoriously difficult problem of estimating information theoretic divergences, we use modern approximation techniques to implement a computationally efficient algorithm designed to scale with in situ spatial transcriptomics technologies. In addition to being highly scalable, we show that our method, which we call maximization of spatial information (Maxspin), improves accuracy across several spatial transcriptomics platforms and a variety of simulations when compared with a variety of state-of-the-art methods. To further demonstrate the method, we generated in situ spatial transcriptomics data in a renal cell carcinoma sample using the CosMx Spatial Molecular Imager and used Maxspin to reveal novel spatial patterns of tumor cell gene expression.

Molecular pathways and therapeutic targets linked to triple-negative breast cancer (TNBC).

Cancer is a group of diseases characterized by uncontrolled cellular growth, abnormal morphology, and altered proliferation. Cancerous cells lose their ability to act as anchors, allowing them to spread throughout the body and infiltrate nearby cells, tissues, and organs. If these cells are not identified and treated promptly, they will likely spread. Around 70% of female breast cancers are caused by a mutation in the BRCA gene, specifically BRCA1. The absence of progesterone, oestrogen and HER2 receptors (human epidermal growth factor)distinguishes the TNBC subtype of breast cancer. There were approximately 6,85,000 deaths worldwide and 2.3 million new breast cancer cases in women in 2020. Breast cancer is the most common cancer globally, affecting 7.8 million people at the end of 2020. Compared to other cancer types, breast cancer causes more women to lose disability-adjusted life years (DALYs). Worldwide, women can develop breast cancer at any age after puberty, but rates increase with age. The maintenance of mammary stem cell stemness is disrupted in TNBC, governed by signalling cascades controlling healthy mammary gland growth and development. Interpreting these essential cascades may facilitate an in-depth understanding of TNBC cancer and the search for an appropriate therapeutic target. Its treatment remains challenging because it lacks specific receptors, which renders hormone therapy and medications ineffective. In addition to radiotherapy, numerous recognized chemotherapeutic medicines are available as inhibitors of signalling pathways, while others are currently undergoing clinical trials. This article summarizes the vital druggable targets, therapeutic approaches, and strategies associated with TNBC.

Raster Intervals: An Approximation Technique for Polygon Intersection Joins

Many data science applications, most notably Geographic Information Systems, require the computation of spatial joins between large object collections. The objective is to find pairs of objects that intersect, i.e., share at least one common point. The intersection test is very expensive especially for polygonal objects. Therefore, the objects are typically approximated by their minimum bounding rectangles (MBRs) and the join is performed in two steps. In the filter step, all pairs of objects whose MBRs intersect are identified as candidates; in the refinement step, each of the candidate pairs is verified for intersection. The refinement step has been shown notoriously expensive, especially for polygon-polygon joins, constituting the bottleneck of the entire process. We propose a novel approximation technique for polygons, which (i) rasterizes them using a fine grid, (ii) models groups of nearby cells that intersect a polygon as an interval, and (iii) encodes each interval by a bitstring that captures the overlap of each cell in it with the polygon. We also propose an efficient intermediate filter, which is applied on the object approximations before the refinement step, to avoid it for numerous object pairs. Via experimentation with real data, we show that the end-to-end spatial join cost can be reduced by up to one order of magnitude with the help of our filter and by at least three times compared to using alternative intermediate filters.

Revolutionizing Radiotoxicity Management with Mesenchymal Stem Cells and Their Derivatives: A Focus on Radiation-Induced Cystitis.

Although radiation therapy plays a crucial role in cancer treatment, and techniques have improved continuously, irradiation induces side effects in healthy tissue. Radiation cystitis is a potential complication following the therapeutic irradiation of pelvic cancers and negatively impacts patients' quality of life (QoL). To date, no effective treatment is available, and this toxicity remains a therapeutic challenge. In recent times, stem cell-based therapy, particularly the use of mesenchymal stem cells (MSC), has gained attention in tissue repair and regeneration due to their easy accessibility and their ability to differentiate into several tissue types, modulate the immune system and secrete substances that help nearby cells grow and heal. In this review, we will summarize the pathophysiological mechanisms of radiation-induced injury to normal tissues, including radiation cystitis (RC). We will then discuss the therapeutic potential and limitations of MSCs and their derivatives, including packaged conditioned media and extracellular vesicles, in the management of radiotoxicity and RC.

The Presence of Guttae in Fuchs Endothelial Corneal Dystrophy Explants Correlates With Cellular Markers of Disease Progression.

