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Summary: The flowering plant life cycle is completed by an alternation of diploid and haploid generations. The diploid sporophytes produce initial cells that undergo meiosis and produce spores. From haploid spores, male or female gametophytes, which produce gametes, develop. The union of gametes at fertilization restores diploidy in the zygote that initiates a new cycle of diploid sporophyte development. During this complex process, cell fate determination occurs at each of the critical stages and necessarily underpins successful plant reproduction. Here, we summarize available knowledge on the regulatory mechanism of cell fate determination at these critical stages of sexual reproduction, including sporogenesis, gametogenesis, and early embryogenesis, with particular emphasis on regulatory pathways of both male and female gametes before fertilization, and both apical and basal cell lineages of a proembryo after fertilization. Investigations reveal that cell fate determination involves multiple regulatory factors, such as positional information, differential distribution of cell fate determinants, cell‐to‐cell communication, and cell type‐specific transcription factors. These factors temporally and spatially act for different cell type differentiation to ensure successful sexual reproduction. These new insights into regulatory mechanisms underlying sexual cell fate determination not only updates our knowledge on sexual plant reproduction, but also provides new ideas and tools for crop breeding. [ABSTRACT FROM AUTHOR]

Main conclusion: We summarize recent findings that have provided new insights into the mechanisms underlying CLE signaling systems in the regulation of plant development and phytonematode interactions. CLAVATA3/EMBRYO SURROUNDING REGION-RELATED (CLE) peptides are short sequences consisting of 12 or 13 amino acids characterized by hydroxylated proline residues, and their presence has been demonstrated in various plant species and phytonematodes across multiple paralogous genes. Here, we review recently conducted research to understanding the signaling pathway of CLE peptide during plant development and infection caused by phytonematodes. Cell-to-cell communication is important for the coherent functioning of living organisms. CLE peptides combined with their specific transmembrane receptors to induce downstream intracellular signaling pathways shows divergent modes of action in many developmental processes in variable species. Moreover, CLE peptide was also involved in plant disease mechanism caused by various plant parasitic nematodes. [ABSTRACT FROM AUTHOR]

COVID-19 has been emerging as the most influential illness which has caused great costs to the heath of population and social economy. Sivelestat sodium (SS) is indicated as an effective cure for lung dysfunction, a characteristic symptom of COVID-19 infection, but its pharmacological target is still unclear. Therefore, a deep understanding of the pathological progression and molecular alteration is an urgent issue for settling the diagnosis and therapy problems of COVID-19. In this study, the bulk ribonucleic acid sequencing (RNA-seq) data of healthy donors and non-severe and severe COVID-19 patients were collected. Then, target differentially expressed genes (DEGs) were screened through integrating sequencing data and the pharmacological database. Besides, with the help of functional and molecular interaction analyses, the potential effect of target gene alteration on COVID-19 progression was investigated. Single-cell sequencing was performed to evaluate the cell distribution of target genes, and the possible interaction of gene-positive cells with other cells was explored by intercellular ligand-receptor pattern analysis. The results showed that matrix metalloproteinase 8 (MMP8) was upregulated in severe COVID-19 patients, which was also identified as a targeting site to SS. Additionally, MMP8 took a core part in the regulatory interaction network of the screened DEGs in COVID-19 and was dramatically correlated with the inflammatory signaling pathway. The further investigations indicated that MMP8 was mainly expressed in myelocytes with a high degree of heterogeneity. MMP8-positive myelocytes interacted with other cell types through RETN-TLR4 and RETN-CAP1 ligand-receptor patterns. These findings emphasize the important role of MMP8 in COVID-19 progression and provide a potential therapeutic target for COVID-19 patients. [ABSTRACT FROM AUTHOR]

Extracellular Vesicles (EVs) are a focus of intense research worldwide, with many groups exploring their potential for both diagnostic and therapeutic applications. Researchers have characterized EVs into various subtypes, modified common surface markers, and developed diverse isolation and purification techniques. Beyond their diagnostic potential, EVs are being engineered as delivery vehicles for various molecules and therapeutics. RNA therapeutics have the potential to be a transformative solution for patients suffering from chronic and genetic disorders and generally targeting undruggable targets. Despite the success of many RNA therapeutics in both in vivo studies and clinical trials, a significant challenge remains in effectively delivering these therapies to the target cells. Many research groups have adopted the use of lipid nanoparticles (LNPs) and other nanocarriers to encapsulate RNA therapeutics, aiming to deliver them as stably as possible to ensure optimal bioavailability and efficacy. While LNPs have proven successful as delivery vehicles, their use is not without drawbacks, such as accumulation within the body. EVs could be a potential solution to many of the problems around LNPs and other nanocarriers. [ABSTRACT FROM AUTHOR]

The Notch signaling pathway plays a major role in embryological development and in the ongoing life processes of many animals. Its role is to provide cell-to-cell communication in which a Sender cell, bearing membrane-embedded ligands, instructs a Receiver cell, bearing membrane-embedded receptors, to adopt one of two available fates. Elucidating the evolution of this pathway is the topic of this paper, which uses an orthologs approach, providing a comprehensive basis for the study. Using BLAST searches, orthologs were identified for all the 49 components of the Notch signaling pathway. The historical time course of integration of these proteins, as the animals evolved, was elucidated. Insofar as cell-to-cell communication is of relevance only in multicellular animals, it is not surprising that the Notch system became functional only with the evolutionary appearance of Metazoa, the first multicellular animals. Porifera contributed a quarter of the Notch pathway proteins, the Cnidaria brought the total to one-half, but the system reached completion only when humans appeared. A literature search elucidated the roles of the Notch system's components in modern descendants of the ortholog-contributing ancestors. A single protein, the protein tyrosine kinase (PTK) of the protozoan Ministeria vibrans, was identified as a possible pre-Metazoan ancestor of all three of the Notch pathway proteins, DLL, JAG, and NOTCH. A scenario for the evolution of the Notch signaling pathway is presented and described as the co-option of its components, clade by clade, in a repurposing of genes already present in ancestral unicellular organisms. [ABSTRACT FROM AUTHOR]

Abstract COVID-19 has been emerging as the most influential illness which has caused great costs to the heath of population and social economy. Sivelestat sodium (SS) is indicated as an effective cure for lung dysfunction, a characteristic symptom of COVID-19 infection, but its pharmacological target is still unclear. Therefore, a deep understanding of the pathological progression and molecular alteration is an urgent issue for settling the diagnosis and therapy problems of COVID-19. In this study, the bulk ribonucleic acid sequencing (RNA-seq) data of healthy donors and non-severe and severe COVID-19 patients were collected. Then, target differentially expressed genes (DEGs) were screened through integrating sequencing data and the pharmacological database. Besides, with the help of functional and molecular interaction analyses, the potential effect of target gene alteration on COVID-19 progression was investigated. Single-cell sequencing was performed to evaluate the cell distribution of target genes, and the possible interaction of gene-positive cells with other cells was explored by intercellular ligand-receptor pattern analysis. The results showed that matrix metalloproteinase 8 (MMP8) was upregulated in severe COVID-19 patients, which was also identified as a targeting site to SS. Additionally, MMP8 took a core part in the regulatory interaction network of the screened DEGs in COVID-19 and was dramatically correlated with the inflammatory signaling pathway. The further investigations indicated that MMP8 was mainly expressed in myelocytes with a high degree of heterogeneity. MMP8-positive myelocytes interacted with other cell types through RETN-TLR4 and RETN-CAP1 ligand-receptor patterns. These findings emphasize the important role of MMP8 in COVID-19 progression and provide a potential therapeutic target for COVID-19 patients.

