scholarly journals An Inactivation Switch Enables Rhythms in a Neurospora Clock Model

2019 ◽  
Vol 20 (12) ◽  
pp. 2985 ◽  
Author(s):  
Abhishek Upadhyay ◽  
Michael Brunner ◽  
Hanspeter Herzel
Keyword(s):  
Feedback Loop ◽  
Design Principle ◽  
Temporal Dynamics ◽  
Model Organism ◽  
Transcription Activator ◽  
White Collar Complex ◽  
Living Organisms ◽  
Underlying Mechanisms ◽  
Molecular Components ◽  
Novel Model

Autonomous endogenous time-keeping is ubiquitous across many living organisms, known as the circadian clock when it has a period of about 24 h. Interestingly, the fundamental design principle with a network of interconnected negative and positive feedback loops is conserved through evolution, although the molecular components differ. Filamentous fungus Neurospora crassa is a well-established chrono-genetics model organism to investigate the underlying mechanisms. The core negative feedback loop of the clock of Neurospora is composed of the transcription activator White Collar Complex (WCC) (heterodimer of WC1 and WC2) and the inhibitory element called FFC complex, which is made of FRQ (Frequency protein), FRH (Frequency interacting RNA Helicase) and CK1a (Casein kinase 1a). While exploring their temporal dynamics, we investigate how limit cycle oscillations arise and how molecular switches support self-sustained rhythms. We develop a mathematical model of 10 variables with 26 parameters to understand the interactions and feedback among WC1 and FFC elements in nuclear and cytoplasmic compartments. We performed control and bifurcation analysis to show that our novel model produces robust oscillations with a wild-type period of 22.5 h. Our model reveals a switch between WC1-induced transcription and FFC-assisted inactivation of WC1. Using the new model, we also study the possible mechanisms of glucose compensation. A fairly simple model with just three nonlinearities helps to elucidate clock dynamics, revealing a mechanism of rhythms’ production. The model can further be utilized to study entrainment and temperature compensation.

scholarly journals An inactivation switch enables rhythms in aNeurosporaclock model

2019 ◽  
Author(s):  
Abhishek Upadhyay ◽  
Michael Brunner ◽  
Hanspeter Herzel
Keyword(s):  
Feedback Loop ◽  
Design Principle ◽  
Temporal Dynamics ◽  
Model Organism ◽  
Transcription Activator ◽  
White Collar Complex ◽  
Living Organisms ◽  
Underlying Mechanisms ◽  
Molecular Components ◽  
Novel Model

AbstractAn autonomous endogenous time-keeping is ubiquitous across many living organisms known as circadian clock when it has a period of about 24 hours. Interestingly, the fundamental design principle with a network of interconnected negative and positive feedback loops is conserved through evolution, although the molecular components differ. Filamentous fungusNeurospora crassais a well established chrono-genetics model organism to investigate the underlying mechanisms. The core negative feedback loop of the clock ofNeurosporais composed of the transcription activator White Collar Complex (WCC) (heterodimer of WC1 and WC2) and the inhibitory element called FFC complex which is made of FRQ (Frequency protein), FRH (Frequency interacting RNA Helicase) and CK1a (Casein kinase 1a). While exploring their temporal dynamics we investigate how limit cycle oscillations arise and how molecular switches support self-sustained rhythms. We develop a mathematical model of 10 variables with 26 parameters to understand the interactions and feedbacks among WC1 and FFC elements in nuclear and cytoplasmic compartments. We performed control and bifurcation analysis to show that our novel model produces robust oscillations with a wild-type period of 22.5 hrs. Our model reveals a switch between WC1 induced transcription and FFC assisted inactivation of WC1. Using the new model we also study possible mechanisms of glucose compensation. A fairly simple model with just 3 non-linearities helps to elucidate clock dynamics revealing a mechanism of rhythms production. The model can further be utilized to study entrainment and temperature compensation.

scholarly journals An Inactivation Switch Enables Rhythms in a Neurospora Clock Model

2019 ◽  
Author(s):  
Abhishek Upadhyay ◽  
Michael Brunner ◽  
Hanspeter Herzel
Keyword(s):  
Feedback Loop ◽  
Design Principle ◽  
Temporal Dynamics ◽  
Model Organism ◽  
Transcription Activator ◽  
White Collar Complex ◽  
Living Organisms ◽  
Underlying Mechanisms ◽  
Molecular Components ◽  
Novel Model

