Nearby Cells Research Articles

Approaches to incorporate extracellular vesicles into exposure science, toxicology, and public health research.

Extracellular vesicles (EVs) represent small, membrane-enclosed particles that are derived from parent cells and are secreted into the extracellular space. Once secreted, EVs can then travel and communicate with nearby or distant cells. Due to their inherent stability and biocompatibility, these particles can effectively transfer RNAs, proteins, and chemicals/metabolites from parent cells to target cells, impacting cellular and pathological processes. EVs have been shown to respond to disease-causing agents and impact target cells. Given that disease-causing agents span environmental contaminants, pathogens, social stressors, drugs, and other agents, the translation of EV methods into public health is now a critical research gap. This paper reviews approaches to translate EVs into exposure science, toxicology, and public health applications, highlighting blood as an example due to its common use within clinical, epidemiological, and toxicological studies. Approaches are reviewed surrounding the isolation and characterization of EVs and molecular markers that can be used to inform EV cell-of-origin. Molecular cargo contained within EVs are then discussed, including an original analysis of blood EV data from Vesiclepedia. Methods to evaluate functional consequences and target tissues of EVs are also reviewed. Lastly, the expanded integration of these approaches into future public health applications is discussed, including the use of EVs as promising biomarkers of exposure, effect, and disease.

Essential roles of YAP-TEAD complex in adult stem cell development during thyroid hormone-induced intestinal remodeling of Xenopus laevis.

During amphibian metamorphosis which is triggered by thyroid hormone (TH), the small intestine is extensively remodeled from the larval to adult form. In the Xenopus laevis intestine, some of the larval epithelial cells dedifferentiate into adult stem cells, which newly form the adult epithelium similar to the mammalian one. We have previously shown that TH-activated Shh, Wnt and Notch signaling pathways play important roles in adult epithelial development. Here we focus on the Hippo signaling pathway, which is known to interact with these pathways in the mammalian intestine. Our quantitative RT-PCR analysis indicates that the expression of genes involved in this pathway including YAP1, TAZ, TEAD1 and core kinases is differently regulated by TH in the metamorphosing intestine. Additionally, we show by in situ hybridization and immunohistochemistry that the transcriptional co-activator YAP1, a major effector of the Hippo signaling, is expressed in the adult stem cells and connective tissue cells surrounding them and that YAP1 protein is localized in either nucleus or cytoplasm of the stem cells. We further show that YAP1 binds its binding partner TEAD1 (transcription factor) in vivo and that their interaction is inhibited by verteporfin (VP). More importantly, by using VP in organ cultureof the tadpole intestine, we experimentally demonstrate that the inhibition of YAP1-TEAD1 interaction decreases both TH-induced stem cells expressing LGR5 and nearby connective tissue cells in number and proliferation, leading to the failure of adult epithelial development. Our results indicate that YAP-TEAD complex is required for stem cell development during intestinal remodeling.

Reconstruction of neocortex: Organelles, compartments, cells, circuits, and activity

We assembled a semi-automated reconstruction of L2/3 mouse primary visual cortex from ∼250× 140× 90μm3 of electron microscopic images, including pyramidal and non-pyramidal neurons, astrocytes, microglia, oligodendrocytes and precursors, pericytes, vasculature, nuclei, mitochondria, and synapses. Visual responses of a subset of pyramidal cells are included. The data are publicly available, along with tools for programmatic and three-dimensional interactive access. Brief vignettes illustrate the breadth of potential applications relating structure to function in cortical circuits and neuronal cell biology. Mitochondria and synapse organization are characterized as a function of path length from the soma. Pyramidal connectivity motif frequencies are predicted accurately using a configuration model of random graphs. Pyramidal cells receiving more connections from nearby cells exhibit stronger and more reliable visual responses. Sample code shows data access and analysis.

