scholarly journals C. elegans pharyngeal pumping provides a whole organism bio-assay to investigate anti-cholinesterase intoxication and antidotes

2020 ◽  
Author(s):  
Patricia G. Izquierdo ◽  
Vincent O’Connor ◽  
Christopher Green ◽  
Lindy Holden-Dye ◽  
John Tattersall
Keyword(s):  
Mode Of Action ◽  
Neuromuscular Junctions ◽  
Acetylcholinesterase Activity ◽  
Cholinesterase Inhibition ◽  
Genetic Determinants ◽  
C Elegans ◽  
Functional Conservation ◽  
Wide Range ◽  
High Degree ◽  
Bio Assay

AbstractInhibition of acetylcholinesterase by either organophosphates or carbamates causes anti-cholinesterase poisoning. This arises through a wide range of neurotoxic effects triggered by the overstimulation of the cholinergic receptors at synapses and neuromuscular junctions. Without intervention, this poisoning can lead to profound toxic effects, including death, and the incomplete efficacy of the current treatments, particularly for oxime-insensitive agents, provokes the need to find better antidotes. Here we show how the non-parasitic nematode Caenorhabditis elegans offers an excellent tool for investigating the acetylcholinesterase intoxication. The C. elegans neuromuscular junctions show a high degree of molecular and functional conservation with the cholinergic transmission that operates in the autonomic, central and neuromuscular synapses in mammals. In fact, the anti-cholinesterase intoxication of the worm’s body wall neuromuscular junction has been unprecedented in understanding molecular determinants of cholinergic function in nematodes and other organisms. We extend the use of the model organism’s feeding behaviour as a tool to investigate carbamate and organophosphate mode of action. We show that inhibition of the cholinergic-dependent rhythmic pumping of the pharyngeal muscle correlates with the inhibition of the acetylcholinesterase activity caused by aldicarb, paraoxons and DFP exposure. Further, this bio-assay allows one to address oxime dependent reversal of cholinesterase inhibition in the context of whole organism recovery. Interestingly, the recovery of the pharyngeal function after such anti-cholinesterase poisoning represents a sensitive and easily quantifiable phenotype that is indicative of the spontaneous recovery or irreversible modification of the worm acetylcholinesterase after inhibition. These observations highlight the pharynx of C. elegans as a new tractable approach to explore anti-cholinesterase intoxication and recovery with the potential to resolve critical genetic determinants of these neurotoxins’ mode of action.

scholarly journals Organophosphate intoxication in C. elegans reveals a new route to mitigate poisoning through the modulation of determinants responsible for nicotinic acetylcholine receptor function

2021 ◽  
Author(s):  
Patricia G. Izquierdo ◽  
Claude L Charvet ◽  
Cedric Neveu ◽  
Christopher A. Green ◽  
John E.H. Tattersall ◽  
...  
Keyword(s):  
Nicotinic Receptors ◽  
Neuromuscular Junctions ◽  
Model Organism ◽  
Pharmacological Intervention ◽  
Environmental Cues ◽  
Scaffolding Proteins ◽  
Receptor Function ◽  
C Elegans ◽  
Wide Range ◽  
Reactive Mechanism

Plasticity is a reactive mechanism that allows the adaptation of organisms to changing environmental cues. The exploitation of this physiological process has a clear benefit to promote the recovery from a wide range of neurological disorders. Here, we show that plasticity-promoting regimes provide candidate mechanisms to supplement the classically used antidotes for anti-cholinesterase poisoning. These neurotoxins inhibit acetylcholinesterase, causing the overstimulation of cholinergic transmission at synapses and neuromuscular junctions. The model organism C. elegans exhibits organophosphate-induced mitigating plasticity that impacts on the recovery of neuromuscular phenotypes, initially impaired by the drug. This is underpinned by overstimulation of nicotinic receptors at the neuromuscular junction. Intrinsic determinants of receptors location and sensitivity modulate the extent of plasticity in the context of persistent cholinergic stimulation. Our results indicate that pharmacological intervention of nicotinic receptors and/or scaffolding proteins that support receptor function might provide a novel treatment route for anti-cholinesterase poisoning.