This paper presents a comprehensive overview of the historical trajectory and development in biophoton studies over the past 100 years, with a particular focus on the recent progress regarding the pivotal role of biophoton in mediating radiation-induced bystander effects (RIBE). The exploration of biophoton mystery starts from the initial observation of mitogenetic radiation and continues to develop to the contemporary science of biophotonics. The properties and underlying mechanisms of biophoton emission are described with illustrative examples from diverse biological systems such as plants, animals and humans. The conclusive evidence of cell-to-cell communication facilitated by biophoton signaling is presented, followed by an elaborate interpretation of potential mechanisms through which biophoton mediates RIBE. The engagement of mitochondria and exosomes in this process is extensively clarified, by highlighting their significant roles in biophoton-mediated RIBE. The advances in biophoton research in respect of bystander response to ionizing radiation may offer profound insights into radiobiology and provide for possible future applications as well in radiation medicine and protection.

Microbes have evolved intricate communication systems that enable individual cells of a population to send and receive signals in response to changes in their immediate environment. In the fission yeast Schizosaccharomyces pombe, the oxylipin nitrogen signaling factor (NSF) is part of such communication system, which functions to regulate the usage of different nitrogen sources. Yet, the pathways and mechanisms by which NSF acts are poorly understood. Here, we show that NSF physically interacts with the mitochondrial sulfide:quinone oxidoreductase Hmt2 and that it prompts a change from a fermentation- to a respiration-like gene expression program without any change in the carbon source. Our results suggest that NSF activity is not restricted to nitrogen metabolism alone and that it could function as a rheostat to prepare a population of S. pombe cells for an imminent shortage of their preferred nutrients. Synopsis: Chemical cell-to-cell communication in the fission yeast Schizosaccharomyces pombe is essential for adaption to environmental changes in nutrient availability. This study uncovers that the extracellular signaling molecule nitrogen signaling factor (NSF) functions to counter nitrogen catabolite repression, and to switch from fermentation to respiratory metabolism. Nitrogen Signaling Factor (NSF) functions in an intra-species communication system of. With increasing cell density during population growth, NSF reaches a critical concentration that triggers a switch from a fermentation- to a respiration-like gene expression program. The putative 1-acyldihydroxyacetone phosphate reductase Ayr1 counteracts NSF signaling. The mitochondrial sulfide:quinone oxidoreductase Hmt2 is a direct and functionally relevant target of NSF. NSF is a transmissible signal that activates mitochondrial respiration to maximize growth. The oxylipin NSF is a transmissible signal that activates mitochondrial respiration to maximize growth. [ABSTRACT FROM AUTHOR]

Nano- and micro-sized vesicular and colloidal structures mediate cell–cell communication. They are important players in the physiology of plants, animals, and humans, and are a subject of increasing interest. We investigated the effect of three surfactants, N-cetylpyridinium chloride (CPC), sodium dodecyl sulfate (SDS), and Triton X-100 (TX100), and two anionic polyelectrolytes, sodium polystyrene sulfonate (NaPSS) and sodium polymethacrylate (NaPMA), on nanoliposomes. In addition, the effect of SDS and TX100 on selected biological membranes (erythrocytes and microalgae) was investigated. The liposomes were produced by extrusion and evaluated by microcalorimetry and light scattering, based on the total intensity of the scattered light (Itot), hydrodynamic radius (Rh), radius of gyration (Rg), shape parameter p (=Rh/Rg,0), and polydispersity index. The EPs shed from erythrocytes and microalgae Dunaliella tertiolecta and Phaeodactylum tricornutum were visualized by scanning electron microscopy (SEM) and analyzed by flow cytometry (FCM). The Rh and Itot values in POPC liposome suspensions with added CPC, SDS, and TX100 were roughly constant up to the respective critical micelle concentrations (CMCs) of the surfactants. At higher compound concentrations, Itot dropped towards zero, whereas Rh increased to values higher than in pure POPC suspensions (Rh ≈ 60–70 nm), indicating the disintegration of liposomes and formation of larger particles, i.e., various POPC–S aggregates. Nanoliposomes were stable upon the addition of NaPSS and NaPMA, as indicated by the constant Rh and Itot values. The interaction of CPC, SDS, or TX100 with liposomes was exothermic, while there were no measurable heat effects with NaPSS or NaPMA. The SDS and TX100 increased the number density of EPs several-fold in erythrocyte suspensions and up to 30-fold in the conditioned media of Dunaliella tertiolecta at the expense of the number density of cells, which decreased to less than 5% in erythrocytes and several-fold in Dunaliella tertiolecta. The SDS and TX100 did not affect the number density of the microalgae Phaeodactylum tricornutum, while the number density of EPs was lower in the conditioned media than in the control, but increased several-fold in a concentration-dependent manner. Our results indicate that amphiphilic molecules need to be organized in nanosized particles to match the local curvature of the membrane for facilitated uptake. To pursue this hypothesis, other surfactants and biological membranes should be studied in the future for more general conclusions. [ABSTRACT FROM AUTHOR]

Lung adenocarcinoma (LUAD) generally presents as an immunosuppressive microenvironment. The characteristics of cell‐to‐cell communication in the LUAD microenvironment has been unclear. In this study, the LUAD bulk RNA‐seq data and single‐cell RNA‐seq data were retrieved from public dataset. Differential expression genes (DEGs) between LUAD tumor and adjacent non‐tumor tissues were calculated by limma algorithm, and then detected by PPI, KEGG, and GO analysis. Cell–cell interactions were explored using the single‐cell RNA‐seq data. Finally, the first 15 CytoHubba genes were used to establish related pathways and these pathways were used to characterize the immune‐related ligands and their receptors in LUAD. Our analyses showed that monocytes or macrophages interact with tissue stem cells and NK cells via SPP1 signaling pathway and tissue stem cells interact with T and B cells via CXCL signaling pathway in different states. Hub genes of SPP1 participated in SPP1 signaling pathway, which was negatively correlated with CD4+ T cell and CD8+ T cell. The expression of SPP1 in LUAD tumor tissues was negatively correlated with the prognosis. While CXCL12 participated in CXCL signaling pathway, which was positively correlated with CD4+ T cell and CD8+ T cell. The role of CXCL12 in LUAD tumor tissues exhibits an opposite effect to that of SPP1. This study reveals that tumor‐associated monocytes or macrophages may affect tumor progression. Moreover, the SPP1 and CXCL12 may be the critic genes of cell‐to‐cell communication in LUAD, and targeting these pathways may provide a new molecular mechanism for the treatment of LUAD. [ABSTRACT FROM AUTHOR]

Limosilactobacillus reuteri ZJ625 and Ligilactobacillus salivarius ZJ614 are potential probiotic bacteria with improved benefits when administered to the host as a multi-strain preparation. To elucidate the mechanisms of cell-to-cell crosstalk between these two strains, we studied their intracellular and extracellular proteomes in co-culture by liquid-chromatography mass-spectrometry (LC-MS) using Dionex Nano-RSLC and fusion mass spectrometer. The experiment consisted of five biological replicates, and samples were collected during the mid-exponential growth phase. The quantitative proteomic profiles revealed several differentially expressed proteins (DEPs), which are down- or up-regulated between and within groups for both the intracellular and extracellular proteomes. These DEPs include proteins synthesising autoinducer-2, a sensor compound for cell-to-cell bacterial crosstalk during quorum sensing in mixed culture. Other important DEPs identified include enolase, phosphoglycerate kinase, and l-lactate dehydrogenase, which play roles in carbohydrate metabolism. Proteins associated with transcription, ATP production and transport across the membrane, DNA repair, and those with the potential to bind to the host epithelium were also identified. The post-translational modifications associated with the proteins include oxidation, deamidation, and ammonia loss. Importantly, this study revealed a significant expression of S-ribosylhomocysteine lyase (luxS) involved in synthesising autoinducer-2 that plays important roles in quorum sensing, aiding bacterial cell-to-cell crosstalk in co-cultures. The proteome of L. salivarius ZJ614 was most affected when co-cultured with L. reuteri ZJ625. In contrast, omitting some medium components from the defined medium exerted more effects on L. reuteri ZJ625 than L. salivarius ZJ614. [ABSTRACT FROM AUTHOR]

