scholarly journals Epithelial stratification shapes infection dynamics

2017 ◽  
Author(s):  
Carmen Lía Murall ◽  
Robert Jackson ◽  
Ingeborg Zehbe ◽  
Nathalie Boulle ◽  
Michel Segondy ◽  
...  
Keyword(s):  
Experimental Models ◽  
Human Papillomaviruses ◽  
Cell Dynamics ◽  
Testing Hypotheses ◽  
Experimental Systems ◽  
Specific Effects ◽  
Pathogen Load ◽  
Infection Dynamics ◽  
Pathogen Burden ◽  
Stratified Epithelia

Infections of stratified epithelia collectively represent a large burden on global health. Experimental models provide a means to understand how the cell dynamics themselves influence the outcomes of these infections. Mathematical approaches are needed to improve quantification and theoretical advancement of these complex systems. Here, we develop a general ecology-inspired model for stratified epithelial dynamics, which allows us to simulate infections and to estimate parameters that are difficult to measure with organotypic cell cultures. To explore how epithelial cell dynamics affect infection dynamics, we focus on two contrasting pathogens of the cervicovaginal epithelium:Chlamydia trachomatisand Human papillomaviruses. We find that key infection symptoms stem from differential interactions with the layers, while clearance and pathogen burden are bottom-up processes. Cell protective responses to infections (e.g. increased cell proliferation) generally lowered pathogen load but there were specific effects based on infection strategies. These generic responses by the epithelium, then, will have varying results depending on the pathogen’s infection strategy. Our modeling approach opens new perspectives for 3D tissue culture experimental systems of infections and, more generally, for developing and testing hypotheses related to infections of stratified epithelia.

scholarly journals Alternative Experimental Models for Studying Influenza Proteins, Host–Virus Interactions and Anti-Influenza Drugs

2019 ◽  
Vol 12 (4) ◽  
pp. 147 ◽  
Author(s):  
Sonja C. J. H. Chua ◽  
Hui Qing Tan ◽  
David Engelberg ◽  
Lina H. K. Lim
Keyword(s):  
Protein Function ◽  
Viral Infections ◽  
Experimental Models ◽  
Host Proteins ◽  
Physiological Basis ◽  
Host Interactions ◽  
Experimental Systems ◽  
Host Virus Interactions ◽  
Virus Interactions ◽  
Unique Potential

Ninety years after the discovery of the virus causing the influenza disease, this malady remains one of the biggest public health threats to mankind. Currently available drugs and vaccines only partially reduce deaths and hospitalizations. Some of the reasons for this disturbing situation stem from the sophistication of the viral machinery, but another reason is the lack of a complete understanding of the molecular and physiological basis of viral infections and host–pathogen interactions. Even the functions of the influenza proteins, their mechanisms of action and interaction with host proteins have not been fully revealed. These questions have traditionally been studied in mammalian animal models, mainly ferrets and mice (as well as pigs and non-human primates) and in cell lines. Although obviously relevant as models to humans, these experimental systems are very complex and are not conveniently accessible to various genetic, molecular and biochemical approaches. The fact that influenza remains an unsolved problem, in combination with the limitations of the conventional experimental models, motivated increasing attempts to use the power of other models, such as low eukaryotes, including invertebrate, and primary cell cultures. In this review, we summarized the efforts to study influenza in yeast, Drosophila, zebrafish and primary human tissue cultures and the major contributions these studies have made toward a better understanding of the disease. We feel that these models are still under-utilized and we highlight the unique potential each model has for better comprehending virus–host interactions and viral protein function.

Discovery of steroidal lactam conjugates of POPAM-NH2 with potent anticancer activity

2020 ◽  
Vol 12 (1) ◽  
pp. 19-35 ◽  
Author(s):  
Dimitrios Trafalis ◽  
Panagiotis Dalezis ◽  
Elena Geromichalou ◽  
Sofia Sagredou ◽  
Eleni Sflakidou ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Anticancer Agents ◽  
Alkylating Agents ◽  
Experimental Models ◽  
The Novel ◽  
Nitrogen Mustards ◽  
Experimental Systems ◽  
High Antitumor Activity

Aim: Steroidal prodrugs of nitrogen mustards such as estramustine and prednimustine have proven effective anticancer agents in clinical use since the 1970s. In this work, we aimed to develop steroidal prodrugs of the novel nitrogen mustard POPAM-NH2. POPAM-NH2 is a melphalan analogue that was coupled with three different steroidal lactams. Methodology: The new conjugates were preclinically tested for anticancer activity against nine human and one rodent cancer experimental models, in vitro and in vivo. Results & conclusion: All the steroidal alkylators showed high antitumor activity, in vitro and in vivo, in the experimental systems tested. Moreover, these hybrid compounds showed by far superior anticancer activity compared with the alkylating agents, melphalan and POPAM-NH2.

