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In this paper, we suggest a generalized fractional hepatitis B viral infection model with two modes of transmission that are cell-to-cell and virus-to-cell. These two modes of transmission will be represented by two generalized incidence functions. We take into account the human body's adaptive immunity, which is represented by antibody and cytotoxic T-lymphocyte immune responses. We begin the study of this model by giving some theorems concerning the existence, positivity and boundness of the model solutions. We have shown that the model has a free-disease equilibrium point and other four endemic steady states. We give the relationship between the existence of these steady states and their corresponding reproductive numbers. By using the Lyapunov method and LaSalle's invariance principle, we have shown the different theorems concerning the global stability of steady states. Some numerical simulations are presented to confirm our theoretical findings about the stability of steady states and to show the effectiveness of fractional derivative order on the stability of all equilibria. We observe that the choice of generalized incidence functions can provide a clearer understanding of the stability of equilibria and can incorporate a wide range of classical incidence functions. Finally, good infection treatment helps considerably to irradiate the infection. [ABSTRACT FROM AUTHOR]

The aim of this article is to formulate and study a mathematical model describing hepatitis C virus (HCV) infection dynamics. The model includes two essential modes of infection transmission, namely, virus-to-cell and cell-to-cell. The effect of therapy and adaptive immunity are incorporated in the suggested model. The adaptive immunity is represented by its two categories, namely, the humoral and cellular immune responses. Our article begins by establishing some mathematical results through proving the model's well-posedness in terms of existence, positivity and boundedness of solutions. We present all the steady states of the problem that depend on specific reproduction numbers. It moves then to the theoretical investigation of the local and global stability analysis of the free disease equilibrium and the four disease equilibria. The local and global stability analysis of the HCV mathematical model are established via the Routh-Hurwitz criteria and Lyapunov-LaSalle invariance principle, respectively. Finally, our article presents some numerical simulations to validate the analytical study of the global stability. Numerical simulations have shown the effect of the drug therapies on the system's dynamical behavior. [ABSTRACT FROM AUTHOR]

In China, porcine reproductive and respiratory syndrome virus (PRRSV) vaccines are widely used. These vaccines, which contain inactivated and live attenuated vaccines (LAVs), are produced by MARC-145 cells derived from the monkey kidney cell line. However, some PRRSV strains in MARC-145 cells have a low yield. Here, we used two type 2 PRRSV strains (CH-1R and HuN4) to identify the genes responsible for virus yield in MARC-145 cells. Our findings indicate that the two viruses have different spread patterns, which ultimately determine their yield. By replacing the viral envelope genes with a reverse genetics system, we discovered that the minor envelope proteins, from GP2a to GP4, play a crucial role in determining the spread pattern and yield of type 2 PRRSV in MARC-145 cells. The cell-free transmission pattern of type 2 PRRSV appears to be more efficient than the cell-to-cell transmission pattern. Overall, these findings suggest that GP2a to GP4 contributes to the spread pattern and yield of type 2 PRRSV. [ABSTRACT FROM AUTHOR]

Cell-to-cell communication plays a cardinal role in the biology of multicellular organisms. H2O2 is an important cell-to-cell signaling molecule involved in the response of mammalian cells to wounding and other stimuli. We previously identified a signaling pathway that transmits wound-induced cell-to-cell H2O2 signals within minutes over long distances, measured in centimeters, in a monolayer of cardiomyocytes. Here we report that this long-distance H2O2 signaling pathway is accompanied by enhanced accumulation of cytosolic H2O2 and altered redox state in cells along its path. We further show that it requires the production of superoxide, as well as the function of gap junctions, and that it is accompanied by changes in the abundance of hundreds of proteins in cells along its path. Our findings highlight the existence of a unique and rapid long-distance H2O2 signaling pathway that could play an important role in different inflammatory responses, wound responses/healing, cardiovascular disease, and/or other conditions.

