scholarly journals Optimal strategies for inhibition of protein aggregation

2018 ◽  
Author(s):  
Thomas C. T. Michaels ◽  
Christoph A. Weber ◽  
L. Mahadevan
Keyword(s):  
Protein Aggregation ◽  
Model Organism ◽  
Optimal Strategies ◽  
Secondary Nucleation ◽  
Treatment Protocols ◽  
C Elegans ◽  
Molecular Events ◽  
And Control ◽  
Opening Up ◽  
Viable Treatment

AbstractProtein aggregation has been implicated in many diseases.1-7 Therapeutic strategies for these diseases propose the use of drugs to inhibit specific molecular events during the aggregation process.8-11 However, viable treatment protocols require balancing the efficacy of the drug with its toxicity while accounting for the underlying events of aggregation and inhibition at the molecular level. Here, we combine aggregation kinetics and control theory to determine optimal protocols which prevent protein aggregation via specific reaction pathways. We find that the optimal inhibition of primary and fibril-dependent secondary nucleation require fundamentally different drug administration protocols. We test the efficacy of our approach on experimental data for Amyloid-β aggregation of Alzheimer’s disease in the model organism C. elegans. Our results pose and answer the question of the link between the molecular basis of protein aggregation and optimal strategies for inhibiting it, opening up new avenues for the design of rational therapies to control pathological protein aggregation.

scholarly journals Optimal control strategies for inhibition of protein aggregation

2019 ◽  
Vol 116 (29) ◽  
pp. 14593-14598 ◽  
Author(s):  
Thomas C. T. Michaels ◽  
Christoph A. Weber ◽  
L. Mahadevan
Keyword(s):  
Protein Aggregation ◽  
Control Strategies ◽  
Model Organism ◽  
Amyloid Β ◽  
Optimal Strategies ◽  
Treatment Protocols ◽  
Medical Disorders ◽  
Molecular Events ◽  
Parkinson’S Diseases ◽  
And Control

Protein aggregation has been implicated in many medical disorders, including Alzheimer’s and Parkinson’s diseases. Potential therapeutic strategies for these diseases propose the use of drugs to inhibit specific molecular events during the aggregation process. However, viable treatment protocols require balancing the efficacy of the drug with its toxicity, while accounting for the underlying events of aggregation and inhibition at the molecular level. To address this key problem, we combine here protein aggregation kinetics and control theory to determine optimal protocols that prevent protein aggregation via specific reaction pathways. We find that the optimal inhibition of primary and fibril-dependent secondary nucleation require fundamentally different drug administration protocols. We test the efficacy of our approach on experimental data for the aggregation of the amyloid-β(1-42) peptide of Alzheimer’s disease in the model organism Caenorhabditis elegans. Our results pose and answer the question of the link between the molecular basis of protein aggregation and optimal strategies for inhibiting it, opening up avenues for the design of rational therapies to control pathological protein aggregation.

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.

Guideline for the management of long tunnelled external ventricular drains in chronic hydrocephalus

2021 ◽  
Vol 30 (7) ◽  
pp. 416-421
Author(s):  
Phillip Correia Copley ◽  
John Emelifeonwu ◽  
Pasquale Gallo ◽  
Drahoslav Sokol ◽  
Jothy Kandasamy ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Nursing Care ◽  
Pilocytic Astrocytoma ◽  
Parental Education ◽  
Chronic Hydrocephalus ◽  
Treatment Protocols ◽  
New Approach ◽  
Viable Treatment

This article reports on the journey of a child with an inoperable hypothalamic-origin pilocytic astrocytoma causing hydrocephalus, which was refractory to treatment with shunts, and required a new approach. With multidisciplinary support, excellent nursing care and parental education, the child's hydrocephalus was managed long term in the community with bilateral long-tunnelled external ventricular drains (LTEVDs). This article describes the patient's journey and highlights the treatment protocols that were created to achieve this feat. Despite the difficulties in initially setting up these protocols, they proved successful and thus the team managing the patient proposed that LTEVDs are a viable treatment option for children with hydrocephalus in the context of inoperable tumours to help maximise quality of life.

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.

scholarly journals Steroid hormones sulfatase inactivation extends lifespan and ameliorates age-related diseases

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Mercedes M. Pérez-Jiménez ◽  
José M. Monje-Moreno ◽  
Ana María Brokate-Llanos ◽  
Mónica Venegas-Calerón ◽  
Alicia Sánchez-García ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Caenorhabditis Elegans ◽  
Protein Aggregation ◽  
Steroid Hormones ◽  
Sensory Neurons ◽  
Environmental Cues ◽  
Steroid Sulfatase ◽  
Loss Of Function ◽  
C Elegans ◽  
Age Related