scholarly journals Effect of different modes of viral spread on the dynamics of multiply infected cells in human immunodeficiency virus infection

2010 ◽  
Vol 8 (55) ◽  
pp. 289-300 ◽  
Author(s):  
Dominik Wodarz ◽  
David N. Levy
Keyword(s):  
Evolutionary Dynamics ◽  
Virological Synapse ◽  
Virus Spread ◽  
Hiv Replication ◽  
Virus Particles ◽  
Viral Spread ◽  
Experimental Systems ◽  
Infection Dynamics ◽  
Immunodeficiency Virus ◽  
Infected Cells

Infection of individual cells with more than one HIV particle is an important feature of HIV replication, which may contribute to HIV pathogenesis via the occurrence of recombination, viral complementation and other outcomes that influence HIV replication and evolutionary dynamics. A previous mathematical model of co-infection has shown that the number of cells infected with i viruses correlates with the i th power of the singly infected cell population, and this has partly been observed in experiments. This model, however, assumed that virus spread from cell to cell occurs only via free virus particles, and that viruses and cells mix perfectly. Here, we introduce a cellular automaton model that takes into account different modes of virus spread among cells, including cell to cell transmission via the virological synapse, and spatially constrained virus spread. In these scenarios, it is found that the number of multiply infected cells correlates linearly with the number of singly infected cells, meaning that co-infection plays a greater role at lower virus loads. The model further indicates that current experimental systems that are used to study co-infection dynamics fail to reflect the true dynamics of multiply infected cells under these specific assumptions, and that new experimental techniques need to be designed to distinguish between the different assumptions.

scholarly journals Demonstration of Co-Infection and Trans-Encapsidation of Viral RNA In Vitro Using Epitope-Tagged Foot-and-Mouth Disease Viruses

Viruses ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2433
Author(s):  
Kay Childs ◽  
Nicholas Juleff ◽  
Katy Moffat ◽  
Julian Seago
Keyword(s):  
Foot And Mouth Disease ◽  
Mouth Disease ◽  
Flag Epitope ◽  
Experimental Systems ◽  
Infection Dynamics ◽  
Mouth Disease Virus ◽  
Foot And Mouth ◽  
Infected Cells ◽  
Vp1 Capsid Protein

Foot-and-mouth disease, caused by foot-and-mouth disease virus (FMDV), is an economically devastating disease affecting several important livestock species. FMDV is antigenically diverse and exists as seven serotypes comprised of many strains which are poorly cross-neutralised by antibodies induced by infection or vaccination. Co-infection and recombination are important drivers of antigenic diversity, especially in regions where several serotypes co-circulate at high prevalence, and therefore experimental systems to study these events in vitro would be beneficial. Here we have utilised recombinant FMDVs containing an HA or a FLAG epitope tag within the VP1 capsid protein to investigate the products of co-infection in vitro. Co-infection with viruses from the same and from different serotypes was demonstrated by immunofluorescence microscopy and flow cytometry using anti-tag antibodies. FLAG-tagged VP1 and HA-tagged VP1 could be co-immunoprecipitated from co-infected cells, suggesting that newly synthesised capsids may contain VP1 proteins from both co-infecting viruses. Furthermore, we provide the first demonstration of trans-encapsidation of an FMDV genome into capsids comprised of proteins encoded by a co-infecting heterologous virus. This system provides a useful tool for investigating co-infection dynamics in vitro, particularly between closely related strains, and has the advantage that it does not depend upon the availability of strain-specific FMDV antibodies.

Invertebrate Models of Nociception

2020 ◽  
pp. 60-100
Author(s):  
Daniel Hesselson ◽  
Denise S. Walker ◽  
Joshua Neil Massingham ◽  
William R. Schafer ◽  
G. Gregory Neely ◽  
...  
Keyword(s):  
Tissue Injury ◽  
Emotional Experience ◽  
Public Health Problem ◽  
Experimental Models ◽  
Model Organisms ◽  
Experimental Systems ◽  
Significant Public Health ◽  
Noxious Stimuli ◽  
Underlying Mechanisms ◽  
High Level

Chronic pain is a significant public health problem, affecting 20–25% of the global population, and there is a clear need for more specific and effective therapeutics. To achieve this, a comprehensive understanding of the underlying mechanisms and molecular machinery driving pain-related diseases is required. The definition of pain as an “unpleasant sensory and emotional experience” associated with tissue injury is innately anthropomorphic, the emotional element being difficult to reconcile in nonhuman organisms. Even simple invertebrates are nevertheless capable of nociception, the neural processing of noxious stimuli. With the significant advantages of simpler nervous systems, experimental tractability, and a high level of conservation, they have a major role to play in advancing our understanding. This chapter reviews our current molecular- and circuit-level understanding of nociception in two of the most widely used invertebrate experimental models, the nematode Caenorhabditis elegans and the fly Drosophila melanogaster. In particular, it summarizes the molecules, cells, and circuits that contribute to nociception in response to diverse noxious stimuli in these model organisms and the behavioral paradigms that we can harness to study them. The chapter discusses how mechanistic insights gained from these experimental systems can improve our understanding of pain in humans.