ABSTRACTWe previously demonstrated that two methyltransferase motifs, K-D-K-E and G-G-D, affect the pathogenicity of Newcastle disease virus (NDV) by regulating mRNA translation and virus transmission. Here, we compared the infectious centre area produced by the NDV strain, rSG10, and methyltransferase motifs mutant rSG10 strains in DF-1 cells. The results show that intercellular transmission was attenuated by methyltransferase motif mutations. We further determined the ability of mutant viruses to spread in cell-free and cell-to-cell situations. Cell-free transmission of rSG10-K1756A was not reduced, indicating that cell-to-cell transmission of rSG10-K1756A was decreased. Using a donor and target system, we demonstrated that NDV can spread from cell-to-cell directly. Furthermore, by comparing the protein distribution area of three strains when treated with 2% agar overlay, we found that rSG10-K1756A was defective in cell-to-cell transmission. Tunnelling nanotubes (TNTs) are an important mode for cell-to-cell transmission. Treatment of cells with cytochalasin D (CytoD) or nocodazole to inhibit the formation of TNTs, reduced protein levels in all strains, but rSG10-K1756A was the least affected. These results indicate that mutation of the K-D-K-E motif is likely to restricted the spread of NDV via TNTs. Finally, we observed that matrix protein (M) and fusion protein (F) promoted the formation of cellular extensions, which may be involved in the cell-to-cell spread of NDV. Our research reveals a novel mechanism by which methyltransferase motifs affect the cell-to-cell spread of NDV and provides insight into dissemination of paramyxoviruses.

The study of neoplastic cells enabled the discovery of important tumor-related biomarkers which resulted in new forms of early diagnosis, therapeutic options, and prognostic markers. Thus, immunofluorescence (IF), a high throughput imaging technology, represents a valuable method that enables the virtual characterization and localization of diverse cell types and targets, preserving tissue architecture and spatial surroundings. IF staining and analysis of formalin-fixed paraffin-embedded (FFPE) tissues are considered a challenge due to several difficulties, such as tissue autofluorescence, non-specific antibody binding, and image acquisition and quality. This study aimed to develop a multiplex-fluorescence staining technique with high-contrast and high-quality multiple-color images to enrich the investigation of important biomarkers. We present a robust optimized multiple-immunofluorescence procedure that reduced sample autofluorescence, enabled the use of simultaneous antibodies on the same sample, and showed super-resolution imaging through precise antigen localization. We illustrated the utility of this powerful method in FFPE neoplastic appendix, lymph node and bone marrow biopsies, and a 3D-coculture system, in which cells are enabled to grow and interact with their surroundings in all 3D dimensions. Our optimized multiple-immunofluorescence method represents a powerful tool for better understanding the complexity of tumor cells, characterizing cell populations and spatial localization, revealing predictive and prognostic biomarkers, and identifying immunologic phenotypes in a single and limited sample. This valuable IF protocol successfully enables tumor microenvironment profiling that could contribute to the study of cellular crosstalk and the niche, and to the identification of predictive biomarkers for neoplasms. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) are composed of bilayer membranes that are released by different cell types and are present in bodily fluids, such as blood, urine, and bile. EVs are thought to play a key role in intracellular communication. Based on their size and density, EVs are classified into small, medium, or large EVs. Cargo composition in EVs reflects physiological changes in health and disease. Patients with irritable bowel syndrome (IBS) exhibit visceral hypersensitivity and mood disorders. Stressful episodes often precede disease symptoms in IBS patients. Stress-induced symptoms include, but are not limited to, abdominal pain and mood swings. Perceived stress responses are mediated by two known G protein-coupled receptors (GPCRs), corticotropin-releasing factor receptor 1 and 2 (CRFRs). CRFRs belong to the Class B secretin receptor family of GPCRs. Here, we show that CRFRs were present in human and murine plasma, and in EVs purified from mouse serum. CRFRs were present in plasma from IBS patients and healthy controls. EVs secreted from immune cells influence both adaptive and innate immune responses via exchange of EVs between different immune cell types. B7-2 (CD86), a plasma membrane antigen-presenting protein, is present on EVs secreted from dendritic, B-, and mast cells, whereas CD9 is present on EVs secreted from dendritic and intestinal epithelial cells. We found that plasma CRFR levels positively correlated with B7-2+ EVs (R = 0.8597, p < 0.0001), but no association was seen with CD9+ EVs. Plasma CRFRs expression negatively correlated with IBS severity scores. Our data suggests that plasma EVs from immune cells carry CRFRs as cargos and influence cell-cell communication in health and disease.

