scholarly journals Emergence of Directional Actomyosin Flows from Active Matter Vibrations

2018 ◽  
Author(s):  
Sven K. Vogel ◽  
Christian Wölfer ◽  
Diego A. Ramirez-Diaz ◽  
Robert J. Flassig ◽  
Kai Sundmacher ◽  
...  
Keyword(s):  
Large Scale ◽  
Model Systems ◽  
Living Systems ◽  
Vibrational States ◽  
Spatial Confinement ◽  
Emulsion Droplets ◽  
Directional Motion ◽  
Key Driver ◽  
Local Motor

AbstractCortical actomyosin flows play pivotal roles in cell motility, cell division and animal morphogenesis. According to many model systems, myosin motor induced local contractions are key for generating cortical flows. However, the original mechanism how large-scale directed flows emerge from local motor activity in an apparently isotropic cortex is unknown. We reconstituted and confined minimal actomyosin cortices to the interfaces of emulsion droplets. The presence of ATP leads to myosin-induced cortical contractions that self-organize into directed flow-like actomyosin motions. By combining our experiments with theory, we found that the large-scale directional motion of actomyosin clusters emerges from individual asymmetric cluster vibrations, caused by intrinsic non-isotropic ATP consumption, in conjunction with spherical confinement. By tracking individual actomyosin clusters, we identified fingerprints of vibrational states as the basis of directed motions. These vibrations may represent a generic key driver of directed actomyosin flows under spatial confinement in vitro and in living systems.

scholarly journals Symmetry Breaking and Emergence of Directional Flows in Minimal Actomyosin Cortices

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1432 ◽  
Author(s):  
Sven K. Vogel ◽  
Christian Wölfer ◽  
Diego A. Ramirez-Diaz ◽  
Robert J. Flassig ◽  
Kai Sundmacher ◽  
...  
Keyword(s):  
Symmetry Breaking ◽  
Large Scale ◽  
Scale Up ◽  
Feedback Mechanism ◽  
Model Systems ◽  
Spatial Confinement ◽  
Emulsion Droplets ◽  
Directional Motion ◽  
Spontaneous Contractions

Cortical actomyosin flows, among other mechanisms, scale up spontaneous symmetry breaking and thus play pivotal roles in cell differentiation, division, and motility. According to many model systems, myosin motor-induced local contractions of initially isotropic actomyosin cortices are nucleation points for generating cortical flows. However, the positive feedback mechanisms by which spontaneous contractions can be amplified towards large-scale directed flows remain mostly speculative. To investigate such a process on spherical surfaces, we reconstituted and confined initially isotropic minimal actomyosin cortices to the interfaces of emulsion droplets. The presence of ATP leads to myosin-induced local contractions that self-organize and amplify into directed large-scale actomyosin flows. By combining our experiments with theory, we found that the feedback mechanism leading to a coordinated directional motion of actomyosin clusters can be described as asymmetric cluster vibrations, caused by intrinsic non-isotropic ATP consumption with spatial confinement. We identified fingerprints of vibrational states as the basis of directed motions by tracking individual actomyosin clusters. These vibrations may represent a generic key driver of directed actomyosin flows under spatial confinement in vitro and in living systems.

scholarly journals Symmetry Breaking and Emergence of Directional Flows in Minimal Actomyosin Cortices

2020 ◽  
Author(s):  
Sven K. Vogel ◽  
Christian Wölfer ◽  
Diego A. Ramirez-Diaz ◽  
Robert J. Flassig ◽  
Kai Sundmacher ◽  
...  
Keyword(s):  
Symmetry Breaking ◽  
Large Scale ◽  
Scale Up ◽  
Feedback Mechanism ◽  
Model Systems ◽  
Spatial Confinement ◽  
Emulsion Droplets ◽  
Directional Motion ◽  
Spontaneous Contractions