Dietary carotenoids, connexins and cancer: what is the connection?

2004 ◽  
Vol 32 (6) ◽  
pp. 985-989 ◽  
Author(s):  
J.S. Bertram
Keyword(s):  
Epidemiological Studies ◽  
Experimental Models ◽  
Genetically Engineered ◽  
Gap Junctional Intercellular Communication ◽  
Independent Manner ◽  
Waste Products ◽  
Initiation Phase ◽  
Experimental Systems ◽  
Junctional Communication ◽  
Wide Scale

Carotenoids and retinoids are chemically related; indeed a major source of vitamin A in humans occurs through enzymic cleavage of β-carotene. However, most dietary carotenoids cannot be converted into retinoids. Retinoids have demonstrated cancer-preventive activities in humans and experimental models; however, their toxicity has precluded wide-scale clinical use. In contrast, carotenoids are essentially non-toxic and their cancer-preventive activities, although strongly supported by epidemiological studies, have only been satisfactorily demonstrated in experimental systems. We have shown that in an experimental cell culture system consisting of carcinogen-treated 10T1/2 cells, both retinoids and all dietary carotenoids examined can reversibly inhibit neoplastic transformation in the post-initiation phase of carcinogenesis. This activity strongly correlates with their ability to increase gap junctional intercellular communication by up-regulating the expression of the gene CX43 (connexin43). Connexins comprise the structural unit of gap junctions, organelles which allow direct transfer of signals, nutrients and waste products between contacting cells. CX43 is the most widely expressed member of the gap junction family of genes, and we have demonstrated that its expression is strongly down-regulated in human cancers and in several premalignant conditions. When several human tumour cell lines were genetically engineered to conditionally express CX43 under the influence of a tetracycline promoter, their neoplastic phenotype was strongly attenuated. Specifically, induced cells were inhibited from growing in an anchorage-independent manner and, additionally, growth as xenografts in immunocompromised animals was also strongly attenuated. Growth inhibition in suspension was associated both with increased G1 cell-cycle arrest and with increased apoptosis. We propose a model whereby junctional communication allows the transfer of growth inhibitory signals from normal to neoplastic cells and that retinoids and carotenoids, by increasing signal transfer, act to prevent cancer.

scholarly journals Antioxidant potential of Helichrysum plicatum DC. (Asteraceae)

2005 ◽  
Vol 51 ◽  
pp. 29-34 ◽  
Author(s):  
Tatjana Kadifkova Panovska ◽  
Svetlana Kulevanova
Keyword(s):  
Radical Scavenging Activity ◽  
Radical Scavenging ◽  
Beta Carotene ◽  
Natural Antioxidants ◽  
Experimental Models ◽  
Antioxidant Potential ◽  
Experimental Systems ◽  
Preventive Activity ◽  
Β Carotene

The present study describes the ability of different extracts of H. plicatum obtained from flowers, stems and leaves, to act as natural antioxidants in different in vitro experimental models in which free radical reactions are involved: inhibition of DPPH (1,1-diphenyl-2- picrylhydrazyl) radical, inhibition of hydroxyl radicals and protection of β-carotene-linoleic acid model system. Investigate extracts showed radical scavenging activity with IC50 from 6 to 11 mg/ml. The extracts are capable to reacting with OH• radical with inhibition of its production ranged between 33-58%. The high preventive activity against the bleaching of beta-carotene (15-49% of initial value after 120 minutes) was also observed. The antioxidative activity of the extracts in the experimental systems was compared with that of reference substances: luteolin, quercetin, BHA, BHT and sylimarin (the main agent of the well-known milk thistle – Silybum marianum L.). Results of this study suggest that Helichrysum plicatum represent a natural source with antioxidant potential.

