scholarly journals Open syntaxin overcomes exocytosis defects of diverse mutants in C. elegans

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Chi-Wei Tien ◽  
Bin Yu ◽  
Mengjia Huang ◽  
Karolina P. Stepien ◽  
Kyoko Sugita ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Neurotransmitter Release ◽  
Alpha Subunit ◽  
Specific Function ◽  
C Elegans ◽  
Closed Conformation ◽  
Disease States ◽  
Wide Range ◽  
Mutant Phenotypes ◽  
Liposome Fusion

Abstract Assembly of SNARE complexes that mediate neurotransmitter release requires opening of a ‘closed’ conformation of UNC-64/syntaxin. Rescue of unc-13/Munc13 mutant phenotypes by overexpressed open UNC-64/syntaxin suggested a specific function of UNC-13/Munc13 in opening UNC-64/ syntaxin. Here, we revisit the effects of open unc-64/syntaxin by generating knockin (KI) worms. The KI animals exhibit enhanced spontaneous and evoked exocytosis compared to WT animals. Unexpectedly, the open syntaxin KI partially suppresses exocytosis defects of various mutants, including snt-1/synaptotagmin, unc-2/P/Q/N-type Ca2+ channel alpha-subunit and unc-31/CAPS, in addition to unc-13/Munc13 and unc-10/RIM, and enhanced exocytosis in tom-1/Tomosyn mutants. However, open syntaxin aggravates the defects of unc-18/Munc18 mutants. Correspondingly, open syntaxin partially bypasses the requirement of Munc13 but not Munc18 for liposome fusion. Our results show that facilitating opening of syntaxin enhances exocytosis in a wide range of genetic backgrounds, and may provide a general means to enhance synaptic transmission in normal and disease states.

scholarly journals Open syntaxin overcomes synaptic transmission defects in diverse C. elegans exocytosis mutants

2020 ◽  
Author(s):  
Chi-Wei Tien ◽  
Bin Yu ◽  
Mengjia Huang ◽  
Karolina P. Stepien ◽  
Kyoko Sugita ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Neurotransmitter Release ◽  
Alpha Subunit ◽  
Specific Function ◽  
Wild Type ◽  
C Elegans ◽  
Closed Conformation ◽  
Disease States ◽  
Wide Range ◽  
Liposome Fusion

SummaryAssembly of SNARE complexes that mediate neurotransmitter release requires opening of a ‘closed’ conformation of UNC-64/syntaxin. Rescue of unc-13/Munc13 phenotypes by overexpressed open UNC-64/syntaxin suggested a specific function of UNC-13/Munc13 in opening UNC-64/ syntaxin. Here, we revisit the effects of open unc-64/syntaxin by generating knockin (KI) worms. The KI animals exhibited enhanced spontaneous and evoked exocytosis compared to wild-type animals. Unexpectedly, the open syntaxin KI partially suppressed exocytosis defects of various mutants, including snt-1/synaptotagmin, unc-2/P/Q/N-type Ca2+ channel alpha-subunit, and unc-31/CAPS in addition to unc-13/Munc13 and unc-10/RIM, and enhanced exocytosis in tom-1/Tomosyn mutants. However, open syntaxin aggravated the defects of unc-18/Munc18 mutants. Correspondingly, open syntaxin partially bypasses the requirement of Munc13 but not Munc18 for liposome fusion. Our results show that facilitating opening of syntaxin enhances exocytosis in a wide range of genetic backgrounds, and may provide a general means to enhance synaptic transmission in normal and disease states.

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 Goα Regulates Volatile Anesthetic Action in Caenorhabditis elegans

Genetics ◽  
2001 ◽  
Vol 158 (2) ◽  
pp. 643-655 ◽  
Author(s):  
Bruno van Swinderen ◽  
Laura B Metz ◽  
Laynie D Shebester ◽  
Jane E Mendel ◽  
Paul W Sternberg ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Novel Mutation ◽  
Volatile Anesthetic ◽  
Loss Of Function ◽  
Wild Type ◽  
Α Subunit ◽  
C Elegans ◽  
Missense Mutant ◽  
Anesthetic Action ◽  
Mutant Phenotypes

