scholarly journals Biophysical analysis of drug efficacy on C. elegans models for neurodegenerative and neuromuscular diseases

PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0246496
Author(s):  
Samuel Sofela ◽  
Sarah Sahloul ◽  
Yong-Ak Song
Keyword(s):  
Drug Screening ◽  
Low Cost ◽  
Neuromuscular Diseases ◽  
Model Organism ◽  
Drug Efficacy ◽  
Fluorescence Assay ◽  
Two Dimensional ◽  
Biophysical Parameter ◽  
C Elegans ◽  
Drug Candidates

Caenorhabditis elegans has emerged as a powerful model organism for drug screening due to its cellular simplicity, genetic amenability and homology to humans combined with its small size and low cost. Currently, high-throughput drug screening assays are mostly based on image-based phenotyping with the focus on morphological-descriptive traits not exploiting key locomotory parameters of this multicellular model with muscles such as its thrashing force, a critical biophysical parameter when screening drugs for muscle-related diseases. In this study, we demonstrated the use of a micropillar-based force assay chip in combination with a fluorescence assay to evaluate the efficacy of various drugs currently used in treatment of neurodegenerative and neuromuscular diseases. Using this two-dimensional approach, we showed that the force assay was generally more sensitive in measuring efficacy of drug treatment in Duchenne Muscular Dystrophy and Parkinson’s Disease mutant worms as well as partly in Amyotrophic Lateral Sclerosis model. These results underline the potential of our force assay chip in screening of potential drug candidates for the treatment of neurodegenerative and neuromuscular diseases when combined with a fluorescence assay in a two-dimensional analysis approach.

scholarly journals Quantitative Analysis of Drug Efficacy on C. elegans Models for Neuromuscular Diseases

2021 ◽  
Author(s):  
Samuel Sofela ◽  
Sarah Sahloul ◽  
Yong-Ak Song
Keyword(s):  
Drug Screening ◽  
Low Cost ◽  
Neuromuscular Diseases ◽  
Model Organism ◽  
Drug Efficacy ◽  
Two Dimensional ◽  
C Elegans ◽  
Drug Candidates ◽  
High Throughput Drug Screening ◽  
Screening Assays

AbstractCaenorhabditis elegans has emerged as a powerful model organism for drug screening due to its cellular simplicity, genetic amenability and homology to humans combined with its small size and low cost. Currently, high-throughput drug screening assays are mostly based on image-based phenotyping not exploiting key locomotory parameters of this multicellular model with muscles such as its thrashing force, a critical parameter when screening drugs for muscle-related diseases. In this study, we demonstrated the use of a micropillar-based force assay chip in combination with an imaging assay to evaluate the efficacy of various drugs currently used in treatment of neuromuscular diseases. Using this two-dimensional approach, we showed that the force assay was generally more sensitive in measuring efficacy of drug treatment in Duchenne Muscular Dystrophy and Parkinson’s Disease mutant worms as well as partly in Amyotrophic Lateral Sclerosis model. These results underline the potential of our force assay chip in screening of potential drug candidates for the treatment of neuromuscular diseases when combined with an imaging assay in a two-dimensional analysis approach.

scholarly journals Mask R-CNN Based C. Elegans Detection with a DIY Microscope

Biosensors ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 257
Author(s):  
Sebastian Fudickar ◽  
Eike Jannik Nustede ◽  
Eike Dreyer ◽  
Julia Bornhorst
Keyword(s):  
Cell Biology ◽  
High Throughput Screening ◽  
Low Cost ◽  
Image Acquisition ◽  
Rapid Development ◽  
Model Organism ◽  
Large Data ◽  
Data Set ◽  
C Elegans ◽  
Do It Yourself

Caenorhabditis elegans (C. elegans) is an important model organism for studying molecular genetics, developmental biology, neuroscience, and cell biology. Advantages of the model organism include its rapid development and aging, easy cultivation, and genetic tractability. C. elegans has been proven to be a well-suited model to study toxicity with identified toxic compounds closely matching those observed in mammals. For phenotypic screening, especially the worm number and the locomotion are of central importance. Traditional methods such as human counting or analyzing high-resolution microscope images are time-consuming and rather low throughput. The article explores the feasibility of low-cost, low-resolution do-it-yourself microscopes for image acquisition and automated evaluation by deep learning methods to reduce cost and allow high-throughput screening strategies. An image acquisition system is proposed within these constraints and used to create a large data-set of whole Petri dishes containing C. elegans. By utilizing the object detection framework Mask R-CNN, the nematodes are located, classified, and their contours predicted. The system has a precision of 0.96 and a recall of 0.956, resulting in an F1-Score of 0.958. Considering only correctly located C. elegans with an [email protected] IoU, the system achieved an average precision of 0.902 and a corresponding F1 Score of 0.906.