Cortical actomyosin flows, among other mechanisms, scale up spontaneous symmetry breaking and thus play pivotal roles in cell differentiation, division, and motility. According to many model systems, myosin motor-induced local contractions of initially isotropic actomyosin cortices are nucleation points for generating cortical flows. However, the positive feedback mechanisms by which spontaneous contractions can be amplified towards large-scale directed flows remain mostly speculative. To investigate such a process on spherical surfaces, we reconstituted and confined initially isotropic minimal actomyosin cortices to the interfaces of emulsion droplets. The presence of ATP leads to myosin-induced local contractions that self-organize and amplify into directed, large-scale actomyosin flows. By combining our experiments with theory, we found that the feedback mechanism leading to a coordinated, directional motion of actomyosin clusters can be described as asymmetric cluster vibrations, caused by intrinsic non-isotropic ATP consumption, in conjunction with spatial confinement. By tracking individual actomyosin clusters, we identified fingerprints of vibrational states as the basis of directed motions. These vibrations may represent a generic key driver of directed actomyosin flows under spatial confinement in vitro and in living systems.

scholarly journals Unbiased in vivo preclinical evaluation of anticancer drugs identifies effective therapy for the treatment of pancreatic adenocarcinoma

2020 ◽  
Vol 117 (48) ◽  
pp. 30670-30678
Author(s):  
Olivera Grbovic-Huezo ◽  
Kenneth L. Pitter ◽  
Nicolas Lecomte ◽  
Joseph Saglimbeni ◽  
Gokce Askan ◽  
...  
Keyword(s):  
Large Scale ◽  
Single Agent ◽  
Model Systems ◽  
Ductal Adenocarcinoma ◽  
In Vivo Model ◽  
Cancer Therapies ◽  
Hsp90 Inhibition ◽  
Dismal Prognosis

Pancreatic ductal adenocarcinoma (PDAC) is typically diagnosed at an advanced stage, which limits surgical options and portends a dismal prognosis. Current oncologic PDAC therapies confer marginal benefit and, thus, a significant unmet clinical need exists for new therapeutic strategies. To identify effective PDAC therapies, we leveraged a syngeneic orthotopic PDAC transplant mouse model to perform a large-scale, in vivo screen of 16 single-agent and 41 two-drug targeted therapy combinations in mice. Among 57 drug conditions screened, combined inhibition of heat shock protein (Hsp)-90 and MEK was found to produce robust suppression of tumor growth, leading to an 80% increase in the survival of PDAC-bearing mice with no significant toxicity. Mechanistically, we observed that single-agent MEK inhibition led to compensatory activation of resistance pathways, including components of the PI3K/AKT/mTOR signaling axis, which was overcome with the addition of HSP90 inhibition. The combination of HSP90(i) + MEK(i) was also active in vitro in established human PDAC cell lines and in vivo in patient-derived organoid PDAC transplant models. These findings encourage the clinical development of HSP90(i) + MEK(i) combination therapy and highlight the power of clinically relevant in vivo model systems for identifying cancer therapies.

Detection of risk of cancer to man

1979 ◽  
Vol 205 (1158) ◽  
pp. 111-120 ◽  
Keyword(s):  
Large Scale ◽  
Human Cancer ◽  
Environmental Pollutants ◽  
Model Systems ◽  
Fourth Power ◽  
Percentage Increase ◽  
Direct Estimate ◽  
Human Carcinogenesis ◽  
Risk Of Cancer