Abstract To identify genes controlling volatile anesthetic (VA) action, we have screened through existing Caenorhabditis elegans mutants and found that strains with a reduction in Go signaling are VA resistant. Loss-of-function mutants of the gene goa-1, which codes for the α-subunit of Go, have EC50s for the VA isoflurane of 1.7- to 2.4-fold that of wild type. Strains overexpressing egl-10, which codes for an RGS protein negatively regulating goa-1, are also isoflurane resistant. However, sensitivity to halothane, a structurally distinct VA, is differentially affected by Go pathway mutants. The RGS overexpressing strains, a goa-1 missense mutant found to carry a novel mutation near the GTP-binding domain, and eat-16(rf) mutants, which suppress goa-1(gf) mutations, are all halothane resistant; goa-1(null) mutants have wild-type sensitivities. Double mutant strains carrying mutations in both goa-1 and unc-64, which codes for a neuronal syntaxin previously found to regulate VA sensitivity, show that the syntaxin mutant phenotypes depend in part on goa-1 expression. Pharmacological assays using the cholinesterase inhibitor aldicarb suggest that VAs and GOA-1 similarly downregulate cholinergic neurotransmitter release in C. elegans. Thus, the mechanism of action of VAs in C. elegans is regulated by Goα, and presynaptic Goα-effectors are candidate VA molecular targets.

scholarly journals An intracellular pathogen response pathway promotes proteostasis in C. elegans

2017 ◽  
Author(s):  
Kirthi C. Reddy ◽  
Tal Dror ◽  
Jessica N. Sowa ◽  
Johan Panek ◽  
Kevin Chen ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Intracellular Pathogen ◽  
Forward Genetic Screen ◽  
C Elegans ◽  
Transcriptional Signature ◽  
Proteotoxic Stress ◽  
Ubiquitin Ligase Complex ◽  
Pathogen Response ◽  
Mutant Phenotypes ◽  
Increased Activity

SummaryMaintenance of proteostasis is critical for organismal health. Here we describe a novel pathway that promotes proteostasis, identified through the analysis of C. elegans genes upregulated by intracellular infection. We named this distinct transcriptional signature the Intracellular Pathogen Response (IPR), and it includes upregulation of several predicted ubiquitin ligase complex components such as the cullin cul-6. Through a forward genetic screen we found pals-22, a gene of previously unknown function, to be a repressor of the cul-6/Cullin gene and other IPR gene expression. Interestingly, pals-22 mutants have increased thermotolerance and reduced levels of stress-induced polyglutamine aggregates, likely due to upregulated IPR expression. We found the enhanced stress resistance of pals-22 mutants to be dependent on cul-6, suggesting that pals-22 mutants have increased activity of a CUL-6/Cullin-containing ubiquitin ligase complex. pals-22 mutant phenotypes are distinct from the well-studied heat shock and insulin signaling pathways, indicating that the IPR is a novel pathway that protects animals from proteotoxic stress.

scholarly journals The DBL-1/TGF-β signaling pathway regulates pathogen-specific innate immune responses in C. elegans

2021 ◽  
Author(s):  
Bhoomi Madhu ◽  
Tina L. Gumienny
Keyword(s):  
Innate Immunity ◽  
Immune Responses ◽  
Signaling Pathway ◽  
Defense Responses ◽  
C Elegans ◽  
Host Immune Responses ◽  
Wide Range ◽  
Independent Functions ◽  
Multiple Cell

Innate immunity in animals is orchestrated by multiple cell signaling pathways, including the TGF-β; superfamily pathway. While the role of TGF-β signaling in innate immunity has been clearly identified, the requirement for this pathway in generating specific, robust responses to different bacterial challenges has not been characterized. Here, we address the role of DBL-1/TGF-β in regulating signature host defense responses to a wide range of bacteria in C. elegans. This work reveals a role of DBL-1/TGF-β in animal survival, organismal behaviors, and molecular responses in different environments. Additionally, we identify a novel role for SMA-4/Smad that suggests both DBL-1/TGF-β-dependent and -independent functions in host avoidance responses. RNA-seq analyses and immunity reporter studies indicate DBL-1/TGF-β differentially regulates target gene expression upon exposure to different bacteria. Furthermore, the DBL-1/TGF-β pathway is itself differentially affected by the bacteria exposure. Collectively, these findings demonstrate bacteria-specific host immune responses regulated by the DBL-1/TGF-β signaling pathway.

scholarly journals Transgenerational fitness effects of lifespan extension by dietary restriction in Caenorhabditis elegans

2020 ◽  
Author(s):  
Edward R. Ivimey-Cook ◽  
Kris Sales ◽  
Hanne Carlsson ◽  
Simone Immler ◽  
Tracey Chapman ◽  
...  
Keyword(s):  
Dietary Restriction ◽  
Mortality Risk ◽  
Future Generations ◽  
Lifespan Extension ◽  
Dietary Interventions ◽  
C Elegans ◽  
Trade Offs ◽  
Wide Range ◽  
Broad Variety