Coupling Effects of Crosstalk and Parasitic Loss on Capacitive Micromachined Ultrasonic Transducers

Capacitive micromachined ultrasonic transducers (CMUTs) have been widely utilized in applications of biomolecule monitoring, ultrasound medical diagnosis, and ultrasound therapy because of their advantages in high-level integration with integrated circuits, good impedance matching for acoustic transmission, and flexible element and array configuration compared with conventional piezoelectric ceramic transducers. Crosstalk effects on dynamics of a CMUT element, <i>i.e.</i> electrical, mechanical, and acoustic performance, would lead to unexpected spurious resonances. In this study, the mutual interaction from fluid and nearby cells in a CMUT element is newly investigated specially aiming to characterize their coupling effects with series and parallel parasitic effects based on a nonlinear Equivalent Circuit Model (ECM). The mutual interaction is evaluated with the electromechanical and acoustic characteristics by comparison between ECM and 3D Finite Element Analysis (FEA). Two representative CMUT element configurations, that are the rectangular with nine cells and the hexagonal with seven cells, are analyzed with different center-to-center distance. The radii of cells are set to be <inline-formula> <tex-math notation="LaTeX">$\lambda $ </tex-math></inline-formula>/8 with different edge-to-edge distances. The parasitic effects are modeled by a series parasitic factor and a parallel-capacitance parasitic ratio. The coupling influence of crosstalk and parasitic effects on the performance of a CMUT element is evaluated, such as the impedance, phase, conductance, velocity, and ultrasound pressure field. The results of ECM-FEA-based methods show good agreements, and the improved ECM can be used for co-parasitic extraction with front-end interface.

Implantable Devices for the Treatment of Breast Cancer.

Breast cancer is one of the leading causes of death in the female population worldwide. Standard treatments such as chemotherapy show noticeable results. However, along with killing cancer cells, it causes systemic toxicity and apoptosis of the nearby healthy cells, therefore patients must endure side effects during the treatment process. Implantable drug delivery devices that enhance therapeutic efficacy by allowing localized therapy with programmed or controlled drug release can overcome the shortcomings of conventional treatments. An implantable device can be composed of biopolymer materials, nanocomposite materials, or a combination of both. This review summarizes the recent research and current state-of-the art in these types of implantable devices and gives perspective for future directions.

Yorkie drives supercompetition by non-autonomous induction of autophagy via bantam microRNA in Drosophila

Mutations in the tumor-suppressor Hippo pathway lead to activation of the transcriptional coactivator Yorkie (Yki), which enhances cell proliferation autonomously and causes cell death non-autonomously. While Yki-induced cell proliferation has extensively been studied, the mechanism by which Yki causes cell death in nearby wild-type cells, a phenomenon called supercompetition, and its role in tumorigenesis remained unknown. Here, we show that Yki-induced supercompetition is essential for tumorigenesis and is driven by non-autonomous induction of autophagy. Clones of cells mutant for a Hippo pathway component fat activate Yki and cause autonomous tumorigenesis and non-autonomous cell death in Drosophila eye-antennal discs. Through a genetic screen in Drosophila, we find that mutations in autophagy-related genes or NF-κB genes in surrounding wild-type cells block both fat-induced tumorigenesis and supercompetition. Mechanistically, fat mutant cells upregulate Yki-target microRNA bantam, which elevates protein synthesis levels via activation of TOR signaling. This induces elevation of autophagy in neighboring wild-type cells, which leads to downregulation of IκB Cactus and thus causes NF-κB-mediated induction of the cell death gene hid. Crucially, upregulation of bantam is sufficient to make cells to be supercompetitors and downregulation of endogenous bantam is sufficient for cells to become losers of cell competition. Our data indicate that cells with elevated Yki-bantam signaling cause tumorigenesis by non-autonomous induction of autophagy that kills neighboring wild-type cells.

Skin senescence: mechanisms and impact on whole-body aging.

The skin is the largest organ and has a key protective role. Similar to any other tissue, the skin is influenced not only by intrinsic/chronological aging, but also by extrinsic aging, triggered by environmental factors that contribute to accelerating the skin aging process. Aged skin shows structural, cellular, and molecular changes and accumulation of senescent cells. These senescent cells can induce or accelerate the age-related dysfunction of other nearby cells from the skin, or from different origins. However, the extent and underlying mechanisms remain unknown. In this opinion, we discuss the possible relevant role of skin senescence in the induction of aging phenotypes to other organs/tissues, contributing to whole-body aging. Moreover, we suggest that topical administration of senolytics/senotherapeutics could counteract the overall whole-body aging phenotype.