An autonomous endogenous time-keeping is ubiquitous across many living organisms known as circadian clock when it has a period of about 24 hours. Interestingly, the fundamental design principle with a network of interconnected negative and positive feedback loops is conserved through evolution, although the molecular components differ. Filamentous fungus \textit{Neurospora crassa} is a well established chrono-genetics model organism to investigate the underlying mechanisms. The core negative feedback loop of the clock of \textit{Neurospora} is composed of the transcription activator White Collar Complex (WCC) (heterodimer of WC1 and WC2) and the inhibitory element called FFC complex which is made of FRQ (Frequency protein), FRH (Frequency interacting RNA Helicase) and CK1a (Casein kinase 1a). While exploring their temporal dynamics we investigate how limit cycle oscillations arise and how molecular switches support self-sustained rhythms. We develop a mathematical model of 10 variables with 26 parameters to understand the interactions and feedbacks among WC1 and FFC elements in nuclear and cytoplasmic compartments. We performed control and bifurcation analysis to show that our novel model produces robust oscillations with a wild-type period of 22.5 hrs. Our model reveals a switch between WC1 induced transcription and FFC assisted inactivation of WC1. Using the new model we also study possible mechanisms of glucose compensation. A fairly simple model with just 3 non-linearities helps to elucidate clock dynamics revealing a mechanism of rhythms production. The model can further be utilized to study entrainment and temperature compensation.

scholarly journals A potential feedback loop underlying glacial-interglacial cycles

2021 ◽  
Author(s):  
Els Weinans ◽  
Anne Willem Omta ◽  
George A. K. van Voorn ◽  
Egbert H. van Nes
Keyword(s):  
Ocean Circulation ◽  
Feedback Loop ◽  
Atmospheric Temperature ◽  
Earth System ◽  
Biological Productivity ◽  
Ocean Ventilation ◽  
The Earth ◽  
Main Driver ◽  
Underlying Mechanisms ◽  
Convergent Cross Mapping

AbstractThe sawtooth-patterned glacial-interglacial cycles in the Earth’s atmospheric temperature are a well-known, though poorly understood phenomenon. Pinpointing the relevant mechanisms behind these cycles will not only provide insights into past climate dynamics, but also help predict possible future responses of the Earth system to changing CO$$_2$$ 2 levels. Previous work on this phenomenon suggests that the most important underlying mechanisms are interactions between marine biological production, ocean circulation, temperature and dust. So far, interaction directions (i.e., what causes what) have remained elusive. In this paper, we apply Convergent Cross-Mapping (CCM) to analyze paleoclimatic and paleoceanographic records to elucidate which mechanisms proposed in the literature play an important role in glacial-interglacial cycles, and to test the directionality of interactions. We find causal links between ocean ventilation, biological productivity, benthic $$\delta ^{18}$$ δ 18 O and dust, consistent with some but not all of the mechanisms proposed in the literature. Most importantly, we find evidence for a potential feedback loop from ocean ventilation to biological productivity to climate back to ocean ventilation. Here, we propose the hypothesis that this feedback loop of connected mechanisms could be the main driver for the glacial-interglacial cycles.

scholarly journals Controlling water evaporation through self-assembly

2016 ◽  
Vol 113 (37) ◽  
pp. 10275-10280 ◽  
Author(s):  
Kevin Roger ◽  
Marianne Liebi ◽  
Jimmy Heimdal ◽  
Quoc Dat Pham ◽  
Emma Sparr
Keyword(s):  
Self Assembly ◽  
Feedback Loop ◽  
Ambient Air ◽  
Underlying Mechanism ◽  
Water Evaporation ◽  
Air Humidity ◽  
X Ray ◽  
X Ray Scattering ◽  
Composition And Structure ◽  
Living Organisms

Water evaporation concerns all land-living organisms, as ambient air is dryer than their corresponding equilibrium humidity. Contrarily to plants, mammals are covered with a skin that not only hinders evaporation but also maintains its rate at a nearly constant value, independently of air humidity. Here, we show that simple amphiphiles/water systems reproduce this behavior, which suggests a common underlying mechanism originating from responding self-assembly structures. The composition and structure gradients arising from the evaporation process were characterized using optical microscopy, infrared microscopy, and small-angle X-ray scattering. We observed a thin and dry outer phase that responds to changes in air humidity by increasing its thickness as the air becomes dryer, which decreases its permeability to water, thus counterbalancing the increase in the evaporation driving force. This thin and dry outer phase therefore shields the systems from humidity variations. Such a feedback loop achieves a homeostatic regulation of water evaporation.