Understanding Conformational Entropy in Small Molecules

2020 ◽  
Author(s):  
Lucian Chan ◽  
Garrett Morris ◽  
Geoffrey Hutchison
Keyword(s):  
Small Molecules ◽  
Degrees Of Freedom ◽  
Absolute Error ◽  
Low Energy ◽  
Standard Entropy ◽  
Free Energies ◽  
Conformational Entropy ◽  
Wide Range ◽  
High Degree ◽  
Empirical Corrections

The calculation of the entropy of flexible molecules can be challenging, since the number of possible conformers grows exponentially with molecule size and many low-energy conformers may be thermally accessible. Different methods have been proposed to approximate the contribution of conformational entropy to the molecular standard entropy, including performing thermochemistry calculations with all possible stable conformations, and developing empirical corrections from experimental data. We have performed conformer sampling on over 120,000 small molecules generating some 12 million conformers, to develop models to predict conformational entropy across a wide range of molecules. Using insight into the nature of conformational disorder, our cross-validated physically-motivated statistical model can outperform common machine learning and deep learning methods, with a mean absolute error ≈4.8 J/mol•K, or under 0.4 kcal/mol at 300 K. Beyond predicting molecular entropies and free energies, the model implies a high degree of correlation between torsions in most molecules, often as- sumed to be independent. While individual dihedral rotations may have low energetic barriers, the shape and chemical functionality of most molecules necessarily correlate their torsional degrees of freedom, and hence restrict the number of low-energy conformations immensely. Our simple models capture these correlations, and advance our understanding of small molecule conformational entropy.

Cerebellotrigeminal Dermal Dysplasia (Gómez-López-Hernández Syndrome)

2018 ◽  
Vol 16 (05) ◽  
pp. 362-368 ◽  
Author(s):  
Federica Sullo ◽  
Agata Polizzi ◽  
Stefano Catanzaro ◽  
Selene Mantegna ◽  
Francesco Lacarrubba ◽  
...  
Keyword(s):  
De Novo ◽  
Chromosomal Rearrangements ◽  
Number Of Patients ◽  
Wide Range ◽  
Visual Problems ◽  
Neurodevelopmental Abnormalities ◽  
Clinical Triad ◽  
High Degree ◽  
Motor Handicap

Cerebellotrigeminal dermal (CTD) dysplasia is a rare neurocutaneous disorder characterized by a triad of symptoms: bilateral parieto-occipital alopecia, facial anesthesia in the trigeminal area, and rhombencephalosynapsis (RES), confirmed by cranial magnetic resonance imaging. CTD dysplasia is also known as Gómez-López-Hernández syndrome. So far, only 35 cases have been described with varying symptomatology. The etiology remains unknown. Either spontaneous dominant mutations or de novo chromosomal rearrangements have been proposed as possible explanations. In addition to its clinical triad of RES, parietal alopecia, and trigeminal anesthesia, CTD dysplasia is associated with a wide range of phenotypic and neurodevelopmental abnormalities.Treatment is symptomatic and includes physical rehabilitation, special education, dental care, and ocular protection against self-induced corneal trauma that causes ulcers and, later, corneal opacification. The prognosis is correlated to the mental development, motor handicap, corneal–facial anesthesia, and visual problems. Follow-up on a large number of patients with CTD dysplasia has never been reported and experience is limited to few cases to date. High degree of suspicion in a child presenting with characteristic alopecia and RES has a great importance in diagnosis of this syndrome.

scholarly journals Controlling Teleportation-Based Locomotion in Virtual Reality with Hand Gestures: A Comparative Evaluation of Two-Handed and One-Handed Techniques

Electronics ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 715
Author(s):  
Alexander Schäfer ◽  
Gerd Reis ◽  
Didier Stricker
Keyword(s):  
Virtual Reality ◽  
Virtual Worlds ◽  
User Preferences ◽  
Interaction Techniques ◽  
Hand Gestures ◽  
Wide Range ◽  
Effectiveness And Efficiency ◽  
High Degree ◽  
Additional Hardware ◽  
Comprehensive Study

Virtual Reality (VR) technology offers users the possibility to immerse and freely navigate through virtual worlds. An important component for achieving a high degree of immersion in VR is locomotion. Often discussed in the literature, a natural and effective way of controlling locomotion is still a general problem which needs to be solved. Recently, VR headset manufacturers have been integrating more sensors, allowing hand or eye tracking without any additional required equipment. This enables a wide range of application scenarios with natural freehand interaction techniques where no additional hardware is required. This paper focuses on techniques to control teleportation-based locomotion with hand gestures, where users are able to move around in VR using their hands only. With the help of a comprehensive study involving 21 participants, four different techniques are evaluated. The effectiveness and efficiency as well as user preferences of the presented techniques are determined. Two two-handed and two one-handed techniques are evaluated, revealing that it is possible to move comfortable and effectively through virtual worlds with a single hand only.

scholarly journals Isolation and Characterization of Strain Exiguobacterium sp. KRL4, a Producer of Bioactive Secondary Metabolites from a Tibetan Glacier