This brief commentary discusses the problem of unpredictable ("emergent") properties of biological complex systems that result from the interactions between their constituents. The emphasis is put on principal impossibility of determining the status of a cell within an organism on the basis of data obtained after its isolation from the multicellular system. The current status of research focused on the origin of multicellularity and the challenges that its emergence introduced into the discussion of the evolution of life on Earth, is briefly reviewed. Integration of the available data in the form of an axiom stating that in a multicellular organisms, at each level of organization, properties arise that are unpredictable based on the properties of individual modules and cells, is suggested. The properties of cells in an organism cannot be deduced from the properties of its constituent cells. [ABSTRACT FROM AUTHOR]

The migrasome, an organelle recently discovered in migrating cells, facilitates intercellular communication and plays crucial roles in various physiological and pathological conditions. The formation of migrasomes is governed by a tightly regulated process that progresses through three distinct stages: nucleation, maturation, and expansion. This process is regulated by essential molecules such as sphingomyelin lsynthase 2 (SMS2), phosphatidylinositol-4-phosphate 5-kinase type I α (PIP5K1α), integrins, and tetraspanins. The formation of migrasomes is propelled by the assembly of membrane microdomains, driven by the dynamic interaction between biochemical reactions and the physical properties of the membrane at migrasome formation sites. Migrasomes, newly identified organelles, play crucial roles in intercellular communication, contributing to organ development and angiogenesis. These vesicles, forming on retraction fibers of migrating cells, showcase a sophisticated architecture. Recent research reveals that migrasome biogenesis is a complicated and highly regulated process. This review summarizes the mechanisms governing migrasome formation, proposing a model in which biogenesis is understood through the lens of membrane microdomain assembly. It underscores the critical interplay between biochemistry and biophysics. The biogenesis unfolds in three distinct stages: nucleation, maturation, and expansion, each characterized by unique morphological, biochemical, and biophysical features. We also explore the broader implications of migrasome research in membrane biology and outline key unanswered questions that represent important directions for future investigation. [ABSTRACT FROM AUTHOR]

Reactive oxygen species (ROS) play a critical role in plant development and stress responses, acting as key components in rapid signalling pathways. The 'ROS wave' triggers essential acclimation processes, ultimately ensuring plant survival under diverse challenges. This review explores recent advances in understanding the composition and functionality of the ROS wave within plant cells. During their initiation and propagation, ROS waves interact with other rapid signalling pathways, hormones and various molecular compounds. Recent research sheds light on the intriguing lack of a rigid hierarchy governing these interactions, highlighting a complex interplay between diverse signals. Notably, ROS waves culminate in systemic acclimation, a crucial outcome for enhanced stress tolerance. This review emphasizes the versatility of ROS, which act as flexible players within a network of short‐ and long‐term factors contributing to plant stress resilience. Unveiling the intricacies of these interactions between ROS and various signalling molecules holds immense potential for developing strategies to augment plant stress tolerance, contributing to improved agricultural practices and overall ecosystem well‐being. Summary statement: Reactive oxygen species waves can be triggered by varying types of stress stimuli in local tissues and spread from cell to cell to induce systemic acclimation. [ABSTRACT FROM AUTHOR]

Since the migrasome concept was first proposed in 2015, extensive research has been conducted on these novel organelles, which grow on retracted fibers at the posterior end of migrating cells. Recently, molecular markers, biological functions, and clinical values based on the initial formation mechanism of migrasomes have emerged. Additionally, researchers are recognizing the significant role that migrasomes play in the pathological and diagnostic processes of clinical diseases. In this review, we summarize recent advances in the biology and clinical application of migrasomes and provide a comprehensive view of the prospective challenges surrounding their clinical application. [ABSTRACT FROM AUTHOR]

Summary: Plasmodesmata are plasma membrane‐lined connections that join plant cells to their neighbours, establishing an intercellular cytoplasmic continuum through which molecules can travel between cells, tissues, and organs. As plasmodesmata connect almost all cells in plants, their molecular traffic carries information and resources across a range of scales, but dynamic control of plasmodesmal aperture can change the possible domains of molecular exchange under different conditions. Plasmodesmal aperture is controlled by specialised signalling cascades accommodated in spatially discrete membrane and cell wall domains. Thus, the composition of plasmodesmata defines their capacity for molecular trafficking. Further, their shape and density can likewise define trafficking capacity, with the cell walls between different cell types hosting different numbers and forms of plasmodesmata to drive molecular flux in physiologically important directions. The molecular traffic that travels through plasmodesmata ranges from small metabolites through to proteins, and possibly even larger mRNAs. Smaller molecules are transmitted between cells via passive mechanisms but how larger molecules are efficiently trafficked through plasmodesmata remains a key question in plasmodesmal biology. How plasmodesmata are formed, the shape they take, what they are made of, and what passes through them regulate molecular traffic through plants, underpinning a wide range of plant physiology. See also the Commentary on this article by Burch-Smith, 243: 5–6. [ABSTRACT FROM AUTHOR]

The ability to precisely control in vitro enzymatic reactions in synthetic cells plays a crucial role in the bottom‐up design of artificial cell models that can recapitulate the key cellular features and functions such as metabolism. However, integration of enzymatic reactions has been limited to bulk or microfluidic emulsions without a membrane, lacking the ability to design more sophisticated higher‐order artificial cell communities for reconstituting spatiotemporal biological information at multiple length scales. Herein, droplet microfluidics is utilized to synthesize artificial cell‐like polymersomes with distinct molecular permeability for spatiotemporal control of enzymatic reactions driven by external signals and fuels. The presence of a competing reverse enzymatic reaction that depletes the active substrates is shown to enable demonstration of fuel‐driven formation of sub‐microcompartments within polymersomes as well as realization of out‐of‐equilibrium systems. In addition, the different permeability characteristics of polymersome membranes are exploited to successfully construct a programmable enzymatic reaction network that mimics cellular communication within a heterogeneous cell community through selective molecular transport. [ABSTRACT FROM AUTHOR]

A biofilm is a layer of microbes that have aggregated to form a colony. The colony attaches to a surface with a slime layer which protects the microorganisms, promoting their growth and survival. Biofilms occur in various environments such as soils, sediments, wastewater, water pipelines, water purifying systems, cooling water systems, medical devices, archaeological monuments, marine vessels, and hospitals. Biofilms may induce adverse effects such as fostering drug-resistant strains. Here, we review biofilms with focus on their formation, occurrence in water systems, impact, microbial interactions, and characterization methods. Communication includes cell-to-cell interactions by quorum sensing, interactions mediated by flagella, gene, and signaling molecules, and interactions mediated by extracellular polymeric substances. Characterization methods comprise surface-enhanced Raman scattering spectroscopy, confocal laser scanning microscopy, scanning electron microscopy, fluorescence microscopy, sensors, and metagenomics analysis. [ABSTRACT FROM AUTHOR]