Epidemiology can pick out large-scale determinants of human cancer, such as smoking. Also, epidemiology can pick out carcinogens such as asbestos to which groups of perhaps a few hundred or a few thousand workers have been heavily exposed for decades. However, if highly exposed groups cannot be studied then epidemiology cannot recognize carcinogens which, although perhaps widely distributed, produce only a small percentage increase in particular cancers. Almost all of the environmental pollutants that can affect human cancer incidence will do so only to a very minor extent, at the levels to which we are currently exposed. For this reason, and also because it is often difficult to define an exposed and an unexposed group which do not differ in other ways as well, it will almost always be impossible to do anything epidemiologically except to set a very crude upper limit on their likely hazards. The only way, therefore, to get any direct estimate of these hazards is by laboratory studies of the effects of high doses on various model systems. For this and for other reasons, it would be highly desirable to have good laboratory models for human carcinogenesis. The characteristics required of satisfactory laboratory systems are reviewed, and it is argued that systematic errors may arise unless one studies epithelial cells from large, long-lived species under conditions of chronic, low-dose exposure to noxious test agents in conjunction with standard chronic doses of agents which may be synergistic with the test agents. (Carcinogenic mutagens may be synergistic with carcinogenic non-mutagens.) For reasons of expense and speed, such studies must be done in vitro . If such in-vitro systems can be developed, either by using tissue explants or cell cultures, an important criterion which they will have to satisfy to be trusted will be that under chronic exposure the rate of transformation should be proportional to something like the fourth power of exposure duration. This paper chiefly reviews the reasons for choosing these specifications for a trustworthy in-vitro model for human carcinogenesis.

scholarly journals Recent progress in translational engineered in vitro models of the central nervous system

Brain ◽  
2020 ◽  
Vol 143 (11) ◽  
pp. 3181-3213 ◽  
Author(s):  
Polyxeni Nikolakopoulou ◽  
Rossana Rauti ◽  
Dimitrios Voulgaris ◽  
Iftach Shlomy ◽  
Ben M Maoz ◽  
...  
Keyword(s):  
Large Scale ◽  
Induced Pluripotent Stem Cell ◽  
In Vitro Models ◽  
Model Systems ◽  
Success Rates ◽  
Recent Developments ◽  
Practical Guidelines ◽  
Organ On A Chip ◽  
Induced Pluripotent

Abstract The complexity of the human brain poses a substantial challenge for the development of models of the CNS. Current animal models lack many essential human characteristics (in addition to raising operational challenges and ethical concerns), and conventional in vitro models, in turn, are limited in their capacity to provide information regarding many functional and systemic responses. Indeed, these challenges may underlie the notoriously low success rates of CNS drug development efforts. During the past 5 years, there has been a leap in the complexity and functionality of in vitro systems of the CNS, which have the potential to overcome many of the limitations of traditional model systems. The availability of human-derived induced pluripotent stem cell technology has further increased the translational potential of these systems. Yet, the adoption of state-of-the-art in vitro platforms within the CNS research community is limited. This may be attributable to the high costs or the immaturity of the systems. Nevertheless, the costs of fabrication have decreased, and there are tremendous ongoing efforts to improve the quality of cell differentiation. Herein, we aim to raise awareness of the capabilities and accessibility of advanced in vitro CNS technologies. We provide an overview of some of the main recent developments (since 2015) in in vitro CNS models. In particular, we focus on engineered in vitro models based on cell culture systems combined with microfluidic platforms (e.g. ‘organ-on-a-chip’ systems). We delve into the fundamental principles underlying these systems and review several applications of these platforms for the study of the CNS in health and disease. Our discussion further addresses the challenges that hinder the implementation of advanced in vitro platforms in personalized medicine or in large-scale industrial settings, and outlines the existing differentiation protocols and industrial cell sources. We conclude by providing practical guidelines for laboratories that are considering adopting organ-on-a-chip technologies.

scholarly journals Functional 3-Dimensional Retinal Organoids: Technological Progress and Existing Challenges

2021 ◽  
Vol 15 ◽  
Author(s):  
Meimanat Fathi ◽  
Cody T. Ross ◽  
Zohreh Hosseinzadeh
Keyword(s):  
Large Scale ◽  
Model Systems ◽  
Artificial Organs ◽  
Human Model ◽  
Biomedical Sciences ◽  
3 Dimensional ◽  
Retinal Tissue ◽  
Cell Transplants ◽  
Functional Features