AbstractAging and fertility are two interconnected processes. From invertebrates to mammals, absence of the germline increases longevity. Here we show that loss of function of sul-2, the Caenorhabditis elegans steroid sulfatase (STS), raises the pool of sulfated steroid hormones, increases longevity and ameliorates protein aggregation diseases. This increased longevity requires factors involved in germline-mediated longevity (daf-16, daf-12, kri-1, tcer-1 and daf-36 genes) although sul-2 mutations do not affect fertility. Interestingly, sul-2 is only expressed in sensory neurons, suggesting a regulation of sulfated hormones state by environmental cues. Treatment with the specific STS inhibitor STX64, as well as with testosterone-derived sulfated hormones reproduces the longevity phenotype of sul-2 mutants. Remarkably, those treatments ameliorate protein aggregation diseases in C. elegans, and STX64 also Alzheimer’s disease in a mammalian model. These results open the possibility of reallocating steroid sulfatase inhibitors or derivates for the treatment of aging and aging related diseases.

scholarly journals Wormicloud: a new text summarization tool based on word clouds to explore the C. elegans literature

Database ◽  
2021 ◽  
Vol 2021 ◽  
Author(s):  
Valerio Arnaboldi ◽  
Jaehyoung Cho ◽  
Paul W Sternberg
Keyword(s):  
Search Engines ◽  
Complex Structure ◽  
Model Organism ◽  
Gene Interaction ◽  
Relevant Information ◽  
Biomedical Literature ◽  
C Elegans ◽  
Word Clouds ◽  
Scientific Papers ◽  
Model Organism Databases

Abstract Finding relevant information from newly published scientific papers is becoming increasingly difficult due to the pace at which articles are published every year as well as the increasing amount of information per paper. Biocuration and model organism databases provide a map for researchers to navigate through the complex structure of the biomedical literature by distilling knowledge into curated and standardized information. In addition, scientific search engines such as PubMed and text-mining tools such as Textpresso allow researchers to easily search for specific biological aspects from newly published papers, facilitating knowledge transfer. However, digesting the information returned by these systems—often a large number of documents—still requires considerable effort. In this paper, we present Wormicloud, a new tool that summarizes scientific articles in a graphical way through word clouds. This tool is aimed at facilitating the discovery of new experimental results not yet curated by model organism databases and is designed for both researchers and biocurators. Wormicloud is customized for the Caenorhabditis  elegans literature and provides several advantages over existing solutions, including being able to perform full-text searches through Textpresso, which provides more accurate results than other existing literature search engines. Wormicloud is integrated through direct links from gene interaction pages in WormBase. Additionally, it allows analysis on the gene sets obtained from literature searches with other WormBase tools such as SimpleMine and Gene Set Enrichment. Database URL: https://wormicloud.textpressolab.com

Behavioral Effects of Volatile Anesthetics in Caenorhabditis elegans

1996 ◽  
Vol 85 (4) ◽  
pp. 901-912 ◽  
Author(s):  
Michael C. Crowder ◽  
Laynie D. Shebester ◽  
Tim Schedl
Keyword(s):  
Nervous System ◽  
Caenorhabditis Elegans ◽  
Time Course ◽  
Model Organism ◽  
Volatile Anesthetic ◽  
Volatile Anesthetics ◽  
Effective Concentration ◽  
Forward Genetics ◽  
C Elegans ◽  
Median Effective Concentration

Background The nematode Caenorhabditis elegans offers many advantages as a model organism for studying volatile anesthetic actions. It has a simple, well-understood nervous system; it allows the researcher to do forward genetics; and its genome will soon be completely sequenced. C. elegans is immobilized by volatile anesthetics only at high concentrations and with an unusually slow time course. Here other behavioral dysfunctions are considered as anesthetic endpoints in C. elegans. Methods The potency of halothane for disrupting eight different behaviors was determined by logistic regression of concentration and response data. Other volatile anesthetics were also tested for some behaviors. Established protocols were used for behavioral endpoints that, except for pharyngeal pumping, were set as complete disruption of the behavior. Time courses were measured for rapid behaviors. Recovery from exposure to 1 or 4 vol% halothane was determined for mating, chemotaxis, and gross movement. All experiments were performed at 20 to 22 degrees C. Results The median effective concentration values for halothane inhibition of mating (0.30 vol%-0.21 mM), chemotaxis (0.34 vol%-0.24 mM), and coordinated movement (0.32 vol% - 0.23 mM) were similar to the human minimum alveolar concentration (MAC; 0.21 mM). In contrast, halothane produced immobility with a median effective concentration of 3.65 vol% (2.6 mM). Other behaviors had intermediate sensitivities. Halothane's effects reached steady-state in 10 min for all behaviors tested except immobility, which required 2 h. Recovery was complete after exposure to 1 vol% halothane but was significantly reduced after exposure to immobilizing concentrations. Conclusions Volatile anesthetics selectively disrupt C. elegans behavior. The potency, time course, and recovery characteristics of halothane's effects on three behaviors are similar to its anesthetic properties in vertebrates. The affected nervous system molecules may express structural motifs similar to those on vertebrate anesthetic targets.

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.

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