Recently, there has been an increasing demand for medicinal plants to control diseases for good health and well-being, as primary health facilities are inadequate in certain populations to cure infections. Since synthetic medicines are toxic to humans and other animals, the present research is thus focused on using traditional medicine for treating various ailments as they are harmless. Based on the above facts, the current study was conducted to assay the antimicrobial, anti-diabetic, anti-cholinesterase, anti-oxidant, anti-quorum sensing, and anti-antibiotic resistance modifying effect of extracts of Cyperus esculentus. This study found 37 and 30 chemicals in butanol and dichloromethane (DCM) extracts using a gas chromatograph mass spectrophotometer (GC-MS). Most active compounds identified were benzofuran, 2,3-dihydro-, 1,2,3-benzenetriol, 3-bornanone, oxime and oleic acid by extracts of butanol whereas dichloromethane extracted three major active compounds (2,3-dihydro-3,5-dihydroxy-, 4H-pyran-4-one 3-deoxy-d-mannoic lactone and 5-hydroxymethylfurfural). Both dichloromethane and butanol extracts showed the highest antimicrobial activity. Compared to aqueous extracts, dichloromethane, and butanol showed excellent anti-diabetic anti-cholinesterase activities and inhibited virulence factors regulated by quorum sensing (QS). Anti-oxidants increased in solvent extracts (DCM and butanol) compared to aqueous extracts. Results of scanning electron microscope (SEM) and Fourier Transmission Infrared (FTIR) indicated damage to the cell membrane of S. aureus by the formation of pits and breakage in functional groups exposed to the extracts of butanol and dichloromethane compared to aqueous extracts. The above results confirmed that C. esculentus can be an alternative medicine for treating diseases.

Abstract The ability to precisely control in vitro enzymatic reactions in synthetic cells plays a crucial role in the bottom‐up design of artificial cell models that can recapitulate the key cellular features and functions such as metabolism. However, integration of enzymatic reactions has been limited to bulk or microfluidic emulsions without a membrane, lacking the ability to design more sophisticated higher‐order artificial cell communities for reconstituting spatiotemporal biological information at multiple length scales. Herein, droplet microfluidics is utilized to synthesize artificial cell‐like polymersomes with distinct molecular permeability for spatiotemporal control of enzymatic reactions driven by external signals and fuels. The presence of a competing reverse enzymatic reaction that depletes the active substrates is shown to enable demonstration of fuel‐driven formation of sub‐microcompartments within polymersomes as well as realization of out‐of‐equilibrium systems. In addition, the different permeability characteristics of polymersome membranes are exploited to successfully construct a programmable enzymatic reaction network that mimics cellular communication within a heterogeneous cell community through selective molecular transport.

Abstract The crosstalk between cancer and stromal cells plays a critical role in tumor progression. Syntenin is a small scaffold protein involved in the regulation of intercellular communication that is emerging as a target for cancer therapy. Here, we show that certain aggressive forms of acute myeloid leukemia (AML) reduce the expression of syntenin in bone marrow stromal cells (BMSC). Stromal syntenin deficiency, in turn, generates a pro‐tumoral microenvironment. From serial transplantations in mice and co‐culture experiments, we conclude that syntenin‐deficient BMSC stimulate AML aggressiveness by promoting AML cell survival and protein synthesis. This pro‐tumoral activity is supported by increased expression of endoglin, a classical marker of BMSC, which in trans stimulates AML translational activity. In short, our study reveals a vicious signaling loop potentially at the heart of AML–stroma crosstalk and unsuspected tumor‐suppressive effects of syntenin that need to be considered during systemic targeting of syntenin in cancer therapy.

Abstract Background Exosomes, a special subtype of extracellular vesicles derived from human cells, serve as vital mediators of intercellular communication by transporting diverse bioactive cargos, including proteins and enzymes. However, the underlying mechanisms governing exosome secretion and regulation remain poorly understood. In this study, we employed a dual-reporter system consisting of bioluminescent Gaussia luciferase and fluorescent proteins to investigate the dynamics and regulation of exosome secretion in cultured human cells. Results Our results demonstrated that the engineered dual-reporters effectively monitored both exosome-mediated and ER-Golgi-mediated secretory pathways in a specific and quantitative manner. Notably, we observed distinct characteristics of exosome-mediated protein secretion, including significantly lower capacity and different dynamics compared to the ER-Golgi pathway. This phenomenon was observed in human kidney 293T cells and liver HepG2 cells, emphasizing the conserved nature of exosome-mediated secretion across cell types. Furthermore, we investigated the impact of brefeldin A (BFA), an inhibitor of ER-to-Golgi membrane trafficking, on protein secretion. Interestingly, BFA inhibited protein secretion via the ER-Golgi pathway while stimulating exosome-mediated protein secretion under same experimental conditions. Conclusions Collectively, our study highlights the utility of the dual-reporter system for real-time monitoring and quantitative analysis of protein secretion through conventional ER-Golgi and unconventional exosome pathways. Moreover, our findings unveil distinct features of exosome-mediated protein secretion, shedding light on its differential capacity, dynamics, and regulatory mechanisms compared to ER-Golgi-mediated proteins in human cells.

mRNAs traffic between plant cells/tissues/organs via plasmodesmata (PDs) and the phloem to act as noncell-autonomous signals controlling diverse biological processes. Some RNA features and RNA-binding proteins important for long-distance mRNA phloem transport have been identified. Transcription factor mRNAs and proteins selectively traffic from cell-to-cell via PDs to regulate cell fates and tissue patterning. Although their transport mechanisms are less well understood, integration of the available information allows the prediction of possible mechanisms. The endomembrane system, cytoskeleton, motor proteins, RNA helicases, and RNA-processing proteins all participate in the cell-to-cell transport of mRNAs. Cell-to-cell transport of mRNAs contributes to the propagation of mobile transcription factor signals. Messenger RNAs (mRNAs) in multicellular organisms can act as signals transported cell-to-cell and over long distances. In plants, mRNAs traffic cell-to-cell via plasmodesmata (PDs) and over long distances via the phloem vascular system to control diverse biological processes – such as cell fate and tissue patterning – in destination organs. Research on long-distance transport of mRNAs in plants has made remarkable progress, including the cataloguing of many mobile mRNAs, characterization of mRNA features important for transport, identification of mRNA-binding proteins involved in their transport, and understanding of the physiological roles of mRNA transport. However, information on short-range mRNA cell-to-cell transport is still limited. This review discusses the regulatory mechanisms and physiological functions of mRNA transport at the cellular and whole plant levels. [ABSTRACT FROM AUTHOR]