2021 ◽  
Vol 9 (5) ◽  
pp. 890
Author(s):  
Pietro Tedesco ◽  
Fortunato Palma Esposito ◽  
Antonio Masino ◽  
Giovanni Andrea Vitale ◽  
Emiliana Tortorella ◽  
...  
Keyword(s):  
Phenotypic Analysis ◽  
Biological Assays ◽  
C Elegans ◽  
Isolation And Characterization ◽  
Wide Range ◽  
Protein Encoding ◽  
Nematocidal Activity ◽  
Extremophilic Microorganisms ◽  
Unique Source

Extremophilic microorganisms represent a unique source of novel natural products. Among them, cold adapted bacteria and particularly alpine microorganisms are still underexplored. Here, we describe the isolation and characterization of a novel Gram-positive, aerobic rod-shaped alpine bacterium (KRL4), isolated from sediments from the Karuola glacier in Tibet, China. Complete phenotypic analysis was performed revealing the great adaptability of the strain to a wide range of temperatures (5–40 °C), pHs (5.5–8.5), and salinities (0–15% w/v NaCl). Genome sequencing identified KRL4 as a member of the placeholder genus Exiguobacterium_A and annotation revealed that only half of the protein-encoding genes (1522 of 3079) could be assigned a putative function. An analysis of the secondary metabolite clusters revealed the presence of two uncharacterized phytoene synthase containing pathways and a novel siderophore pathway. Biological assays confirmed that the strain produces molecules with antioxidant and siderophore activities. Furthermore, intracellular extracts showed nematocidal activity towards C. elegans, suggesting that strain KRL4 is a source of anthelmintic compounds.

scholarly journals Specific heparan sulfate modifications stabilize the synaptic organizer MADD-4/Punctin at C. elegans neuromuscular junctions

Genetics ◽  
2021 ◽  
Author(s):  
Mélissa Cizeron ◽  
Laure Granger ◽  
Hannes E BÜlow ◽  
Jean-Louis Bessereau
Keyword(s):  
Heparan Sulfate ◽  
Matrix Protein ◽  
Neuromuscular Junctions ◽  
Core Protein ◽  
Extracellular Matrix Protein ◽  
Inhibitory Synapses ◽  
Single Chain ◽  
C Elegans ◽  
Sugar Chains

Abstract Heparan sulfate proteoglycans contribute to the structural organization of various neurochemical synapses. Depending on the system, their role involves either the core protein or the glycosaminoglycan chains. These linear sugar chains are extensively modified by heparan sulfate modification enzymes, resulting in highly diverse molecules. Specific modifications of glycosaminoglycan chains may thus contribute to a sugar code involved in synapse specificity. Caenorhabditis elegans is particularly useful to address this question because of the low level of genomic redundancy of these enzymes, as opposed to mammals. Here, we systematically mutated the genes encoding heparan sulfate modification enzymes in C. elegans and analyzed their impact on excitatory and inhibitory neuromuscular junctions. Using single chain antibodies that recognize different heparan sulfate modification patterns, we show in vivo that these two heparan sulfate epitopes are carried by the SDN-1 core protein, the unique C. elegans syndecan orthologue, at neuromuscular junctions. Intriguingly, these antibodies differentially bind to excitatory and inhibitory synapses, implying unique heparan sulfate modification patterns at different neuromuscular junctions. Moreover, while most enzymes are individually dispensable for proper organization of neuromuscular junctions, we show that 3-O-sulfation of SDN-1 is required to maintain wild-type levels of the extracellular matrix protein MADD-4/Punctin, a central synaptic organizer that defines the identity of excitatory and inhibitory synaptic domains at the plasma membrane of muscle cells.

Krypton 85 myocardial blood flow: precordial scintillation versus coronary sinus sampling

1965 ◽  
Vol 209 (4) ◽  
pp. 705-710 ◽  
Author(s):  
Michael D. Klein ◽  
Lawrence S. Cohen ◽  
Richard Gorlin
Keyword(s):  
Blood Flow ◽  
Myocardial Blood Flow ◽  
Coronary Sinus ◽  
Human Subjects ◽  
Radioactive Decay ◽  
Empirical Correction ◽  
Wide Range ◽  
Actual Flow ◽  
Flow Through ◽  
High Degree

Myocardial blood flow in human subjects was assessed by comparative simultaneous measurement of krypton 85 radioactive decay from coronary sinus and precordial scintillation. Empirical correction of postclearance background from precordial curves yielded a high degree of correlation between flows derived from the two sampling sites (r = .889, P < .001). Comparison of left and right coronary flows in nine subjects revealed similarity in flow through the two vessels over a wide range of actual flow values (r = .945, P < .001).