The interplay between reactive oxygen species (ROS) and the redox state of cells is deeply rooted in the biology of almost all organisms, regulating development, growth, and responses to the environment. Recent studies revealed that the ROS levels and redox state of one cell can be transmitted, as an information 'state' or 'currency', to other cells and spread by cell-to-cell communication within an entire community of cells or an organism. Here, we discuss the different pathways that mediate cell-to-cell signaling in plants, their hierarchy, and the different mechanisms that transmit ROS/redox signaling between different cells. We further hypothesize that ROS/redox signaling between different organisms could play a key role within the 'one world' principle, impacting human health and our future. [Display omitted] • The interplay between ROS and redox is deeply rooted in the biology of many different organisms. • The ROS/redox state of one cell can be transmitted to other cells generating a chain of cell-to-cell signaling events. • ROS/redox signaling is linked with other signal transduction pathways in cells controlling systemic signaling/acclimation. • Cell-to-cell transfer of ROS/redox states between different organisms links environmental stress to human health. • Hydrogen peroxide is a universal cell-to-cell signal and possibly one of the first stress hormones to emerge on Earth. [ABSTRACT FROM AUTHOR]

In this paper, we propose and analyse a delayed HIV-1 model with both viral and cellular transmissions and virus waning. We obtain the threshold dynamics of the proposed model, characterized by the basic reproduction number $R_0 $. If $R_0 \lt 1 $, the infection-free steady state is globally asymptotically stable; whereas if $R_0 \gt 1 $, the system is uniformly persistent. When the delays are positive, we show that the intracellular delays in both viral and cellular infections may lead to stability switches of the infected steady state. Both analytical and numerical results indicate that if the effect of cell-to-cell transmission is ignored, then the risk of HIV-1 infection will be underestimated. Moreover, the viral load of model without virus waning is higher than the one of model with virus waning. These results highlight the important role of two ways of viral transmission and virus waning on HIV-1 infection.

A selection switch based cell-to-cell voltage equalizer requires only one dual-port dc–dc converter shared by all the cells. A cell-to-cell voltage equalizer is proposed that utilizes a capacitively level-shifted Cuk converter and low-frequency cell selection switches. The absence of isolation transformer and diodes in the equalizer leads to high efficiency, and the use of low-frequency selection switches significantly reduces the cost of the drive circuits. A low-frequency cell selection network is proposed using bipolar voltage buses, where the switch count is almost half, compared to the existing low-frequency cell-to-cell equalizers for the case of a large number of cells. A novel approach for cell voltage recovery compensation is proposed, which reduces the number of operations of the selection switches and the equalization time. The proposed equalizer is implemented with relays and verified with an eight-cell Li-ion stack. The developed prototype shows the efficiency of over 90% and good voltage balancing performance during charging, discharging, and varying load conditions. Experimental results also show about one order of magnitude reduction in the number of relay switchings and a significant reduction in equalization time using the proposed voltage compensation. [ABSTRACT FROM AUTHOR]

There is tremendous variation in biological traits, and much of it is not accounted for by variation in DNA sequence, including human diseases and lifespan. Emerging evidence points to differences in the execution of the genetic program as a key source of variation, be it stochastic variation or programmed variation. Here we discuss variation in gene expression as an intrinsic property and how it could contribute to variation in traits, including the rate of aging. The review is divided into sections describing the historical context and evidence to date for nongenetic variation, the different approaches that may be used to detect nongenetic variation, and recent findings showing that the amount of variation in gene expression can be both genetically programmed and epigenetically controlled. Finally, we present evidence that changes in cell-to-cell variation in gene expression emerge as part of the aging process and may be linked to disease vulnerability as a function of age. These emerging concepts are likely to be important across the spectrum of biomedical research and may well underpin what we understand as biological aging. [ABSTRACT FROM AUTHOR]

Cell-to-cell communication plays a cardinal role in the biology of multicellular organisms. H 2 O 2 is an important cell-to-cell signaling molecule involved in the response of mammalian cells to wounding and other stimuli. We previously identified a signaling pathway that transmits wound-induced cell-to-cell H 2 O 2 signals within minutes over long distances, measured in centimeters, in a monolayer of cardiomyocytes. Here we report that this long-distance H 2 O 2 signaling pathway is accompanied by enhanced accumulation of cytosolic H 2 O 2 and altered redox state in cells along its path. We further show that it requires the production of superoxide, as well as the function of gap junctions, and that it is accompanied by changes in the abundance of hundreds of proteins in cells along its path. Our findings highlight the existence of a unique and rapid long-distance H 2 O 2 signaling pathway that could play an important role in different inflammatory responses, wound responses/healing, cardiovascular disease, and/or other conditions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