Reliability of Error Correction Codes Against Multiple Events by Accumulation

Modern nanoscale devices with storage capacity typically implement error correction codes (ECCs) in order to cope with the effects of natural radiation. Thus, different state-of-the-art ECC techniques aim at preventing data corruption when different numbers of errors (or bitflips) occur in the same logical memory word. However, even though bit interleaving prevents a single particle (such as a proton or a neutron) from flipping several cells in the same word, it cannot be discarded that two independent events may affect nearby cells in the same word and, therefore, would provoke a multiple bit upset (MBU) or equivalent. This article studies the reliability of various state-of-the-art ECC techniques designed for memories to maintain their data integrity under radiation or any other hazardous conditions, where said event accumulation is likely to occur. For this purpose, a set of easy-to-use equations will be provided to estimate the probability of error occurrence in a memory that implements different ECCs, as a function of the number of accumulated bitflips, size of the memory, and word size.

SODAR: Segmenting Objects by Dynamically Aggregating Neighboring Mask Representations.

Recent state-of-the-art one-stage instance segmentation model SOLO divides the input image into a grid and directly predicts per grid cell object masks with fully-convolutional networks, yielding comparably good performance as traditional two-stage Mask R-CNN yet enjoying much simpler architecture and higher efficiency. We observe SOLO generates similar masks for an object at nearby grid cells, and these neighboring predictions can complement each other as some may better segment certain object part, most of which are however directly discarded by non-maximum-suppression. Motivated by the observed gap, we develop a novel learning-based aggregation method that improves upon SOLO by leveraging the rich neighboring information while maintaining the architectural efficiency. The resulting model is named SODAR. Unlike the original per grid cell object masks, SODAR is implicitly supervised to learn mask representations that encode geometric structure of nearby objects and complement adjacent representations with context. The aggregation method further includes two novel designs: 1) a mask interpolation mechanism that enables the model to generate much fewer mask representations by sharing neighboring representations among nearby grid cells, and thus saves computation and memory; 2) a deformable neighbour sampling mechanism that allows the model to adaptively adjust neighbor sampling locations thus gathering mask representations with more relevant context and achieving higher performance. SODAR significantly improves the instance segmentation performance, e.g., it outperforms a SOLO model with ResNet-101 backbone by 2.2 AP on COCO test set, with only about 3% additional computation. We further show consistent performance gain with the SOLOv2 model.

Role of Ferritin in Immunity, Inflammation and Malignancy

Since it has been used as the principal iron storage protein in cells for over 70 years, ferritin has been the subject of ongoing research. Recently the multifunctional role of ferritin protein has been observed with potential involvement in proliferation, angiogenesis, immunosuppression, and iron transport, as per several studies and evidence. Ferritin may promote tumour growth, promote angiogenesis, and suppress the immune system of the host. A higher ferritin level in cancer cells is linked to disease progression, therapy resistance, and a worse prognosis. Additionally, certain cancer cells have the ability to generate ferritin, which allows them to be partially independent of external iron supplies, or they can rob iron from nearby cells and tissues and retain it as ferritin to maintain their accelerated multiplication. The purpose of this research is to review the available information about the role of ferritin in immunity, inflammation and malignancy. Elevated ferritin levels are among the significant factors affecting defence mechanism during infection, which deprive bacterial growth of iron and safeguard immune cell function. Additionally, it might be protective by reducing free radical generation and regulating immunomodulation. With levels that reflect the severity of acute and chronic inflammation in infectious, rheumatologic, hematologic, and neoplastic disease, serum ferritin is a well-known acute-phase reactant. While it is well established that ferritin levels and inflammatory activity are correlated, and ferritin has a direct causative role in mediating inflammatory diseases. However further research is needed to elaborately study the role and mechanism of ferratin in inflammation, immunity and malignancy.

Exosome Marker Proteins of Tumor-Associated Fibroblasts and Exosome-Derived miR-92a-3p Act as Potential Biomarkers for Liver Cancer.