Fuchs endothelial corneal dystrophy (FECD) is characterized by an accelerated depletion of corneal endothelial cells. There is growing evidence that mitochondrial exhaustion is central in the pathology. Indeed, endothelial cells loss in FECD forces the remaining cells to increase their mitochondrial activity, leading to mitochondrial exhaustion. This generates oxidation, mitochondrial damage, and apoptosis, fueling a vicious cycle of cells' depletion. This depletion ultimately causes corneal edema and irreversible loss of transparency and vision. Concurrently to endothelial cells loss, the formation of extracellular mass called guttae on the Descemet's membrane, is a hallmark of FECD. The pathology origins at the center of the cornea and progress outward, like the appearance of guttae. Using corneal endothelial explants from patients with late-stage FECD at the time of their corneal transplantation, we correlated mitochondrial markers (mitochondrial mass, potential, and calcium) and the level of oxidative stress and apoptotic cells, with the area taken by guttae. The different markers have been analyzed using fluorescent-specific probes and microscopic analysis. We observed a positive correlation between the presence of guttae and the level of mitochondrial calcium and apoptotic cells. We found a negative correlation between the presence of guttae and the level of mitochondrial mass, membrane potential, and oxidative stress. Taken together, these results show that the presence of guttae is correlated with negative outcome in the mitochondrial health, oxidative status, and survival of nearby endothelial cells. This study provides insight on FECD etiology that could lead to treatment targeting mitochondrial stress and guttae.

Single-cell transcriptomics of pathological pregnancies

Pregnancy is a complicated process involving various anatomical and physiological changes to provide a suitable environment for fetal development, to meet the increased metabolic demands, and to prepare for labor. While most pregnancies and births are uneventful, all pregnancies are at risk of complications. No less than 15% of all pregnant women develop a potentially lifethreatening complication or may also experience an unpleasant outcome. Conventional sequencing has been widely used in this field for diagnoses and treatment planning. However, it lacks the precise resolution to identify transcriptomic variation between the nearby cell types. Single-cell RNA sequencing is a novel approach that through single-cell isolation, transcript capturing, and development and sequencing of expression libraries allows the assessments of fundamental biological properties of cell populations and biological systems at unprecedented resolution. The single-cell sequencing technology is a powerful tool for investigating cell distribution and cell-to-cell relationships in human reproduction. Since 2016, the technique has contributed to the discovery of many transcriptomic atlases of human embryos, placenta, decidua, and endometrium and the identification of various crucial regulatory pathways in fetal development. Here, we briefly describe the application of single-cell RNA sequencing in the studies of physiological processes and pathological mechanisms of pregnancy.

Dynamic Biophysical Cues Near the Tip Cell Microenvironment Provide Distinct Guidance Signals to Angiogenic Neovessels.

The formation of new vascular networks via angiogenesis is a crucial biological mechanism to balance tissue metabolic needs, yet the coordination of factors that influence the guidance of growing neovessels remain unclear. This study investigated the influence of extracellular cues within the immediate environment of sprouting tips over multiple hours and obtained quantitative relationships describing their effects on the growth trajectories of angiogenic neovessels. Three distinct microenvironmental cues-fibril tracks, ECM density, and the presence of nearby cell bodies-were extracted from 3D time series image data. The prominence of each cue was quantified along potential sprout trajectories to predict the response to multiple microenvironmental factors simultaneously. Sprout trajectories significantly correlated with the identified microenvironmental cues. Specifically, ECM density and nearby cellular bodies were the strongest predictors of the trajectories taken by neovessels (p < 0.001 and p = 0.016). Notwithstanding, direction changing trajectories, deviating from the initial neovessel orientation, were significantly correlated with fibril tracks (p = 0.003). Direction changes also occurred more frequently with strong microenvironmental cues. This provides evidence for the first time that local matrix fibril alignment influences changes in sprout trajectories but does not materially contribute to persistent sprouting. Together, our results suggest the microenvironmental cues significantly contribute to guidance of sprouting trajectories. Further, the presented methods quantitatively distinguish the influence of individual microenvironmental stimuli during guidance.

A particle-size dependent smoothing scheme for polydisperse Euler-Lagrange simulations

In Euler-Lagrange models for particulate systems, the information exchange of multiphase coupling terms, i.e. drag force, heat transfer, or mass transfer, is often smoothed from particles' location to nearby computational cells when the cell and particle sizes are comparable. The diffusion-based smoothing is among the most popular approach. However, when it comes to polydisperse systems, the state-of-the-art constant diffusivity approach does not consider variation in particle sizes, resulting in an even smoothing of exchanged information across all particles with different sizes.In this paper, a particle-size dependent smoothing scheme named “non-constant diffusivity approach” is proposed. This approach distributes the exchanged information based on the local Sauter diameter d32 such that the area of influence per particle varies by size. The one-dimensional analytical solution of the non-constant diffusivity approach is first derived and two control parameters L⁎ and S are identified, where L⁎ determines the characteristic length of the diffusivity and S determines the magnitude of the diffusivity. Together they control the characteristic length scale ℓ˜c of the smoothing operation. In the one-dimensional study, it is found that the proposed smoothing method is most suitable for the dilute particulate regime. The investigation is extended to a three-dimensional dilute particle flow based on the experiment of the CRIEPI (Central Research Institute of Electric Power Industry) pulverized coal burner. It is shown that using the non-constant diffusivity smoothing, the prediction of the O2 concentration is more accurate than when using the constant diffusivity smoothing approach, which assumes a universal smoothing length for all sizes of particles. The findings suggest that when it comes to polydisperse particulate systems, the area of influence per particle on the fluid depends on the particle size. The proposed non-constant diffusivity approach can describe that with the benefits of cheap computational cost, conservation of exchanged quantities, and easy-to-implement.