In China, porcine reproductive and respiratory syndrome virus (PRRSV) vaccines are widely used. These vaccines, which contain inactivated and live attenuated vaccines (LAVs), are produced by MARC-145 cells derived from the monkey kidney cell line. However, some PRRSV strains in MARC-145 cells have a low yield. Here, we used two type 2 PRRSV strains (CH-1R and HuN4) to identify the genes responsible for virus yield in MARC-145 cells. Our findings indicate that the two viruses have different spread patterns, which ultimately determine their yield. By replacing the viral envelope genes with a reverse genetics system, we discovered that the minor envelope proteins, from GP2a to GP4, play a crucial role in determining the spread pattern and yield of type 2 PRRSV in MARC-145 cells. The cell-free transmission pattern of type 2 PRRSV appears to be more efficient than the cell-to-cell transmission pattern. Overall, these findings suggest that GP2a to GP4 contributes to the spread pattern and yield of type 2 PRRSV., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Bai, Sun, Liu, Zhang, An, Wang, Tian, Qiao, Cai and Tang.)

In this paper, we propose and analyse a delayed HIV-1 model with both viral and cellular transmissions and virus waning. We obtain the threshold dynamics of the proposed model, characterized by the basic reproduction number R 0 . If R 0 < 1 , the infection-free steady state is globally asymptotically stable; whereas if R 0 > 1 , the system is uniformly persistent. When the delays are positive, we show that the intracellular delays in both viral and cellular infections may lead to stability switches of the infected steady state. Both analytical and numerical results indicate that if the effect of cell-to-cell transmission is ignored, then the risk of HIV-1 infection will be underestimated. Moreover, the viral load of model without virus waning is higher than the one of model with virus waning. These results highlight the important role of two ways of viral transmission and virus waning on HIV-1 infection. [ABSTRACT FROM AUTHOR]

The misfolding of transactive response DNA-binding protein (TDP-43) is a major contributor to the pathogenesis of TDP-43 proteinopathies, including amyotrophic lateral sclerosis and frontotemporal lobar degeneration with TDP-43 inclusions, but also plays a role in other neurodegenerative diseases including Alzheimer disease. It is thought that different truncations at the N- and C-termini of TDP-43 contribute to its misfolding and aggregation in the brain, and that these aberrant TDP-43 fragments contribute to disease. Despite this, little is known about whether different truncation events influence the protein’s transmissibility between cells and how this cell-to-cell transfer occurs. In this study, we use a well-established cellular model to study the efficiency by which full-length and truncated TDP-43 fragments are transferred between neuron-like cells. We demonstrate that preservation of the N-terminus of TDP-43 enhances its transmissibility between cells and that this protein transmission occurs in a manner exclusive of extracellular vesicles, instead requiring cellular proximity for efficient propagation. These data indicate that the N-terminus of TDP-43 might be a useful target in the generation of therapeutics to limit the spread of TDP-43 pathology.

Voltage equalizers are used to ensure that there is no overcharge or overdischarge of cells in series-connected battery stacks. A novel fast multicell-to-multicell voltage equalizer topology is proposed in this article. The equalizer has a modular structure consisting of one half-bridge converter leg, one inductor, and one capacitor for each battery. Only battery voltage sensing is sufficient for controlling the equalizer. The proposed equalizer can transfer charge from multiple batteries to multiple batteries in a string simultaneously. The equalization current does not depend on the battery voltage differences and, hence does not reduce as the battery voltages approach each other during voltage equalization. A modularization method is proposed for this topology with two additional passive elements per module. This method provides a direct charge transfer path from any cell in one module to any cell in another module. Thus, the equalization time does not increase with the number of modules. The proposed topology is theoretically analyzed and experimentally verified with a prototype equalizer in a series-connected lead-acid battery string, a Li-ion battery string, and a hybrid ultracapacitor string. The proposed modularization method is verified experimentally with two modules tested together in a battery string. [ABSTRACT FROM AUTHOR]

The misfolding of transactive response DNA-binding protein (TDP-43) is a major contributor to the pathogenesis of TDP-43 proteinopathies, including amyotrophic lateral sclerosis and frontotemporal lobar degeneration with TDP-43 inclusions, but also plays a role in other neurodegenerative diseases including Alzheimer disease. It is thought that different truncations at the N- and C-termini of TDP-43 contribute to its misfolding and aggregation in the brain, and that these aberrant TDP-43 fragments contribute to disease. Despite this, little is known about whether different truncation events influence the protein's transmissibility between cells and how this cell-to-cell transfer occurs. In this study, we use a well-established cellular model to study the efficiency by which full-length and truncated TDP-43 fragments are transferred between neuron-like cells. We demonstrate that preservation of the N-terminus of TDP-43 enhances its transmissibility between cells and that this protein transmission occurs in a manner exclusive of extracellular vesicles, instead requiring cellular proximity for efficient propagation. These data indicate that the N-terminus of TDP-43 might be a useful target in the generation of therapeutics to limit the spread of TDP-43 pathology. [ABSTRACT FROM AUTHOR]