Introduction: In recent decades, many theories have been proposed about the cause of hereditary diseases such as cancer. However, most studies state genetic and environmental factors as the most important parameters. It has been shown that gene expression data are valuable information about hereditary diseases and their analysis can identify the relationships between these diseases. Objective: Identification of damaged genes from various diseases can be done through the discovery of cell-to-cell biological communications. Also, extraction of intercellular communications can identify relationships between different diseases. For example, gene disorders that cause damage to the same cells in both breast and blood cancers. Hence, the purpose is to discover cell-to-cell biological communications in gene expression data. Methodology: The identification of cell-to-cell biological communications for various cancer diseases has been widely performed by clustering algorithms. However, this field remains open due to the abundance of unprocessed gene expression data. Accordingly, this paper focuses on the development of a semi-supervised ensemble clustering algorithm that can discover relationships between different diseases through the extraction of cell-to-cell biological communications. The proposed clustering framework includes a stratified feature sampling mechanism and a novel similarity metric to deal with high-dimensional data and improve the diversity of primary partitions. Results: The performance of the proposed clustering algorithm is verified with several datasets from the UCI machine learning repository and then applied to the FANTOM5 dataset to extract cell-to-cell biological communications. The used version of this dataset contains 108 cells and 86,427 promoters from 702 samples. The strength of communication between two similar cells from different diseases indicates the relationship of those diseases. Here, the strength of communication is determined by promoter, so we found the highest cell-to-cell biological communication between “basophils” and “ciliary.epithelial.cells” with 62,809 promoters. Conclusion: The maximum cell-to-cell biological similarity in each cluster can be used to detect the relationship between different diseases such as cancer. [ABSTRACT FROM AUTHOR]

The crosstalk between cancer and stromal cells plays a critical role in tumor progression. Syntenin is a small scaffold protein involved in the regulation of intercellular communication that is emerging as a target for cancer therapy. Here, we show that certain aggressive forms of acute myeloid leukemia (AML) reduce the expression of syntenin in bone marrow stromal cells (BMSC). Stromal syntenin deficiency, in turn, generates a pro‐tumoral microenvironment. From serial transplantations in mice and co‐culture experiments, we conclude that syntenin‐deficient BMSC stimulate AML aggressiveness by promoting AML cell survival and protein synthesis. This pro‐tumoral activity is supported by increased expression of endoglin, a classical marker of BMSC, which in trans stimulates AML translational activity. In short, our study reveals a vicious signaling loop potentially at the heart of AML–stroma crosstalk and unsuspected tumor‐suppressive effects of syntenin that need to be considered during systemic targeting of syntenin in cancer therapy. Synopsis: The lack of syntenin in the tumor microenvironment, particularly in bone marrow stromal cells (BMSCs), enhances acute myeloid leukemia (AML) aggressiveness. AML blasts overexpressing miR‐155 can suppress syntenin expression in BMSCSyntenin deficiency increases the level of endoglin in BMSC stimulating AML EEF1A2 protein levels and translational activity [ABSTRACT FROM AUTHOR]

The interaction between proteins and nucleic acids is a core element of life. Many proteins bind nucleic acids via a sequence-specific manner, but there are also many types of proteins that recognize various structural motifs. Researchers have recently found that proteins that can recognize DNA and RNA G-quadruplexes (G4s) are very important for basic cellular processes, particularly in eukaryotes. Some of these proteins are located outside the nucleus and interact with RNA, potentially affecting miRNA functions in intercellular communication, which is facilitated by small extracellular vesicles (sEVs). Imbalances in the production of sEVs are associated with various pathologies and senescence in humans. The distribution of miRNA into sEVs is regulated by two RNA-binding proteins, Alyref and FUS. Both proteins possess G-rich recognition motifs that are compatible with the formation of RNA parallel G4 structures. This lends credence to the new hypothesis that G4-formation in RNAs and their interaction with G4-binding proteins can affect the fate of miRNAs and control their distribution in sEVs that are associated with senescence and aging. • The distribution of miRNA into sEVs is regulated by two RNA-binding proteins, Alyref and FUS. • Alyref and FUS.possess G-rich recognition motifs compatible with the formation of RNA parallel G4 structures. • G4-formation in RNAs can control sEVs that are associated with senescence and aging. [ABSTRACT FROM AUTHOR]

The gut microbiota widely varies from individual to individual, but the variation shows stability over a period of time. The presence of abundant bacterial taxa is a common structure that determines the microbiota of human being. The presence of this microbiota greatly varies from geographic location, sex, food habits and age. Microbiota existing within the gut plays a significant role in nutrient absorption, development of immunity, curing of diseases and various developmental phases. With change in age, chronology diversification and variation of gut microbiota are observed within human being. But it has been observed that with the enhancement of age the richness of the microbial diversity has shown a sharp decline. The enhancement of age also results in the drift of the characteristic of the microbes associated with the microbiota from commensals to pathogenic. Various studies have shown that age associated gut-dysbiosis may result in decrease in tlongevity along with unhealthy aging. The host signalling pathways regulate the presence of the gut microbiota and their longevity. The presence of various nutrients regulates the presence of various microbial species. Innate immunity can be triggered due to the mechanism of gut dysbiosis resulting in the development of various age-related pathological syndromes and early aging. The gut microbiota possesses the ability to communicate with the host system with the help of various types of biomolecules, epigenetic mechanisms and various types of signalling-independent pathways. Drift in this mechanism of communication may affect the life span along with the health of the host. Thus, this review would focus on the use of gut-microbiota in anti-aging and healthy conditions of the host system. [ABSTRACT FROM AUTHOR]

Yue-Ling Peng,1 Yan Zhang,1 Lin Pang,2 Ya-Fang Dong,3 Mu-Ye Li,4 Hui Liao,5 Rong-Shan Li1 1Department of Nephrology, Shanxi Provincial People’s Hospital (Fifth Hospital of Shanxi Medical University), Taiyuan, People’s Republic of China; 2Department of Health Statistics, School of Public Health, Shanxi Medical University, Taiyuan, People’s Republic of China; 3Department of Pathology and Pathophysiology, School of Basic Medicine, Shanxi Medical University, Taiyuan, People’s Republic of China; 4Department of Ocular Fundus Diseases, Shanxi Eye Hospital, Shanxi Medical University, Taiyuan, People’s Republic of China; 5Drug Clinical Trial Institution, Shanxi Provincial People’s Hospital (Fifth Hospital of Shanxi Medical University), Taiyuan, People’s Republic of ChinaCorrespondence: Rong-Shan Li, Department of Nephrology, Shanxi Provincial People’s Hospital (Fifth Hospital of Shanxi Medical University), Taiyuan, People’s Republic of China, Email rongshanli@126.comBackground: Increasing evidence suggests that immune modulation contributes to the pathogenesis and progression of diabetic nephropathy (DN). However, the role of immune modulation in DN has not been elucidated. The purpose of this study was to search for potential immune-related therapeutic targets and molecular mechanisms of DN.Methods: Gene expression datasets were obtained from the Gene Expression Omnibus (GEO) database. A total of 1793 immune-related genes were acquired from the Immunology Database and Analysis Portal (ImmPort). Weighted gene co-expression network analysis (WGCNA) was performed for GSE142025, and the red and turquoise co-expression modules were found to be key for DN progression. We utilized four machine learning algorithms, namely, random forest (RF), support vector machine (SVM), adaptive boosting (AdaBoost), and k-nearest neighbor (KNN), to evaluate the diagnostic value of hub genes. Immune infiltration patterns were analyzed using the CIBERSORT algorithm, and the correlation between immune cell type abundance and hub gene expression was also investigated.Results: A total of 77 immune-related genes of advanced DN were selected for subsequent analyzes. Functional enrichment analysis showed that the regulation of cytokine–cytokine receptor interactions and immune cell function play a corresponding role in the progression of DN. The final 10 hub genes were identified through multiple datasets. In addition, the expression levels of the identified hub genes were corroborated through a rat model. The RF model exhibited the highest AUC. CIBERSORT analysis and single-cell sequencing analysis revealed changes in immune infiltration patterns between control subjects and DN patients. Several potential drugs to reverse the altered hub genes were identified through the Drug-Gene Interaction database (DGIdb).Conclusion: This pioneering work provided a novel immunological perspective on the progression of DN, identifying key immune-related genes and potential drug targets, thus stimulating future mechanistic research and therapeutic target identification for DN.Keywords: diabetic nephropathy, machine learning, single cell, cell-to-cell communication, immune therapy