Stem cell scientists have developed methods for the self-formation of artificial organs, often referred to as organoids. Organoids can be used as model systems for research in multiple biological disciplines. Yoshiki Sasai’s innovation for deriving mammalian retinal tissue from in vitro stem cells has had a large impact on the study of the biology of vision. New developments in retinal organoid technology provide avenues for in vitro models of human retinal diseases, studies of pathological mechanisms, and development of therapies for retinal degeneration, including electronic retinal implants and gene therapy. Moreover, these innovations have played key roles in establishing models for large-scale drug screening, studying the stages of retinal development, and providing a human model for personalized therapeutic approaches, like cell transplants to replace degenerated retinal cells. Here, we first discuss the importance of human retinal organoids to the biomedical sciences. Then, we review various functional features of retinal organoids that have been developed. Finally, we highlight the current limitations of retinal organoid technologies.

Large-scale in vitro expansion of polyclonal human CD4+CD25high regulatory T cells

Blood ◽  
2004 ◽  
Vol 104 (3) ◽  
pp. 895-903 ◽  
Author(s):  
Petra Hoffmann ◽  
Ruediger Eder ◽  
Leoni A. Kunz-Schughart ◽  
Reinhard Andreesen ◽  
Matthias Edinger
Keyword(s):  
T Cells ◽  
T Cell ◽  
Clinical Application ◽  
Large Scale ◽  
Treg Cells ◽  
Model Systems ◽  
High Dose ◽  
Solid Organ ◽  
Potential Clinical Application

AbstractCD4+CD25+ regulatory T (Treg) cells are pivotal for the maintenance of self-tolerance, and their adoptive transfer gives protection from autoimmune diseases and pathogenic alloresponses after solid organ or bone marrow transplantation in murine model systems. In vitro, human CD4+CD25+ Treg cells display phenotypic and functional characteristics similar to those of murine CD4+CD25+ Treg cells: namely, hyporesponsiveness to T-cell receptor (TCR) stimulation and suppression of CD25- T cells. Thus far, the detailed characterization and potential clinical application of human CD4+CD25+ Treg cells have been hampered by their paucity in peripheral blood and the lack of appropriate expansion protocols. Here we describe the up to 40 000-fold expansion of highly purified human CD4+CD25high T cells in vitro through the use of artificial antigen-presenting cells for repeated stimulation via CD3 and CD28 in the presence of high-dose interleukin 2 (IL-2). Expanded CD4+CD25high T cells were polyclonal, maintained their phenotype, exceeded the suppressive activity of freshly isolated CD4+CD25high T cells, and maintained expression of the lymph node homing receptors L-selectin (CD62L) and CCR7. The ability to rapidly expand human CD4+CD25high Treg cells on a large scale will not only facilitate their further exploration but also accelerate their potential clinical application in T cell–mediated diseases and transplantation medicine.

scholarly journals Identification and characterization of the Cucurbitacins, a novel class of small-molecule inhibitors of Tropomyosin receptor kinase a

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Yueling Zhong ◽  
Hong Xu ◽  
Yi Zhong ◽  
Xuemiao Zhang ◽  
Ting Zeng ◽  
...  
Keyword(s):  
Medicinal Plants ◽  
Pc12 Cell ◽  
Large Scale ◽  
Kinase Inhibitors ◽  
Cell Model ◽  
Model Systems ◽  
Bitter Gourd ◽  
Leaf Extracts ◽  
Chinese Medicinal Plants