In this paper, a Caputo fractional-order HCV Periodic immune response model with saturation incidence, cell-to-cell and drug control was proposed. We derive two different basic reproductive numbers and their relation with infection-free equilibrium and the immune-exhausted equilibrium. Moreover, there exists some symmetry in the relationship between the two equilibria and the basic reproduction numbers. We obtain the global stability of the infection-free equilibrium by using Lyapunov function and the local stability of the immune-exhausted equilibrium. The optimal control problem is also considered and two control strategies are given; one is for ITX5061 monotherapy, the other is for ITX5061 and DAAs combination therapy. Matlab numerical simulation shows that combination therapy has lower objective function value; therefore, it is worth trying to use combination therapy to treat HCV infection.

We previously demonstrated that two methyltransferase motifs, K-D-K-E and G-G-D, affect the pathogenicity of Newcastle disease virus (NDV) by regulating mRNA translation and virus transmission. Here, we compared the infectious centre area produced by the NDV strain, rSG10, and methyltransferase motifs mutant rSG10 strains in DF-1 cells. The results show that intercellular transmission was attenuated by methyltransferase motif mutations. We further determined the ability of mutant viruses to spread in cell-free and cell-to-cell situations. Cell-free transmission of rSG10-K1756A was not reduced, indicating that cell-to-cell transmission of rSG10-K1756A was decreased. Using a donor and target system, we demonstrated that NDV can spread from cell-to-cell directly. Furthermore, by comparing the protein distribution area of three strains when treated with 2% agar overlay, we found that rSG10-K1756A was defective in cell-to-cell transmission. Tunnelling nanotubes (TNTs) are an important mode for cell-to-cell transmission. Treatment of cells with cytochalasin D (CytoD) or nocodazole to inhibit the formation of TNTs, reduced protein levels in all strains, but rSG10-K1756A was the least affected. These results indicate that mutation of the K-D-K-E motif is likely to restricted the spread of NDV via TNTs. Finally, we observed that matrix protein (M) and fusion protein (F) promoted the formation of cellular extensions, which may be involved in the cell-to-cell spread of NDV. Our research reveals a novel mechanism by which methyltransferase motifs affect the cell-to-cell spread of NDV and provides insight into dissemination of paramyxoviruses.

Abstract HIV infection persists despite long-term administration of antiretroviral therapy. The mechanisms underlying HIV persistence are not fully understood. Direct viral transmission from infected to uninfected cells (cell-to-cell transmission) may be one of them. During cell-to-cell transmission, multiple virions are delivered to an uninfected cell, making it possible that at least one virion can escape HIV drugs and establish infection. In this paper, we develop a mathematical model that includes cell-to-cell viral transmission to study HIV persistence. During cell-to-cell transmission, it is assumed that various number of virus particles are transmitted with different probabilities and antiretroviral therapy has different effectiveness in blocking their infection. We analyze the model by deriving the basic reproduction number and investigating the stability of equilibria. Sensitivity analysis and numerical simulation show that the viral load is still sensitive to the change of the treatment effectiveness in blocking cell-free virus infection. To reduce this sensitivity, we modify the model by including density-dependent infected cell death or HIV latent infection. The model results suggest that although cell-to-cell transmission may have reduced susceptibility to HIV drugs, HIV latency represents a major reason for HIV persistence in patients on suppressive treatment. [ABSTRACT FROM AUTHOR]