scholarly journals Microfluidic Technologies for High Throughput Screening Through Sorting and On-Chip Culture of C. elegans

Molecules ◽  
2019 ◽  
Vol 24 (23) ◽  
pp. 4292 ◽  
Author(s):  
Daniel Midkiff ◽  
Adriana San-Miguel
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Model Organism ◽  
Large Data ◽  
Large Data Sets ◽  
Data Sets ◽  
C Elegans ◽  
Drug Candidates ◽  
On Chip ◽  
And Behavior

The nematode Caenorhabditis elegans is a powerful model organism that has been widely used to study molecular biology, cell development, neurobiology, and aging. Despite their use for the past several decades, the conventional techniques for growth, imaging, and behavioral analysis of C. elegans can be cumbersome, and acquiring large data sets in a high-throughput manner can be challenging. Developments in microfluidic “lab-on-a-chip” technologies have improved studies of C. elegans by increasing experimental control and throughput. Microfluidic features such as on-chip control layers, immobilization channels, and chamber arrays have been incorporated to develop increasingly complex platforms that make experimental techniques more powerful. Genetic and chemical screens are performed on C. elegans to determine gene function and phenotypic outcomes of perturbations, to test the effect that chemicals have on health and behavior, and to find drug candidates. In this review, we will discuss microfluidic technologies that have been used to increase the throughput of genetic and chemical screens in C. elegans. We will discuss screens for neurobiology, aging, development, behavior, and many other biological processes. We will also discuss robotic technologies that assist in microfluidic screens, as well as alternate platforms that perform functions similar to microfluidics.

scholarly journals C. elegans expressing D76N β2-microglobulin: a model for in vivo screening of drug candidates targeting amyloidosis

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Giulia Faravelli ◽  
Sara Raimondi ◽  
Loredana Marchese ◽  
Frederick A. Partridge ◽  
Cristina Soria ◽  
...  
Keyword(s):  
Genetic Model ◽  
Model Organism ◽  
Chemical Screening ◽  
C Elegans ◽  
Drug Candidates ◽  
Molecular Events ◽  
Wild Type Phenotype ◽  
Familial Form ◽  
Automated Phenotyping

AbstractThe availability of a genetic model organism with which to study key molecular events underlying amyloidogenesis is crucial for elucidating the mechanism of the disease and the exploration of new therapeutic avenues. The natural human variant of β2-microglobulin (D76N β2-m) is associated with a fatal familial form of systemic amyloidosis. Hitherto, no animal model has been available for studying in vivo the pathogenicity of this protein. We have established a transgenic C. elegans line, expressing the human D76N β2-m variant. Using the INVertebrate Automated Phenotyping Platform (INVAPP) and the algorithm Paragon, we were able to detect growth and motility impairment in D76N β2-m expressing worms. We also demonstrated the specificity of the β2-m variant in determining the pathological phenotype by rescuing the wild type phenotype when β2-m expression was inhibited by RNA interference (RNAi). Using this model, we have confirmed the efficacy of doxycycline, an inhibitor of the aggregation of amyloidogenic proteins, in rescuing the phenotype. In future, this C. elegans model, in conjunction with the INVAPP/Paragon system, offers the prospect of high-throughput chemical screening in the search for new drug candidates.

scholarly journals The Zebrafish Xenograft Models for Investigating Cancer and Cancer Therapeutics

Biology ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 252
Author(s):  
John T. Gamble ◽  
Daniel J. Elson ◽  
Juliet A. Greenwood ◽  
Robyn L. Tanguay ◽  
Siva K. Kolluri
Keyword(s):  
Larval Fish ◽  
Human Cancer ◽  
Low Cost ◽  
Model Organism ◽  
Cancer Therapeutics ◽  
Biological Models ◽  
Orthologous Genes ◽  
Drug Candidates ◽  
Human Cancer Cells ◽  
Xenograft Models

In order to develop new cancer therapeutics, rapid, reliable, and relevant biological models are required to screen and validate drug candidates for both efficacy and safety. In recent years, the zebrafish (Danio rerio) has emerged as an excellent model organism suited for these goals. Larval fish or immunocompromised adult fish are used to engraft human cancer cells and serve as a platform for screening potential drug candidates. With zebrafish sharing ~80% of disease-related orthologous genes with humans, they provide a low cost, high-throughput alternative to mouse xenografts that is relevant to human biology. In this review, we provide background on the methods and utility of zebrafish xenograft models in cancer research.