Yoselin Benitez Alfonso, a professor in interdisciplinary plant sciences at the University of Leeds, shares her journey and passion for plant science. Growing up in Cuba, she developed a love for nature and later pursued a degree in chemistry in Spain. Despite not having a biology background, she taught herself plant biology and became interested in plasmodesmata research. She is motivated by her love for research, the success of her students, and the impact of her contributions to teaching and diversity. She considers her father and various mentors as role models and enjoys reading papers on plasmodesmata research and plant symbiosis. Her favorite plant is the olive tree due to its symbolism, climate resilience, and economic significance. Yoselin is also involved in the Black in Plant Science Network and has received recognition for her leadership and academic achievements. [Extracted from the article]

ABSTRACTAcyl-homoserine lactones (AHLs) are typical quorum-sensing molecules of gram-negative bacteria. Recent evidence suggests that AHLs may also affect gram-positives, although knowledge of these interactions remains scarce. Here, we assessed the effect of AHLs on biofilm formation and transcriptional regulations in the gram-positive Enterococcus faecalis. Five E. faecalis strains were investigated herein. Crystal violet was employed to quantify the biomass formed, and confocal microscopy in combination with SYTO9/PI allowed the visualisation of biofilms’ structure. The differential expression of 10 genes involved in quorum-sensing, biofilm formation and stress responses was evaluated using reverse-transcription-qPCR. The AHL exposure significantly increased biofilm production in strain ATCC 29212 and two isolates from infected dental roots, UmID4 and UmID5. In strains ATCC 29212 and UmID7, AHLs up-regulated the quorum-sensing genes (fsrC, cylA), the adhesins ace, efaA and asa1, together with the glycosyltransferase epaQ. In strain UmID7, AHL exposure additionally up-regulated two membrane-stress response genes (σV, groEL) associated with increased stress-tolerance and virulence. Altogether, our results demonstrate that AHLs promote biofilm formation and up-regulate a transcriptional network involved in virulence and stress tolerance in several E. faecalis strains. These data provide yet-unreported insights into E. faecalis biofilm responses to AHLs, a family of molecules long-considered the monopole of gram-negative signalling.

Liver diseases, characterized by high morbidity and mortality, represent a substantial medical problem globally. The current therapeutic approaches are mainly aimed at reducing symptoms and slowing down the progression of the diseases. Organ transplantation remains the only effective treatment method in cases of severe liver pathology. In this regard, the development of new effective approaches aimed at stimulating liver regeneration, both by activation of the organ's own resources or by different therapeutic agents that trigger regeneration, does not cease to be relevant. To date, many systematic reviews and meta-analyses have been published confirming the effectiveness of mesenchymal stromal cell (MSC) transplantation in the treatment of liver diseases of various severities and etiologies. However, despite the successful use of MSCs in clinical practice and the promising therapeutic results in animal models of liver diseases, the mechanisms of their protective and regenerative action remain poorly understood. Specifically, data about the molecular agents produced by these cells and mediating their therapeutic action are fragmentary and often contradictory. Since MSCs or MSC-like cells are found in all tissues and organs, it is likely that many key intercellular interactions within the tissue niches are dependent on MSCs. In this context, it is essential to understand the mechanisms underlying communication between MSCs and differentiated parenchymal cells of each particular tissue. This is important both from the perspective of basic science and for the development of therapeutic approaches involving the modulation of the activity of resident MSCs. With regard to the liver, the research is concentrated on the intercommunication between MSCs and hepatocytes under normal conditions and during the development of the pathological process. The goals of this review were to identify the key factors mediating the crosstalk between MSCs and hepatocytes and determine the possible mechanisms of interaction of the two cell types under normal and stressful conditions. The analysis of the hepatocyte–MSC interaction showed that MSCs carry out chaperone-like functions, including the synthesis of the supportive extracellular matrix proteins; prevention of apoptosis, pyroptosis, and ferroptosis; support of regeneration; elimination of lipotoxicity and ER stress; promotion of antioxidant effects; and donation of mitochondria. The underlying mechanisms suggest very close interdependence, including even direct cytoplasm and organelle exchange. [ABSTRACT FROM AUTHOR]

Lipid signalling plays a crucial role in extracellular vesicle (EV)-mediated cell-to-cell communication. Extracellular vesicles are small membrane-bound structures released by various cell types into the extracellular environment. They include exosomes, microvesicles, and apoptotic bodies. These vesicles contain a variety of bioactive molecules, including proteins, nucleic acids (such as miRNAs and mRNAs), and lipids. Lipids are important components of EVs and are involved in various aspects of their biogenesis, cargo sorting, and functional effects on target cells. In this review, we will discuss how lipid signalling is involved in EV-mediated cell-to-cell communication. In summary, lipid signalling is intricately involved in extracellular vesicle-mediated cell-to-cell communication. The lipid composition of EVs influences their biogenesis, cargo sorting, interactions with target cells, and functional effects on recipient cells. Understanding the role of lipids in EV-mediated communication is essential for deciphering the mechanisms underlying intercellular signalling and developing potential therapeutic strategies based on EVs. [Display omitted] • The lipid cargo of EVs is specific to their cell of origin and can vary based on various factors. • EVs' lipid composition is linked to various diseases. • Lipids within EVs are not static but can undergo enzymatic and nonenzymatic reactions. • EVs play a role in cell communication by transferring lipid-related signalling molecules between cells. • EVs are gaining attention as potential clinical biomarkers for various diseases due to their cargo diversity. [ABSTRACT FROM AUTHOR]

Chemoresistance constitute a major obstacle in cancer treatment, leading to limited options and decreased patient survival. Recent studies have revealed a novel mechanism of chemoresistance acquisition: the transfer of information via exosomes, small vesicles secreted by various cells. Exosomes play a crucial role in intercellular communication by carrying proteins, nucleic acids, and metabolites, influencing cancer cell behavior and response to treatment. One crucial mechanism of resistance is cancer metabolic reprogramming, which involves alterations in the cellular metabolic pathways to support the survival and proliferation of drug-resistant cancer cells. This metabolic reprogramming often includes increased glycolysis, providing cancer cells with the necessary energy and building blocks to evade the effects of chemotherapy. Notably, exosomes have been found to transport glycolytic enzymes, as identified in proteomic profiling, leading to the reprogramming of metabolic pathways, facilitating altered glucose metabolism and increased lactate production. As a result, they profoundly impact the tumor microenvironment, promoting tumor progression, survival, immune evasion, and drug resistance.Understanding the complexities of such exosome-mediated cell-to-cell communication might open new therapeutic avenues and facilitate biomarker development in managing cancers characterized by aggressive glycolytic features. Moreover, given the intricate nature of metabolic abnormalities combining future exosome-based-targeted therapies with existing treatments like chemotherapy, immunotherapy, and targeted therapies holds promise for achieving synergistic effects to overcome resistance and improve cancer treatment outcomes. [Display omitted] • Chemoresistance is a significant challenge for cancer patients' survival. • One crucial mechanism of chemoresistance involves cancer metabolic reprogramming. • Exosomes are emerging as key players in cell-communication which can profoundly influence the tumor and tumor microenvironment, promoting cancer metabolic reprogramming and chemoresistance, thus exacerbating the challenges of cancer treatment. • Understanding the complexities of exosome-mediated cell-to-cell communication may open new therapeutic avenues and facilitate biomarker development for managing cancers with aggressive glycolytic features. [ABSTRACT FROM AUTHOR]