Many recent studies have shown that microRNAs (miRNAs) in exosomes can be absorbed by nearby or distant cells, and the abnormal expression of these exosomal miRNAs is associated with most pathological progresses. In this study, we explored the diagnostic value of exosome marker proteins and exosome-derived miR-92a-3p in liver cancer. The clinicopathological data of 60 patients with liver cancer admitted to Tanghan Gongren Hospital from October 2017 to October 2019 were collected. Tumor tissue and adjacent tissue were collected during surgery. Quantitative reverse transcription polymerase chain reaction and Western blot were used to detect the expression levels of miR-92a-3p in exosomes of fibroblasts and tumor tissue, and exosome marker proteins. In liver cancer tissue and fibroblast exosomes, the expression of miR-92a-3p was significantly increased. The receiver operator characteristic curve of the expression level of miR-92a-3p in exosomes and tissue showed that the area under the curve was 0.906 and 0.911, respectively. HSP70 and CD63 were highly expressed in the tissue of liver cancer and fibroblast exosomes. miR-92a-3p was positively correlated with HSP70 and CD63 in the exosomes of liver cancer fibroblasts. In addition, miR-92a-3p and exosome marker proteins (HSP70 and CD63) were highly expressed in tumors with a diameter greater than 5 cm, and were higher in liver cancer patients with BCLC stage B/C. Tumor fibroblast-derived exosome marker proteins and miR-92a-3p have good diagnostic value in liver cancer, indicating that they may be new diagnostic markers for liver cancer.

Exosomes: Key tools for cancer liquid biopsy

Precision medicine is based on the identification of biomarkers of tumor development and progression. Liquid biopsy is at the forefront of the ability to gather diagnostic and prognostic information on tumors, as it can be noninvasively performed prior or during treatment. Liquid biopsy mostly utilizes circulating tumor cells, or free DNA, but also exosomes. The latter are nanovesicles secreted by most cell types, found in any body fluid that deliver proteins, nucleic acids and lipids to nearby and distant cells with a unique homing ability. Exosomes function in signalling between the tumor microenvironment and the rest of the body, promoting metastasis, immune remodelling and drug resistance. Exosomes are emerging as a key tool in precision medicine for cancer liquid biopsy, as they efficiently preserve their biomarker cargo. Moreover, exosomes strongly resemble the parental cell, which can help in assessing the oxidative and metabolic state of the donor cell. In this respect, exosomes represent one of the most promising new tools to fight cancer. This review will discuss the clinical applications of profiling exosomal proteins and lipids by high-throughput proteomics and metabolomics, and nucleic acids by next generation sequencing, as well as how this may allow cancer diagnosis, therapy response monitoring and recurrence detection.

A Review of QCA Nanotechnology as an Alternate to CMOS

Background: The human ken and understanding about esoteric phenomenon develops the period from space to the sub-atomic level. The passion to further explore the unexplored domains and dimensions boosts the human advancement in a cyclic way. A significant part of such passion follows in the electronics industry. Moore’s law is reaching the practical limitations because of further scaling of metal oxide semiconductor (MOS) devices. The need of a more dexterous and effective technology approach is demanded. Quantum-dot cellular automata (QCA) is an emerging technology which avoids the physical limitations of the MOS device. QCA is a dynamic computational transistor paradigm that addresses device density, power, operating frequency and interconnection problems. It requires an extensive study to know the fundamentals of logic implementation. Objective: Immense research and experiments due same vigor led to the evolving nanotechnology and a feasible alternative to complementary metal oxide semiconductor (CMOS) technology. A comprehensive study is presented in the paper to enhance the basics of QCA technology and the way of implementation of the logic circuits. Different existing circuits using QCA technology are discussed and compared for different parameters. Methods: Scaling the devices can reduce the power consumption of the MOS device. Quantum dots are nanostructures made from semi-conductive conventional materials. It is possible to model these constructions as 3-dimensional (3D) quantum energy wells. Logical operations and data movement are performed using Columbic interaction between nearby QCA cells instead of current flow. Results: The focus of this review paper is to study the trends which have been proposed and compared the designs for various digital circuits. The performance of different circuits such as XOR, adder, reversible gates and flip-flops are provided. Different logic circuits are compared on the parameters such as cell count, area and latency. At least 10 QCA cells are used for the XOR gate with 1 clock latency. Minimum 44 QCA cells are required to make a full adder with 1.25 clock latency. Conclusion: Designer may choose the best fitted circuit in their logic implementation on the basis of the comparison. The comprehensive study of the QCA technology helps the researchers to learn this field fast and work for the design of less cells count and latency.