Historical Dynamics

2018 ◽  
Author(s):  
Peter Turchin
Keyword(s):  
Religious Conversion ◽  
Synthetic Approach ◽  
Dynamical Processes ◽  
Factors Affecting ◽  
Historical Processes ◽  
Wide Range ◽  
Historical Dynamics ◽  
State Breakdown ◽  
Political Economic ◽  
High Degree

Many historical processes are dynamic. Populations grow and decline. Empires expand and collapse. Religions spread and wither. Natural scientists have made great strides in understanding dynamical processes in the physical and biological worlds using a synthetic approach that combines mathematical modeling with statistical analyses. Taking up the problem of territorial dynamics—why some polities at certain times expand and at other times contract—this book shows that a similar research program can advance our understanding of dynamical processes in history. The book develops hypotheses from a wide range of social, political, economic, and demographic factors: geopolitics, factors affecting collective solidarity, dynamics of ethnic assimilation/religious conversion, and the interaction between population dynamics and sociopolitical stability. It then translates these into a spectrum of mathematical models, investigates the dynamics predicted by the models, and contrasts model predictions with empirical patterns. The book's highly instructive empirical tests demonstrate that certain models predict empirical patterns with a very high degree of accuracy. For instance, one model accounts for the recurrent waves of state breakdown in medieval and early modern Europe. And historical data confirm that ethno-nationalist solidarity produces an aggressively expansive state under certain conditions (such as in locations where imperial frontiers coincide with religious divides). The strength of the book's results suggests that the synthetic approach advocated can significantly improve our understanding of historical dynamics.

Main approaches to treatment of hypoxia in acute respiratory distress syndrome, bacterial and viral pneumonia (part III)

2021 ◽  
pp. 38-55
Author(s):  
A. V. Vlasenko ◽  
E. A. Evdokimov ◽  
E. P. Rodionov
Keyword(s):  
Respiratory Failure ◽  
Distress Syndrome ◽  
Experimental Studies ◽  
Viral Pneumonia ◽  
Medical Technologies ◽  
Clinical Observations ◽  
Wide Range ◽  
Prevention And Treatment ◽  
High Degree

The paper summarizes data on modern approaches to the diagnosis, prevention and treatment of severe acute parenchymal respiratory failure of various origins, including ARDS due to bacterial viral pneumonia. The work is based on the data of modern well-organized studies, analysis of international clinical guidelines with a high degree of evidence, as well as the results of our own long-term experimental studies and clinical observations of the treatment of patients with ARDS of various origins, including viral pneumonia of 2009, 2016, 2020. Scientifically grounded algorithms for prevention, differential diagnosis and personalized therapy of severe acute respiratory failure using innovative medical technologies and a wide range of respiratory and adjuvant treatment methods have been formulated. The authors tried to adapt as much as possible the existing current recommendations for the daily clinical practice of anesthesiologists and resuscitators.

scholarly journals Insights into the Mode of Action of Chitosan as an Antibacterial Compound

2008 ◽  
Vol 74 (12) ◽  
pp. 3764-3773 ◽  
Author(s):  
Dina Raafat ◽  
Kristine von Bargen ◽  
Albert Haas ◽  
Hans-Georg Sahl
Keyword(s):  
Antimicrobial Activity ◽  
Cell Wall ◽  
Cell Membrane ◽  
Mode Of Action ◽  
Membrane Lipids ◽  
Expression Profiles ◽  
Transcriptional Response ◽  
Response Analysis ◽  
Sequence Of Events ◽  
Wide Range

ABSTRACT Chitosan is a polysaccharide biopolymer that combines a unique set of versatile physicochemical and biological characteristics which allow for a wide range of applications. Although its antimicrobial activity is well documented, its mode of action has hitherto remained only vaguely defined. In this work we investigated the antimicrobial mode of action of chitosan using a combination of approaches, including in vitro assays, killing kinetics, cellular leakage measurements, membrane potential estimations, and electron microscopy, in addition to transcriptional response analysis. Chitosan, whose antimicrobial activity was influenced by several factors, exhibited a dose-dependent growth-inhibitory effect. A simultaneous permeabilization of the cell membrane to small cellular components, coupled to a significant membrane depolarization, was detected. A concomitant interference with cell wall biosynthesis was not observed. Chitosan treatment of Staphylococcus simulans 22 cells did not give rise to cell wall lysis; the cell membrane also remained intact. Analysis of transcriptional response data revealed that chitosan treatment leads to multiple changes in the expression profiles of Staphylococcus aureus SG511 genes involved in the regulation of stress and autolysis, as well as genes associated with energy metabolism. Finally, a possible mechanism for chitosan's activity is postulated. Although we contend that there might not be a single classical target that would explain chitosan's antimicrobial action, we speculate that binding of chitosan to teichoic acids, coupled with a potential extraction of membrane lipids (predominantly lipoteichoic acid) results in a sequence of events, ultimately leading to bacterial death.

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