We make a mathematical analysis of an age structured HIV infection model with both virus-to-cell and cell-to-cell transmissions to understand the dynamical behavior of HIV infection in vivo. In the model, we consider the proliferation of uninfected CD 4 + T cells by a logistic function and the infected CD 4 + T cells are assumed to have an infection-age structure. Our main results concern the Hopf bifurcation of the model by using the theory of integrated semigroup and the Hopf bifurcation theory for semilinear equations with nondense domain. Bifurcation analysis indicates that there exist some parameter values such that this HIV infection model has a nontrivial periodic solution which bifurcates from the positive equilibrium. The numerical simulations are also carried out. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) are composed of bilayer membranes that are released by different cell types and are present in bodily fluids, such as blood, urine, and bile. EVs are thought to play a key role in intracellular communication. Based on their size and density, EVs are classified into small, medium, or large EVs. Cargo composition in EVs reflects physiological changes in health and disease. Patients with irritable bowel syndrome (IBS) exhibit visceral hypersensitivity and mood disorders. Stressful episodes often precede disease symptoms in IBS patients. Stress-induced symptoms include, but are not limited to, abdominal pain and mood swings. Perceived stress responses are mediated by two known G protein-coupled receptors (GPCRs), corticotropin-releasing factor receptor 1 and 2 (CRFRs). CRFRs belong to the Class B secretin receptor family of GPCRs. Here, we show that CRFRs were present in human and murine plasma, and in EVs purified from mouse serum. CRFRs were present in plasma from IBS patients and healthy controls. EVs secreted from immune cells influence both adaptive and innate immune responses via exchange of EVs between different immune cell types. B7-2 (CD86), a plasma membrane antigen-presenting protein, is present on EVs secreted from dendritic, B-, and mast cells, whereas CD9 is present on EVs secreted from dendritic and intestinal epithelial cells. We found that plasma CRFR levels positively correlated with B7-2+ EVs (R = 0.8597, p < 0.0001), but no association was seen with CD9+ EVs. Plasma CRFRs expression negatively correlated with IBS severity scores. Our data suggests that plasma EVs from immune cells carry CRFRs as cargos and influence cell-cell communication in health and disease.

We present a nonstandard finite difference scheme for a delayed viral infection model with virus-to-cell and cell-to-cell transmissions. We prove that the system is permanent if the basic reproduction number. Then we show that the infection-free equilibrium is globally asymptotically stable if, and the infection equilibrium is globally asymptotically stable if. Numerical simulations are presented to illustrate our theoretical results. [ABSTRACT FROM PUBLISHER]

The infection routes of HIV-1 can affect several viral properties, including dissemination, pathogenesis, and immune evasion. In this study, we evaluated the inhibitory activity of a wide variety of anti-HIV drugs, focusing on the impact that different infection pathways have on their efficacy. Compared to cell-free infection, inhibitory activities were reduced in cell-to-cell productive transmission for all drugs tested. We detected weak reporter-expressing target cells after cell-to-cell transmission in the presence of integrase strand transfer inhibitors (INSTIs). Further analysis revealed that this expression was mainly due to unintegrated circular HIV (cHIV) DNAs, consisting of 1-LTR and 2-LTR circles. When in vitro -constructed cHIV DNAs were introduced into cells, the production of infectious and intercellular transmittable virions was observed, suggesting that cHIV DNA could be a source of infectious virus. These results highlight some advantages of the cell-to-cell infection mode for viral expansion, particularly in the presence of anti-retroviral drugs. [ABSTRACT FROM AUTHOR]

Direct cell-to-cell transfer of HIV-1 is found to be a more potent and efficient means of virus propagation than virus-to-cell infection. In this paper we propose a mathematical model to consider these two modes of viral infection and spread, in which infection age is also incorporated. By a rigorous analysis of the model, we show that the model demonstrates a global threshold dynamics, fully described by the basic reproduction number, which is identified explicitly. The formula for the basic reproduction number of our model reveals that the basic reproduction number of a model that neglects either cell-to-cell spread or virus-to-cell infection might be underevaluated. [ABSTRACT FROM AUTHOR]

Highlights: [•] p7 Inhibitors were tested for their ability to block HCV cell-free and cell-to-cell transmission. [•] p7 Inhibitor BIT225 reduced the infectivity of diverse HCV extracellular virus. [•] p7 Inhibitors had minimal effect on HCV cell-to-cell transmission. [•] Important to consider HCV transmission route when assessing assembly inhibitors. [Copyright &y& Elsevier]