Background: Exosomes, a special subtype of extracellular vesicles derived from human cells, serve as vital mediators of intercellular communication by transporting diverse bioactive cargos, including proteins and enzymes. However, the underlying mechanisms governing exosome secretion and regulation remain poorly understood. In this study, we employed a dual-reporter system consisting of bioluminescent Gaussia luciferase and fluorescent proteins to investigate the dynamics and regulation of exosome secretion in cultured human cells. Results: Our results demonstrated that the engineered dual-reporters effectively monitored both exosome-mediated and ER-Golgi-mediated secretory pathways in a specific and quantitative manner. Notably, we observed distinct characteristics of exosome-mediated protein secretion, including significantly lower capacity and different dynamics compared to the ER-Golgi pathway. This phenomenon was observed in human kidney 293T cells and liver HepG2 cells, emphasizing the conserved nature of exosome-mediated secretion across cell types. Furthermore, we investigated the impact of brefeldin A (BFA), an inhibitor of ER-to-Golgi membrane trafficking, on protein secretion. Interestingly, BFA inhibited protein secretion via the ER-Golgi pathway while stimulating exosome-mediated protein secretion under same experimental conditions. Conclusions: Collectively, our study highlights the utility of the dual-reporter system for real-time monitoring and quantitative analysis of protein secretion through conventional ER-Golgi and unconventional exosome pathways. Moreover, our findings unveil distinct features of exosome-mediated protein secretion, shedding light on its differential capacity, dynamics, and regulatory mechanisms compared to ER-Golgi-mediated proteins in human cells. [ABSTRACT FROM AUTHOR]

Cell-to-cell communication via different signalling pathways often results in population-level synchronization of certain gene expressions in noisy cellular environments organized. How exactly such synchronization is accomplished within a population level remains elusive. Here, we have developed a stochastic kinetic mathematical model by taking the Notch signalling pathway as an example to understand the nature of such kind of synchronization observed for Hes1 (Hairy and enhancer of split-1) gene expression. Our stochastic simulations revealed that the periodic pulsatile input to the intrinsic genetic Hes1-oscillator leads to population-level synchrony by reducing the variability of the parent oscillator. Additionally, we demonstrate how the degree of synchronization can be changed by controlling the network motifs that drive the oscillation of the parent oscillator. Our model further successfully identifies the conditions for maximum synchronization. This study indicates how cells within a population filter out fluctuations while living in a heterogeneous cellular environment. A stochastic kinetic model is developed to investigate the population-level synchronization of oscillatory gene expression that occurs in a noisy cellular environment. The study unravels that pulsatile input reduces variability to orchestrate synchronization of the intrinsic oscillator and highlights how cells filter out fluctuations in heterogeneous cellular environments. [ABSTRACT FROM AUTHOR]

Human tumors are increasingly being described as a complex "ecosystem", that includes many different cell types, secreted growth factors, extracellular matrix (ECM) components, and microvessels, that altogether create the tumor microenvironment (TME). Within the TME, epithelial cancer cells control the function of surrounding stromal cells and the non-cellular ECM components in an intricate orchestra of signaling networks specifically designed for cancer cells to exploit surrounding cells for their own benefit. Tumor-derived extracellular vesicles (EVs) released into the tumor microenvironment are essential mediators in the reprogramming of surrounding stromal cells, which include cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), tumor-infiltrating lymphocytes (TILs), and tumor endothelial cells (TECs), which are responsible for the promotion of neo-angiogenesis, immune cell evasion, and invasion which are essential for cancer progression. Perhaps most importantly, tumor-derived EVs play critical roles in the metastatic dissemination of tumor cells through their two-fold role in initiating cancer cell invasion and the establishment of the pre-metastatic niche, both of which are vital for tumor cell migration, homing, and colonization at secondary tumor sites. This review discusses extracellular vesicle trafficking within the tumor microenvironment and pre-metastatic niche formation, focusing on the complex role that EVs play in orchestrating cancer-to-stromal cell communication in order to promote the metastatic dissemination of cancer cells. [ABSTRACT FROM AUTHOR]

Simple Summary: This paper presents a brief mathematical study in which the communication between cells is modelled. Understanding cell communication mathematically is useful across many medical fields from drug delivery to understanding how the body responds to infection. In this paper, the random motions of proteins are explored using stochastic differential equations. The study demonstrates the Brownian motion exhibited by proteins during cell communication. The movement of proteins through the cell membrane is essential for cell-to-cell communication, which is a process that allows the body's immune system to identify any foreign cells, such as cells from another organism and pathogens; this movement is also essential for protein-to-protein interactions and protein-to-membrane interactions which play a significant role in drug discovery. This paper presents the stochastic nature exhibited by proteins during cell-to-cell communication. We study the movement of proteins through the cell membrane under the influence of an external force F and drag force with drag coefficient γ. We derive the stochastic diffusion equation, which governs the motion of the proteins; we start by describing the random motion exhibited by the proteins in terms of probability using a one-dimensional lattice model; this occurs when proteins move inside the cell membrane and bind with other proteins inside the cell membrane. We then introduce an external force and a drag coefficient into a Brownian motion description of the movement of proteins when they move outside the cell membrane and bind with proteins from other cells; this phenomenon occurs during cell communication when one cell releases messenger proteins to relay information to other cells. This, in turn, allows us to obtain the stochastic diffusion equation by applying I t o ^ 's Lemma. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) are lipid bilayer–enclosed nanoparticles that deliver bioactive proteins, nucleic acids, lipids, and other small molecules from donor to recipient cells. They have attracted significant interest recently due to their important roles in regulating plant-microbe interaction. During microbial infection, plant EVs play a prominent role in defense by delivering small regulatory RNA into pathogens, resulting in the silencing of pathogen virulence genes. Pathogens also deliver small RNAs into plant cells to silence host immunity genes. Recent evidence indicates that microbial EVs may be involved in pathogenesis and host immunity modulation by transporting RNAs and other biomolecules. However, the biogenesis and function of microbial EVs in plant-microbe interaction remain ill-defined. In this review, we discuss various aspects of microbial EVs, with a particular focus on current methods for EV isolation, composition, biogenesis, and their roles in plant-microbe interaction. We also discussed the potential role of microbial EVs in cross-kingdom RNA trafficking from pathogens to plants, as it is a highly likely possibility to explore in the future. [Graphic: see text] Copyright © 2023 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Summary: Multicellular organisms need mechanisms for communication between cells so that they can fulfill their purpose in the organism as a whole. Over the last two decades, several small post‐translationally modified peptides (PTMPs) have been identified as components of cell‐to‐cell signaling modules in flowering plants. Such peptides most often influence growth and development of organs not universally conserved among land plants. PTMPs have been matched to subfamily XI leucine‐rich repeat receptor‐like kinases with > 20 repeats. Phylogenetic analyses, facilitated by recently published genomic sequences of non‐flowering plants, have identified seven clades of such receptors with a history back to the common ancestor of bryophytes and vascular plants. This raises a number of questions: When did peptide signaling arise during land plant evolution? Have orthologous peptide–receptor pairs preserved their biological functions? Has peptide signaling contributed to major innovations, such as stomata, vasculature, roots, seeds, and flowers? Using genomic, genetic, biochemical, and structural data and non‐angiosperm model species, it is now possible to address these questions. The vast number of peptides that have not yet found their partners suggests furthermore that we have far more to learn about peptide signaling in the coming decades. [ABSTRACT FROM AUTHOR]