Abstract Background NGF-TrkA is well known to play a key role in propagating and sustaining pruritogenic signals, which form the pathology of chronic pruritus. Inhibition of NGF-TrkA is a known strategy for the treatment of pruritus. In the present paper, we describe the identification, in vitro characterization, structure–activity analysis, and inhibitory evaluation of a novel TrkA inhibitory scaffold exemplified by Cucurbitacins (Cus). Methods Cus were identified as TrkA inhibitors in a large-scale kinase library screen. To obtain structural models of Cus as TrkA inhibitors, AutoDock was used to explore their binding to TrkA. Furthermore, PC12 cell culture systems have been used to study the effects of Cus and traditional Chinese medicinal plants (Tian Gua Di and bitter gourd leaf) extracts on the kinase activity of TrkA. Results Cus block the phosphorylation of TrkA on several tyrosine sites, including Tyr490, Tyr674/675, and Tyr785, and inhibit downstream Akt and MAPK phosphorylation in response to NGF in PC12 cell model systems. Furthermore, traditional Chinese medicinal plants (Tian Gua Di and bitter gourd leaf) containing Cu extracts were shown to inhibit the phosphorylation of TrkA and Akt. These data reveal mechanisms, at least partly, of the anti-pruritus bioactivity of Cus. Conclusion Taken together, with the recent discovery of the important role of TrkA as a therapeutic target, Cus could be the basis for the design of improved TrkA kinase inhibitors, which could someday help treat pruritus.

scholarly journals Controlled Complexity: Optimized Systems to Study the Role of the Gut Microbiome in Host Physiology

2021 ◽  
Vol 12 ◽  
Author(s):  
Robert W. P. Glowacki ◽  
Morgan J. Engelhart ◽  
Philip P. Ahern
Keyword(s):  
Gut Microbiome ◽  
Large Scale ◽  
Molecular Mechanisms ◽  
Human Microbiome ◽  
Model Systems ◽  
Wild Mice ◽  
Host Health ◽  
Host Physiology ◽  
The Impact

The profound impact of the gut microbiome on host health has led to a revolution in biomedical research, motivating researchers from disparate fields to define the specific molecular mechanisms that mediate host-beneficial effects. The advent of genomic technologies allied to the use of model microbiomes in gnotobiotic mouse models has transformed our understanding of intestinal microbial ecology and the impact of the microbiome on the host. However, despite incredible advances, our understanding of the host-microbiome dialogue that shapes host physiology is still in its infancy. Progress has been limited by challenges associated with developing model systems that are both tractable enough to provide key mechanistic insights while also reflecting the enormous complexity of the gut ecosystem. Simplified model microbiomes have facilitated detailed interrogation of transcriptional and metabolic functions of the microbiome but do not recapitulate the interactions seen in complex communities. Conversely, intact complex communities from mice or humans provide a more physiologically relevant community type, but can limit our ability to uncover high-resolution insights into microbiome function. Moreover, complex microbiomes from lab-derived mice or humans often do not readily imprint human-like phenotypes. Therefore, improved model microbiomes that are highly defined and tractable, but that more accurately recapitulate human microbiome-induced phenotypic variation are required to improve understanding of fundamental processes governing host-microbiome mutualism. This improved understanding will enhance the translational relevance of studies that address how the microbiome promotes host health and influences disease states. Microbial exposures in wild mice, both symbiotic and infectious in nature, have recently been established to more readily recapitulate human-like phenotypes. The development of synthetic model communities from such “wild mice” therefore represents an attractive strategy to overcome the limitations of current approaches. Advances in microbial culturing approaches that allow for the generation of large and diverse libraries of isolates, coupled to ever more affordable large-scale genomic sequencing, mean that we are now ideally positioned to develop such systems. Furthermore, the development of sophisticated in vitro systems is allowing for detailed insights into host-microbiome interactions to be obtained. Here we discuss the need to leverage such approaches and highlight key challenges that remain to be addressed.

Panel Discussion II: Usefulness of in vitro and in vivo Model Systems for Predicting the Adverse Public Health Outcome for Antimicrobial Drug Residues in Food

2000 ◽  
Vol 12 (3) ◽  
pp. 45-53
Author(s):  
Andrew Beaulieu ◽  
Jacques Boisseau ◽  
Carl Cerniglia ◽  
Denis Corpet ◽  
A. Haydée Fernández ◽  
...  
Keyword(s):  
Public Health ◽  
Health Outcome ◽  
Panel Discussion ◽  
Antimicrobial Drug ◽  
Model Systems ◽  
In Vivo Model ◽  
Drug Residues ◽  
Public Health Outcome
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