Microglia at the Crossroads of Pathogen-Induced Neuroinflammation.

Microglia are the resident tissue macrophages of the central nervous system (CNS). Recent findings point out that in the steady state the major role of microglia, is to instruct and regulate the correct function of the neuronal networks and different components of the neurovascular unit in the adult CNS, while providing immune surveillance. Paradoxically, during CNS infection immune activation of microglia generates an inflammatory milieu that contributes to the clearance of the pathogen but can, in the process, harm nearby cells of CNS. Most of the knowledge about the harmful effects of activated microglia on CNS has arisen from studies on neurodegenerative diseases. In this review we will focus on the beneficial role and detrimental functions of microglial cells on the neighboring cells of the CNS upon infection.

Double-edged Sword Role of Iron-loaded Ferritin in Extracellular Vesicles.

Human epidemiological and animal studies have demonstrated that excess iron is a risk for cancer. The responsible mechanisms are: 1) increased intracellular iron catalyzes the Fenton reaction to generate hydroxyl radicals, leading to mutagenic oxidative DNA lesions; 2) iron is necessary for cellular proliferation as cofactors of many enzymes. Thus, iron-excess milieu promotes selecting cellular evolution to ferroptosis-resistance, a major basis for carcinogenesis. Ferritin is a 24-subunit nanocage protein required for iron storage under the regulation of the iron-regulatory protein (IRP)/iron-responsive element (IRE) system. Ferritin is a serum marker, representing total body iron storage. However, how ferritin is secreted extracellularly has been unelucidated. We recently discovered that an exosomal marker CD63 is regulated by the IRP/IRE system and that iron-loaded ferritin is secreted as extracellular vesicles under the guidance of nuclear receptor coactivator 4 (NCOA4). On the other hand, we found that macrophages under asbestos-induced ferroptosis emit ferroptosis-dependent extracellular vesicles (FedEVs), which are received by nearby mesothelial cells, resulting in significant mutagenic DNA damage. Therefore, cells, including macrophages, can share excess iron with other cells, via iron-loaded ferritin packaged in extracellular vesicles as safe non-catalytic iron. However, similar process, such as one involving FedEVs, may cause accumulation of excess iron in other specific cells, which may eventually promote carcinogenesis.

History and Basic Principles of Photodynamic Therapy Use in Ophthalmology

Photodynamic therapy (PDT) is a therapy that uses drugs, called photosensitizers or photosensitizing agents, and a specific type of light. When photosensitizers are exposed to certain wavelengths of light, they produce oxygen that kills nearby cells. PDT is achieved by a photodynamic reaction induced by the excitation of a photosensitizer exposed to light. In the field of ophthalmology, PDT was approved for the first time about ten years ago for cases of age-related macular degeneration (AMD). Neovascular age-related macular degeneration (AMD) is a vision-threatening disease characterized by pathological macular neovascularization. After that, PDT was approved for use in choroidal neovascularization (CNV) cases in pathological myopia.3 This literature review aims to describe the history of PDT use and the basic principles of photodynamic therapy in ophthalmology.

Harmful behaviour through plasmid transfer: a successful evolutionary strategy of bacteria harbouring conjugative plasmids.

Conjugative plasmids are extrachromosomal mobile genetic elements pervasive among bacteria. Plasmids' acquisition often lowers cells' growth rate, so their ubiquity has been a matter of debate. Chromosomes occasionally mutate, rendering plasmids cost-free. However, these compensatory mutations typically take hundreds of generations to appear after plasmid arrival. By then, it could be too late to compete with fast-growing plasmid-free cells successfully. Moreover, arriving plasmids would have to wait hundreds of generations for compensatory mutations to appear in the chromosome of their new host. We hypothesize that plasmid-donor cells may use the plasmid as a 'weapon' to compete with plasmid-free cells, particularly in structured environments. Cells already adapted to plasmids may increase their inclusive fitness through plasmid transfer to impose a cost to nearby plasmid-free cells and increase the replication opportunities of nearby relatives. A mathematical model suggests conditions under which the proposed hypothesis works, and computer simulations tested the long-term plasmid maintenance. Our hypothesis explains the maintenance of conjugative plasmids not coding for beneficial genes. This article is part of the theme issue 'The secret lives of microbial mobile genetic elements'.