Natural Transmission and Experimental Models of SARS‑CoV‑2 Infection in Animals

2021 ◽  
Author(s):  
Jessica C Noll ◽  
Gabriela M do Nascimento ◽  
Diego G Diel
Keyword(s):  
Animal Species ◽  
Viral Pathogenesis ◽  
Experimental Models ◽  
World Health ◽  
Disease Development ◽  
Infected People ◽  
Preclinical Evaluation ◽  
Infection Dynamics ◽  
The World ◽  
Health Organization

Since the World Health Organization declared COVID-19 a pandemic in March 2020, millions of people have contracted SARS-CoV-2 and died from the infection. Several domestic and wild species have contracted the disease as well. From the beginning, scientists have been working to develop vaccines and establish therapies that can prevent disease development and improve the clinical outcome in infected people. To understand various aspects of viral pathogenesis and infection dynamics and to support preclinical evaluation of vaccines and therapeutics, a diverse number of animal species have been evaluated for use as models of the disease and infection in humans. Here, we discuss natural SARS-CoV-2 infection of domestic and captive wild animals, as well as the susceptibility of several species to experimental infection with this virus.

scholarly journals Comparison of Simian Immunodeficiency Virus SIVagmVer Replication and CD4+ T-Cell Dynamics in Vervet and Sabaeus African Green Monkeys

2006 ◽  
Vol 80 (10) ◽  
pp. 4868-4877 ◽  
Author(s):  
Simoy Goldstein ◽  
Charles R. Brown ◽  
Ilnour Ourmanov ◽  
Ivona Pandrea ◽  
Alicia Buckler-White ◽  
...  
Keyword(s):  
T Cells ◽  
Experimental Models ◽  
Cell Dynamics ◽  
Ki 67 ◽  
Antiviral Immune Response ◽  
Wide Range ◽  
Immunodeficiency Virus ◽  
Experimental Inoculation ◽  
Siv Infection ◽  
Green Monkeys

ABSTRACT The simian immunodeficiency viruses (SIV) naturally infect a wide range of African primates, including African green monkeys (AGM). Despite moderate to high levels of plasma viremia in naturally infected AGM, infection is not associated with immunodeficiency. We recently reported that SIVagmVer90 isolated from a naturally infected vervet AGM induced AIDS following experimental inoculation of pigtailed macaques. The goal of the present study was to evaluate the replication of this isolate in two species of AGM, sabaeus monkeys (Chlorocebus sabaeus) and vervets (C. pygerythrus). Inoculation of sabaeus AGM with SIVagmVer90 resulted in low and variable primary and set-point viremia (<102 to 104 copies/ml). In contrast, inoculation of vervet AGM with either SIVagmVer90 or blood from a naturally infected vervet (Ver1) resulted in high primary viremia and moderate plateau levels, similar to the range seen in naturally infected vervets from this cohort. CD4+ T cells remained stable throughout infection, even in AGM with persistent high viremia. Despite the lack of measurable lymphadenopathy, infection was associated with an increased number of Ki-67+ T cells in lymph node biopsies, consistent with an early antiviral immune response. The preferential replication of SIVagmVer in vervet versus sabaeus AGM shows that it is critical to match AGM species and SIV strains for experimental models of natural SIV infection.

scholarly journals Retrograde Amnesia – A Question of Disturbed Calcium Levels?

2021 ◽  
Vol 15 ◽  
Author(s):  
Dirk Montag
Keyword(s):  
Retrograde Amnesia ◽  
Traumatic Event ◽  
Neuronal Loss ◽  
Anterograde Amnesia ◽  
Experimental Models ◽  
Model Systems ◽  
Associative Memories ◽  
Specific Effects ◽  
Underlying Mechanisms ◽  
The Many

Retrograde amnesia is the inability to remember events or information. The successful acquisition and memory of information is required before retrograde amnesia may occur. Often, the trigger for retrograde amnesia is a traumatic event. Loss of memories may be caused in two ways: either by loss/erasure of the memory itself or by the inability to access the memory, which is still present. In general, memories and learning are associated with a positive connotation although the extinction of unpleasant experiences and memories of traumatic events may be highly welcome. In contrast to the many experimental models addressing learning deficits caused by anterograde amnesia, the incapability to acquire new information, retrograde amnesia could so far only be investigated sporadically in human patients and in a limited number of model systems. Apart from models and diseases in which neurodegeneration or dementia like Alzheimer’s disease result in loss of memory, retrograde amnesia can be elicited by various drugs of which alcohol is the most prominent one and exemplifies the non-specific effects and the variable duration. External or internal impacts like traumatic brain injury, stroke, or electroconvulsive treatments may similarly result in variable degrees of retrograde amnesia. In this review, I will discuss a new genetic approach to induce retrograde amnesia in a mouse model and raise the hypothesis that retrograde amnesia is caused by altered intracellular calcium homeostasis. Recently, we observed that neuronal loss of neuroplastin resulted in retrograde amnesia specifically for associative memories. Neuroplastin is tightly linked to the expression of the main Ca2+ extruding pumps, the plasma membrane calcium ATPases (PMCAs). Therefore, neuronal loss of neuroplastin may block the retrieval and storage of associative memories by interference with Ca2+ signaling cascades. The possibility to elicit retrograde amnesia in a controlled manner allows to investigate the underlying mechanisms and may provide a deeper understanding of the molecular and circuit processes of memory.

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