Cells rarely exist alone, which drives the evolution of diverse mechanisms for identifying and responding appropriately to the presence of other nearby cells. Filamentous fungi depend on somatic cell-to-cell communication and fusion for the development and maintenance of a multicellular, interconnected colony that is characteristic of this group of organisms. The filamentous fungus Neurospora crassa is a model for investigating the mechanisms of somatic cell-to-cell communication and fusion. N. crassa cells chemotropically grow toward genetically similar cells, which ultimately make physical contact and undergo cell fusion. Here, we describe the development of a Pprm1-luciferase reporter system that differentiates whether genes function upstream or downstream of a conserved MAP kinase (MAPK) signaling complex, by using a set of mutants required for communication and cell fusion. The vast majority of these mutants are deficient for self-fusion and for fusion when paired with wild-type cells. However, the Δham-11 mutant is unique in that it fails to undergo self-fusion, but chemotropic interactions and cell fusion are restored in Δham-11 + wild-type interactions. In genetically dissimilar cells, chemotropic interactions are regulated by genetic differences at doc-1 and doc-2, which regulate prefusion non-self recognition; cells with dissimilar doc-1 and doc-2 alleles show greatly reduced cell-fusion frequencies. Here, we show that HAM-11 functions in parallel with the DOC-1 and DOC-2 proteins to regulate the activity of the MAPK signaling complex. Together, our data support a model of integrated self and non-self recognition processes that modulate somatic cell-to-cell communication in N. crassa.

The plant immune system relies on the perception of molecules that signal the presence of a microbe threat. This triggers signal transduction that mediates a range of cellular responses via a collection of molecular machinery including receptors, small molecules, and enzymes. One response to pathogen perception is the restriction of cell-to-cell communication by plasmodesmal closure. We previously found that while chitin and flg22 trigger specialized immune signaling cascades in the plasmodesmal plasma membrane, both execute plasmodesmal closure via callose synthesis at the plasmodesmata. Therefore, the signaling pathways ultimately converge at or upstream of callose synthesis. To establish the hierarchy of signaling at plasmodesmata and characterize points of convergence in microbe elicitor-triggered signaling, we profiled the dependence of plasmodesmal responses triggered by different elicitors on a range of plasmodesmal signaling machinery. We identified that, like chitin, flg22 signals via RESPIRATORY BURST OXIDASE HOMOLOGUE D (RBOHD) to induce plasmodesmal closure. Further, we found that PLASMODESMATA-LOCATED PROTEIN 1 (PDLP1), PDLP5, and CALLOSE SYNTHASE 1 (CALS1) are common to microbe- and salicylic acid (SA)-triggered responses, identifying PDLPs as a candidate signaling nexus. To understand how PDLPs relay a signal to CALS1, we screened for PDLP5 interactors and found NON-RACE SPECIFIC DISEASE RESISTANCE/HIN1 HAIRPIN-INDUCED-LIKE protein 3 (NHL3), which is also required for chitin-, flg22- and SA-triggered plasmodesmal responses and PDLP-mediated activation of callose synthesis. We conclude that a PDLP-NHL3 complex acts as an integrating node of plasmodesmal signaling cascades, transmitting multiple immune signals to activate CALS1 and plasmodesmata closure. [ABSTRACT FROM AUTHOR]

Summary: Plasmodesmata (PD) facilitate movement of molecules between plant cells. Regulation of this movement is still not understood. Plasmodesmata are hard to study, being deeply embedded within cell walls and incorporating several membrane types. Thus, structure and protein composition of PD remain enigmatic. Previous studies of PD protein composition identified protein lists with few validations, making functional conclusions difficult.We developed a PD scoring approach in iteration with large‐scale systematic localization, defining a high‐confidence PD proteome of Physcomitrium patens (HC300). HC300, together with bona fide PD proteins from literature, were placed in Pddb. About 65% of proteins in HC300 were not previously PD‐localized.Callose‐degrading glycolyl hydrolase family 17 (GHL17) is an abundant protein family with representatives across evolutionary scale. Among GHL17s, we exclusively found members of one phylogenetic clade with PD localization and orthologs occur only in species with developed PD. Phylogenetic comparison was expanded to xyloglucan endotransglucosylases/hydrolases and Exordium‐like proteins, which also diversified into PD‐localized and non‐PD‐localized members on distinct phylogenetic clades.Our high‐confidence PD proteome HC300 provides insights into diversification of large protein families. Iterative and systematic large‐scale localization across plant species strengthens the reliability of HC300 as basis for exploring structure, function, and evolution of this important organelle. [ABSTRACT FROM AUTHOR]

Purpose: Small extracellular vesicles (sEV) containing proteins and RNAs play important roles as intercellular signal mediators. A critical issue is that there are multiple methods to prepare sEV fractions. The purpose of this study was to examine whether cancer cell-derived sEV fractions prepared by different isolation methods show similar responses for the induction of inflammatory cytokines in macrophages. Methods: sEV fractions from the conditioned medium of MCF-7 cells were prepared by ultracentrifugation (UC), the MagCapture Exosome Isolation Kit PS (PS), or the ExoQuick-TC kit (EQ). The mRNA levels of inflammatory cytokines in differentiated THP-1 cells treated with the sEV fractions were evaluated. Results: The yields of sEV fractions obtained from 1 mL conditioned medium by UC, PS, or EQ were 3.2×108 particles (0.27 μg protein), 12.8×108 particles (0.87 μg protein) and 23.5 ×108 particles (4.50 μg protein), respectively. The average particle sizes in the UC, PS, and EQ fractions were 184.8 ± 1.8 nm, 157.8 ± 1.3 nm and 165.8 ± 1.1 nm, respectively. CD9 and CD81, markers of sEV, were most highly detected in the PS fraction, followed by the EQ and UC fractions. These results suggest that PS gave sEV with relatively high purity, and many protein contaminants appear to be included in the EQ fraction. The mRNA levels of inflammatory cytokines in THP-1 macrophages were most prominently increased by treatment with the UC fraction, followed by the EQ and PS fractions, suggesting that contaminants rather than sEV may largely induce an inflammatory response. Conclusion: The isolation method affects the evaluation of sEV function. [ABSTRACT FROM AUTHOR]

The immune system, unlike other systems, must be flexible and able to "adapt" to fully cope with lurking dangers. The transition from intracorporeal balance to homeostasis disruption is associated with activation of inflammatory signaling pathways, which causes modulation of the immunology response. Chemotactic cytokines, signaling molecules, and extracellular vesicles act as critical mediators of inflammation and participate in intercellular communication, conditioning the immune system's proper response. Among the well-known cytokines allowing for the development and proper functioning of the immune system by mediating cell survival and cell-death-inducing signaling, the tumor necrosis factor α (TNF-α) and transforming growth factor β (TGF-β) are noteworthy. The high bloodstream concentration of those pleiotropic cytokines can be characterized by anti- and pro-inflammatory activity, considering the powerful anti-inflammatory and anti-oxidative stress capabilities of TGF-β known from the literature. Together with the chemokines, the immune system response is also influenced by biologically active chemicals, such as melatonin. The enhanced cellular communication shows the relationship between the TGF-β signaling pathway and the extracellular vesicles (EVs) secreted under the influence of melatonin. This review outlines the findings on melatonin activity on TGF-β-dependent inflammatory response regulation in cell-to-cell communication leading to secretion of the different EV populations. [ABSTRACT FROM AUTHOR]