Establishing Irreversible Electroporation Electric Field Potential Threshold in A Suspension In Vitro Model for Cardiac and Neuronal Cells.

Aims: Irreversible electroporation is an ablation technique being adapted for the treatment of atrial fibrillation. Currently, there are many differences reported in the in vitro and pre-clinical literature for the effective voltage threshold for ablation. The aim of this study is a direct comparison of different cell types within the cardiovascular system and identification of optimal voltage thresholds for selective cell ablation. Methods: Monophasic voltage pulses were delivered in a cuvette suspension model. Cell viability and live–dead measurements of three different neuronal lines, cardiomyocytes, and cardiac fibroblasts were assessed under different voltage conditions. The immediate effects of voltage and the evolution of cell death was measured at three different time points post ablation. Results: All neuronal and atrial cardiomyocyte lines showed cell viability of less than 20% at an electric field of 1000 V/cm when at least 30 pulses were applied with no significant difference amongst them. In contrast, cardiac fibroblasts showed an optimal threshold at 1250 V/cm with a minimum of 50 pulses. Cell death overtime showed an immediate or delayed cell death with a proportion of cell membranes re-sealing after three hours but no significant difference was observed between treatments after 24 h. Conclusions: The present data suggest that understanding the optimal threshold of irreversible electroporation is vital for achieving a safe ablation modality without any side-effect in nearby cells. Moreover, the evolution of cell death post electroporation is key to obtaining a full understanding of the effects of IRE and selection of an optimal ablation threshold.

Regulatory effects of microRNAs on hepatic stellate cell activation and liver fibrogenesis

Hepatic fibrogenesis (HF) is the common consequence of various chronic liver diseases (CLD) induced by a variety of pathogenic factors. The mechanism of HF involves the interactions within different types of liver cells, cytokines, chemokines, cell mediators and multiple signaling pathways in a way of networks. As a result, excessive production and deposition of extracellular matrix (ECM) mainly composed of type I and type III fibril forming collagen destroys the original morphology, structure and function of the liver. The activation of hepatic stellate cells (HSCs), the major scar forming cells in liver, plays a crucial role in hepatic fibrogenesis. MicroRNAs are a group of short, single stranded, non-coding RNAs that can inhibit mRNA expression at the transcriptional and post transcriptional levels. They can be loaded and transferred as cargos by exosomes, to regulate the function of nearby and distant receptive cells. The expressions of many microRNAs such as miR-21, miR-29, miR-708, miR-101, miR-455, miR-146, miR-193 change significantly in activated HSCs, which regulate the activation, fibrogenic function, proliferation, apoptosis and autophagy of HSCs via affecting target genes expression and signaling pathway molecules. They are important substances and regulatory mechanism that mediate the initiation and progression of HF.

Recent Advances in Bio‐Compatible Oxygen Singlet Generation and Its Tumor Treatment

AbstractLight‐dependent singlet oxygen (1O2) produced in photodynamic therapy (PDT), is a biologically compatible reactive oxygen species showing the potential to kill tumor cells with fewer side effects on nearby normal healthy cells. The development of a high 1O2 generating photosensitizer is a particularly demanding research areas. Based on Jablonski's diagram, the photophysical factors influencing the generation of 1O2 are intersystem crossing, triplet quantum yield and life, and the singlet‐triplet energy gap. Moreover, nanocarriers are also an emerging research topic with enhanced/localized delivery of photosensitizers to improve the dosage of light and enriched production of 1O2. In this review, the production principle of 1O2 in PDT and its killing mechanism with respect to tumor cells are reviewed. In addition, the progress of PDT has been supplemented in clinical applications in recent years and the emergent preclinical tactics for prospective solutions to these challenges are discussed to improve the effectiveness and usefulness of these procedures. Moreover, the remaining research gaps and future work is outlined. This review is anticipated to heighten the research for developing new strategies for modulating the photophysical properties and improved the delivery of photosensitizers.