C. elegans models of neuromuscular diseases expedite translational research

2010 ◽  
Vol 1 (3) ◽  
Author(s):  
James Sleigh ◽  
David Sattelle
Keyword(s):  
Large Scale ◽  
Genetic Model ◽  
Muscular Atrophy ◽  
Neuromuscular Disorders ◽  
Neuromuscular Diseases ◽  
Model Organism ◽  
Disease Genes ◽  
Chemical Library ◽  
C Elegans

AbstractThe nematode Caenorhabditis elegans is a genetic model organism and the only animal with a complete nervous system wiring diagram. With only 302 neurons and 95 striated muscle cells, a rich array of mutants with defective locomotion and the facility for individual targeted gene knockdown by RNA interference, it lends itself to the exploration of gene function at nerve muscle junctions. With approximately 60% of human disease genes having a C. elegans homologue, there is growing interest in the deployment of lowcost, high-throughput, drug screens of nematode transgenic and mutant strains mimicking aspects of the pathology of devastating human neuromuscular disorders. Here we explore the contributions already made by C. elegans to our understanding of muscular dystrophies (Duchenne and Becker), spinal muscular atrophy, amyotrophic lateral sclerosis, Friedreich’s ataxia, inclusion body myositis and the prospects for contributions to other neuromuscular disorders. A bottleneck to low-cost, in vivo, large-scale chemical library screening for new candidate therapies has been rapid, automated, behavioural phenotyping. Recent progress in quantifying simple swimming (thrashing) movements is making such screening possible and is expediting the translation of drug candidates towards the clinic.

Ti3C2-MXene/Bismuth Ferrite Nanohybrids for Efficient Degradation of Organic Dye and Colorless Pollutant

2019 ◽  
Author(s):  
Ayesha Tariq ◽  
M. Abdullah Iqbal ◽  
S. Irfan Ali ◽  
Muhammad Z. Iqbal ◽  
Deji Akinwande ◽  
...  
Keyword(s):  
Surface Area ◽  
Low Cost ◽  
Bismuth Ferrite ◽  
Organic Dye ◽  
Two Dimensional ◽  
Electron Hole ◽  
Photocatalytic Application ◽  
Electron Hole Pair ◽  
Pair Generation ◽  
Photocatalytic Applications

<p>Nanohybrids, made up of Bismuth ferrites/Carbon allotropes, are extensively used in photocatalytic applications nowadays. Our work proposes a nanohybrid system composed of Bismuth ferrite nanoparticles with two-dimensional (2D) MXene sheets namely, the BiFeO<sub>3</sub> (BFO)/Ti<sub>3</sub>C<sub>2</sub> (MXene) nanohybrid for enhanced photocatalytic activity. We have fabricated the BFO/MXene nanohybrid using simple and low cost double solvent solvothermal method. The SEM and TEM images show that the BFO nanoparticles were attached onto the MXene surface and in the inter-layers of two-dimensional (2D) MXene sheets. The photocatalytic application is tested for the visible light irradiation which showed the highest efficiency among all pure-BFO based photocatalysts, i.e. 100% degradation in 42 min for organic dye (Congo Red) and colorless aqueous pollutant (acetophenone) in 150 min, respectively. The present BFO-based hybrid system exhibited the large surface area of 147 m<sup>2</sup>g<sup>-1</sup>measured via Brunauer-Emmett-Teller (BET) sorption-desorption technique, and is found to be largest among BFO and its derivatives. Also, the photoluminescence (PL) spectra indicate large electron-hole pair generation. Fast and efficient degradation of organic molecules is supported by both factors; larger surface area and lower electron-hole recombination rate. The BFO/MXene nanohybrid presented here is a highly efficient photocatalyst compared to other nanostructures based on pure BiFeO<sub>3</sub> which makes it a promising candidate for many future applications.</p>

scholarly journals Automation of absolute protein-ligand binding free energy calculations for docking refinement and compound evaluation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Germano Heinzelmann ◽  
Michael K. Gilson
Keyword(s):  
Free Energy ◽  
Early Stage ◽  
Binding Free Energy ◽  
Low Cost ◽  
Free Energy Calculations ◽  
Free Energies ◽  
Energy Calculations ◽  
Drug Candidates ◽  
Binding Free Energy Calculations ◽  
Binding Free Energies