AbstractDietary restriction increases lifespan in a broad variety of organisms and improves health in humans. However, long-term transgenerational consequences of dietary interventions are poorly understood. Here we investigated the effect of dietary restriction by temporary fasting (TF) on mortality risk, age-specific reproduction and fitness across three generations of descendants in C. elegans. We show that while TF robustly reduces mortality risk and improves late-life reproduction in the parental generation (P0), it has a wide range of both positive and deleterious effects on future generations (F1-F3). Remarkably, great-grandparental exposure to TF in early-life reduces fitness and increases mortality risk of F3 descendants to such an extent that TF no longer promotes a lifespan extension. These findings reveal that transgenerational trade-offs accompany the instant benefits of dietary restriction underscoring the need to consider fitness of future generations in pursuit of healthy ageing.

scholarly journals Predicting COVID-19 Severity with a Specific Nucleocapsid Antibody plus Disease Risk Factor Score

mSphere ◽  
2021 ◽  
Vol 6 (2) ◽  
Author(s):  
Sanjana R. Sen ◽  
Emily C. Sanders ◽  
Kristin N. Gabriel ◽  
Brian M. Miller ◽  
Hariny M. Isoda ◽  
...  
Keyword(s):  
Risk Factor ◽  
Factor Score ◽  
Disease Risk ◽  
Severe Disease ◽  
Enzyme Linked Immunosorbent Assay ◽  
Disease Risk Factor ◽  
Disease States ◽  
Wide Range ◽  
Risk Factor Score ◽  
Prognostic Prediction

ABSTRACT Effective methods for predicting COVID-19 disease trajectories are urgently needed. Here, enzyme-linked immunosorbent assay (ELISA) and coronavirus antigen microarray (COVAM) analysis mapped antibody epitopes in the plasma of COVID-19 patients (n = 86) experiencing a wide range of disease states. The experiments identified antibodies to a 21-residue epitope from nucleocapsid (termed Ep9) associated with severe disease, including admission to the intensive care unit (ICU), requirement for ventilators, or death. Importantly, anti-Ep9 antibodies can be detected within 6 days post-symptom onset and sometimes within 1 day. Furthermore, anti-Ep9 antibodies correlate with various comorbidities and hallmarks of immune hyperactivity. We introduce a simple-to-calculate, disease risk factor score to quantitate each patient’s comorbidities and age. For patients with anti-Ep9 antibodies, scores above 3.0 predict more severe disease outcomes with a 13.42 likelihood ratio (96.7% specificity). The results lay the groundwork for a new type of COVID-19 prognostic to allow early identification and triage of high-risk patients. Such information could guide more effective therapeutic intervention. IMPORTANCE The COVID-19 pandemic has resulted in over two million deaths worldwide. Despite efforts to fight the virus, the disease continues to overwhelm hospitals with severely ill patients. Diagnosis of COVID-19 is readily accomplished through a multitude of reliable testing platforms; however, prognostic prediction remains elusive. To this end, we identified a short epitope from the SARS-CoV-2 nucleocapsid protein and also a disease risk factor score based upon comorbidities and age. The presence of antibodies specifically binding to this epitope plus a score cutoff can predict severe COVID-19 outcomes with 96.7% specificity.

scholarly journals Neuropeptides and Behaviors: How Small Peptides Regulate Nervous System Function and Behavioral Outputs

2021 ◽  
Vol 14 ◽  
Author(s):  
Umer Saleem Bhat ◽  
Navneet Shahi ◽  
Siju Surendran ◽  
Kavita Babu
Keyword(s):  
Nervous System ◽  
Behavioral Plasticity ◽  
Environmental Changes ◽  
Sensory Information ◽  
Synaptic Activity ◽  
Small Peptides ◽  
C Elegans ◽  
Wide Range ◽  
Nervous System Function ◽  
Insight Into

One of the reasons that most multicellular animals survive and thrive is because of the adaptable and plastic nature of their nervous systems. For an organism to survive, it is essential for the animal to respond and adapt to environmental changes. This is achieved by sensing external cues and translating them into behaviors through changes in synaptic activity. The nervous system plays a crucial role in constantly evaluating environmental cues and allowing for behavioral plasticity in the organism. Multiple neurotransmitters and neuropeptides have been implicated as key players for integrating sensory information to produce the desired output. Because of its simple nervous system and well-established neuronal connectome, C. elegans acts as an excellent model to understand the mechanisms underlying behavioral plasticity. Here, we critically review how neuropeptides modulate a wide range of behaviors by allowing for changes in neuronal and synaptic signaling. This review will have a specific focus on feeding, mating, sleep, addiction, learning and locomotory behaviors in C. elegans. With a view to understand evolutionary relationships, we explore the functions and associated pathophysiology of C. elegans neuropeptides that are conserved across different phyla. Further, we discuss the mechanisms of neuropeptidergic signaling and how these signals are regulated in different behaviors. Finally, we attempt to provide insight into developing potential therapeutics for neuropeptide-related disorders.

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