Revealing the mechanisms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry and cell-to-cell spread might provide insights for understanding the underlying mechanisms of viral pathogenesis, tropism, and virulence. The signaling pathways involved in SARS-CoV-2 entry and viral spike-mediated cell-to-cell fusion remain elusive. In the current study, we found that macropinocytosis inhibitors significantly suppressed SARS-CoV-2 infection at both the entry and viral spike-mediated cell-to-cell fusion steps. We demonstrated that SARS-CoV-2 entry required the small GTPase Rac1 and its effector kinase p21-activated kinase 1 by dominant-negative and RNAi assays in human embryonic kidney 293T-angiotensin-converting enzyme 2 cells and that the serine protease transmembrane serine protease 2 reversed the decrease in SARS-CoV-2 entry caused by the macropinocytosis inhibitors. Moreover, in the cell-to-cell fusion assay, we confirmed that macropinocytosis inhibitors significantly decreased viral spike-mediated cell-to-cell fusion. Overall, we provided evidence that SARS-CoV-2 utilizes a macropinocytosis pathway to enter target cells and to efficiently promote viral spike-mediated cell-to-cell fusion., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Hepatitis C virus (HCV) poses a global health problem, with over 170million chronically infected individuals at risk of developing progressive liver disease. The ability of a virus to spread within a host is a key determinant of its persistence and virulence. HCV can transmit in vitro by cell-free particle diffusion or via contact(s) between infected and naïve hepatocytes. However, limited information is available on the relative efficiency of these routes, our aim is to develop physiologically relevant assays to quantify these processes. Methods: We developed a single-cycle infection assay to measure HCV transmission rates. Results: We compared HCV spread in proliferating and arrested cell systems and demonstrated a significant reduction in cell-to-cell infection of arrested target cells. Comparison of cell-free and cell-to-cell virus spread demonstrated relatively poor transmission rates, with 10–50 infected producer cells required to infect a single naïve target cell. We found HCV strain J6/JFH to be 10-fold more efficient at spreading via the cell-to-cell route than cell-free, whereas SA13/JFH and HK6/JFH strains showed comparable rates of infection via both routes. Importantly, the level of infectious virus released from cells did not predict the ability of a virus to spread in vitro, highlighting the importance of studying cell-associated viruses. Conclusions: These studies demonstrate the relatively poor infectivity of HCV and highlight differences between strains in their efficiency and preferred route of transmission that may inform future therapeutic strategies that target virus entry. [ABSTRACT FROM AUTHOR]

Background: Since cell-mediated infection of human immunodeficiency virus type 1 (HIV-1) is more efficient than cell-free infection, cell-to-cell propagation plays a crucial role in the pathogenesis of HIV-1 infection. Transmission of HIV-1 is enabled by two types of cellular contacts, namely, virological synapses between productively infected cells and uninfected target cells and infectious synapses between uninfected dendritic cells (DC) harboring HIV-1 and uninfected target cells. While virological synapses are driven by expression of the viral envelope glycoprotein on the cell surface, little is known about the role of envelope glycoprotein during contact between DC and T cells. We explored the contribution of HIV-1 envelope glycoprotein, adhesion molecules, and antigen recognition in the formation of conjugates comprising mature DC (mDC) and CD4+ T cells in order to further evaluate their role in mDC-mediated HIV-1 transmission at the immunological synapse. Results: Unlike virological synapse, HIV-1 did not modulate the formation of cell conjugates comprising mDC harboring HIV-1 and non-activated primary CD4+ T cells. Disruption of interactions between ICAM-1 and LFA-1, however, resulted in a 60% decrease in mDC-CD4+ T-cell conjugate formation and, consequently, in a significant reduction of mDC-mediated HIV-1 transmission to non-activated primary CD4+ T cells (p < 0.05). Antigen recognition or sustained MHC-TcR interaction did not enhance conjugate formation, but significantly boosted productive mDC-mediated transmission of HIV-1 (p < 0.05) by increasing T-cell activation and proliferation. Conclusions: Formation of the infectious synapse is independent of the presence of the HIV-1 envelope glycoprotein, although it does require an interaction between ICAM-1 and LFA-1. This interaction is the main driving force behind the formation of mDC-CD4+ T-cell conjugates and enables transmission of HIV-1 to CD4+ T cells. Moreover, antigen recognition boosts HIV-1 replication without affecting the frequency of cellular conjugates. Our results suggest a determinant role for immune activation driven by mDC-CD4+ T-cell contacts in viral dissemination and that this activation likely contributes to the pathogenesis of HIV-1 infection. [ABSTRACT FROM AUTHOR]