AbstractAbsolute binding free energy calculations with explicit solvent molecular simulations can provide estimates of protein-ligand affinities, and thus reduce the time and costs needed to find new drug candidates. However, these calculations can be complex to implement and perform. Here, we introduce the software BAT.py, a Python tool that invokes the AMBER simulation package to automate the calculation of binding free energies for a protein with a series of ligands. The software supports the attach-pull-release (APR) and double decoupling (DD) binding free energy methods, as well as the simultaneous decoupling-recoupling (SDR) method, a variant of double decoupling that avoids numerical artifacts associated with charged ligands. We report encouraging initial test applications of this software both to re-rank docked poses and to estimate overall binding free energies. We also show that it is practical to carry out these calculations cheaply by using graphical processing units in common machines that can be built for this purpose. The combination of automation and low cost positions this procedure to be applied in a relatively high-throughput mode and thus stands to enable new applications in early-stage drug discovery.

scholarly journals Health and longevity studies in C. elegans: the “healthy worm database” reveals strengths, weaknesses and gaps of test compound-based studies

2021 ◽  
Vol 22 (2) ◽  
pp. 215-236
Author(s):  
Nadine Saul ◽  
Steffen Möller ◽  
Francesca Cirulli ◽  
Alessandra Berry ◽  
Walter Luyten ◽  
...  
Keyword(s):  
Healthy Aging ◽  
Model Organism ◽  
Research Field ◽  
Aging Research ◽  
Genetic Manipulations ◽  
C Elegans ◽  
Starting Point ◽  
Health Related ◽  
Phenotype Measurement ◽  
Or Gene

AbstractSeveral biogerontology databases exist that focus on genetic or gene expression data linked to health as well as survival, subsequent to compound treatments or genetic manipulations in animal models. However, none of these has yet collected experimental results of compound-related health changes. Since quality of life is often regarded as more valuable than length of life, we aim to fill this gap with the “Healthy Worm Database” (http://healthy-worm-database.eu). Literature describing health-related compound studies in the aging model Caenorhabditis elegans was screened, and data for 440 compounds collected. The database considers 189 publications describing 89 different phenotypes measured in 2995 different conditions. Besides enabling a targeted search for promising compounds for further investigations, this database also offers insights into the research field of studies on healthy aging based on a frequently used model organism. Some weaknesses of C. elegans-based aging studies, like underrepresented phenotypes, especially concerning cognitive functions, as well as the convenience-based use of young worms as the starting point for compound treatment or phenotype measurement are discussed. In conclusion, the database provides an anchor for the search for compounds affecting health, with a link to public databases, and it further highlights some potential shortcomings in current aging research.

Benefits of Using the Invertebrate Model Organism C. Elegans in an Inquiry-Based Laboratory Activity

2021 ◽  
pp. 009862832110296
Author(s):  
Angy J. Kallarackal
Keyword(s):  
American Psychological Association ◽  
Model Organism ◽  
Learning Goals ◽  
Research Skills ◽  
Final Exam ◽  
Laboratory Activity ◽  
Writing Ability ◽  
C Elegans ◽  
Invertebrate Model ◽  
Laboratory Experiences

Background: The goals of laboratory experiences include developing knowledge base, research skills, and scientific communication abilities. Objective: The aim was to assess an inquiry-based laboratory activity using the model organism Caenorhabditis elegans in relation to learning goals. Method: Students in a Biopsychology laboratory course worked in groups to test the effect of various drugs (e.g., nicotine, ethanol, fluoxetine, and melatonin) on C. elegans behavior. The activity included literature review, experimental design, and a final lab report. A cumulative final exam included a synaptic communication question related to the content of the activity. Results: Students showed better retention of laboratory-related content compared to other topics from the course, as demonstrated through performance on the final exam and were able to replicate previous research demonstrating effects of drug on locomotion. However, students did not improve writing ability compared to performance on a previous American Psychological Association style lab report. Conclusion: This study demonstrates that using a student-designed, multi-week laboratory assignment in an undergraduate Biopsychology course supports the growth of psychology knowledge and the development of research skills. Teaching Implications: Instructors should consider using the described laboratory activity for biopsychology or behavioral neuroscience classes or consider similarly designed laboratory formats for other courses in Psychology.

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