RNA silencing, including gene quelling in fungi and RNA interference in animals, refers to a process of homologous, sequence-specific, RNA-based, post-transcriptional gene silencing triggered by double- stranded RNA that requires a conserved set of gene products. RNA-induced, homology-dependent gene silencing can also spread locally and systemically between cells to orchestrate developmental programs in plants. The mobile RNAi signal could consist of a complex of small RNAs and proteins. In plants, the mobile RNAi signals may traffic beyond sites of initiation through plasmodesmata channels (cell-to-cell movement) and also over long distances through the phloem (systemic movement). Small interfering RNA processed by DICER-like proteins is considered a hallmark of RNAi mobility, and the phloem represents a unique highway for long-distance spreading of RNAi signals. To date, molecular and genetic studies have identified a few RNA molecules and protein components that function in silencing spread mechanisms. However, the processes involved in cell-to-cell movement of RNAi signals remain poorly understood. To gain further insight into noncell- autonomous RNAi spreading networks, it is critical to discover and characterize the distinct functions of the various genetic and molecular components involved. In this review, we discuss current advances, as well as gaps, in our understanding of cell-to-cell RNAi spread pathways and their implications for fundamental biology in plants. [ABSTRACT FROM AUTHOR]

Abstract: A Florida isolate of Tomato spotted wilt virus (TSWV) was able to complement cell-to-cell movement of a movement-defective Tobacco mosaic virus (TMV) vector expressing the jellyfish green fluorescent protein (GFP). To test for complementation of movement in the absence of other TSWV proteins, the open reading frame for the NSm protein was expressed from TMV constructs encoding only the TMV replicase proteins. NSm was expressed from either the coat protein or movement protein subgenomic promoter, creating virus hybrids that moved cell to cell in inoculated leaves of tobacco, providing the first functional demonstration that NSm is the TSWV movement protein. Furthermore, these CP-deficient hybrids moved into upper leaves of Nicotiana benthamiana, demonstrating that NSm can support long-distance movement of viral RNAs. Tubules, characteristic of the NSm protein, were also formed in tobacco protoplasts infected with the TMV–TSWV hybrids. The C-terminus of the NSm protein was shown to be required for movement. TMV–TSWV hybrids expressing NSm and GFP moved within inoculated leaves. Our combination of single-cell and intact plant experiments to examine multiple functions of a heterologous viral protein provides a generalized strategy with wider application to other viruses also lacking a reverse genetic system. [Copyright &y& Elsevier]

In this paper, a Caputo fractional-order HCV Periodic immune response model with saturation incidence, cell-to-cell and drug control was proposed. We derive two different basic reproductive numbers and their relation with infection-free equilibrium and the immune-exhausted equilibrium. Moreover, there exists some symmetry in the relationship between the two equilibria and the basic reproduction numbers. We obtain the global stability of the infection-free equilibrium by using Lyapunov function and the local stability of the immune-exhausted equilibrium. The optimal control problem is also considered and two control strategies are given; one is for ITX5061 monotherapy, the other is for ITX5061 and DAAs combination therapy. Matlab numerical simulation shows that combination therapy has lower objective function value; therefore, it is worth trying to use combination therapy to treat HCV infection. [ABSTRACT FROM AUTHOR]

Horizontal gene transfer (HGT) is a driving force for bacterial evolution that occurs via conjugation, transduction, and transformation. Whereas conjugation and transduction depend on nonbacterial vehicles, transformation is considered a naturally occurring process in which naked DNA molecules are taken up by a competent recipient cell. Here, we report that HGT occurred between two Bacillus subtilis strains cocultured on a minimum medium agar plate for 10 h. This process was almost completely resistant to DNase treatment and appeared to require close proximity between cells. The deletion of comK in the recipient completely abolished gene transfer, indicating that the process involved transformation. This process was also highly efficient, reaching 1.75 × 106 transformants/µg DNA compared to 5.3 × 10³ and 1.86 × 105 transformants/µg DNA for DNA-to-cell transformation by the same agar method and the standard two-step procedure, respectively. Interestingly, when three distantly localized chromosomal markers were selected simultaneously, the efficiency of cell-to-cell transformation still reached 6.26 × 104 transformants/µg DNA, whereas no transformants were obtained when free DNA was used as the donor. Stresses, such as starvation and exposure to antibiotics, further enhanced transformation efficiency by affecting the donor cells, suggesting that stress served as an important signal for promoting this type of HGT. Taken together, our results defined a bona fide process of cell-to-cell natural transformation (CTCNT) in B. subtilis and related species. This finding reveals the previously unrecognized role of donor cells in bacterial natural transformation and improves our understanding of how HGT drives bacterial evolution at a mechanistic level. [ABSTRACT FROM AUTHOR]