Abstract 344: Finding the Achilles’ heel of Muscle Giant---TALEN-mediated Gene-editing in Zebrafish Titin

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Yu-Huan Shih ◽  
Xiaolei Xu
Keyword(s):  
Alternative Splicing ◽  
Gene Editing ◽  
Muscle Development ◽  
Exon Skipping ◽  
Transcription Activator ◽  
Detailed Characterization ◽  
A Domains ◽  
Underlying Mechanisms ◽  
Sarcomere Assembly

Background: TITIN (TTN) has more than 300 exons and encodes a gigantic protein that is crucial for heart and muscle development. Mutations in TTN caused a variety of human diseases including cardiomyopathy and muscular dystrophy. Recently, dilated cardiomyopathy-associated mutations on TTN have been found more frequently in exons encoding A-band domains but less in exons encoding the N-terminal Z-disc domains, suggesting that mutations in different exons of TTN cause distinct consequences. To elucidate the underlying mechanisms, we leveraged the Transcription Activator-Like Effects Nuclease (TALEN) technology in zebrafish to introduce truncating mutations in different exons of ttn, and then study their effects on heart and somites. Results: We generated truncational mutations in different exons of zebrafish titins encoding Z-disc, N2B, Novex-3, and A domains, respectively. Because zebrafish contains two titin homologues, ttna and ttnb, we introduced mutations in both genes at the corresponding loci. While both Z-disc and A band mutations on ttna disrupted sarcomere assembly in heart and somites, Z-disc or A band mutations on ttnb only affect somites without affecting the heart. Interestingly, a Z-disc mutation on ttna resulted in milder phenotypes than an A-band mutation, while a Z-disc mutation on ttnb generated severer phenotypes than an A-band mutation. No phenotype was observed in the homozygous fish in either ttna-novex-3 or ttnb-N2B mutant fish. Conclusions: A spectrum of truncational mutations in ttna and ttnb has been generated in zebrafish using the TALEN technology. Mutations in different exons result in different phenotypes. Detailed characterization of these mutants and double mutants will be presented, which shall elicit distinct contribution of alternative splicing and exon skipping as two candidate mechanisms during pathogenesis of Titinopathies.

scholarly journals In vivo biomimetic calcification of selected organic scaffolds using snail shell regeneration: a new methodological approach

2020 ◽  
Vol 126 (6) ◽  
Author(s):  
Tomasz Machałowski ◽  
Marcin Wysokowski ◽  
Iaroslav Petrenko ◽  
Enrico Langer ◽  
Dmitry Tsurkan ◽  
...  
Keyword(s):  
Methodological Approach ◽  
Model Organism ◽  
Common Garden ◽  
Substantial Effect ◽  
Research Trend ◽  
Ability To Regenerate ◽  
Shell Regeneration ◽  
Cornu Aspersum ◽  
Living Organisms

Abstract In vivo biomimetic biomineralization using living organisms known as biomineralizers is currently a major research trend. Industrially cultivated terrestrial snails, such as the common garden snail Cornu aspersum, represent a simple model organism that is ideal for use in experiments on the regeneration of the calcified shell after the excavation of a corresponding shell fragment. The mollusk’s artificially damaged shell is regenerated via the formation of an organic regenerative membrane, which serves as a native template for in vivo biocalcification. In this study, for the first time, a special plexiglass device for non-lethal fixation of living snails, enabling real-time monitoring of their ability to regenerate their shells using digital microscopy, has been proposed and tested. As an alternative to natural biomineralization using the mollusk’s own sources, we propose chitin- and collagen-based templates, which have been shown to be effectively calcified by living snails. The results indicate that the type of organic template used for in vivo biomineralization has a substantial effect on the nature of the mineral phases.

scholarly journals LINC01106 drives colorectal cancer growth and stemness through a positive feedback loop to regulate the Gli family factors

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Kun Guo ◽  
Wenbin Gong ◽  
Qin Wang ◽  
Guosheng Gu ◽  
Tao Zheng ◽  
...  
Keyword(s):  
Feedback Loop ◽  
Colon Adenocarcinoma ◽  
Family Factors ◽  
Transcription Activator ◽  
Normal Colon ◽  
Protein Coding ◽  
Non Coding Rnas ◽  
High Level ◽  
Ucsc Database

Abstract Long non-coding RNAs (lncRNAs) are essential contributors to the progression of various human cancers. Long intergenic non-protein coding RNA 1106 is a member of lncRNAs family. Until now, the specific role of LINC01106 in CRC remains undefined. The aim the current study was to unveil the functions of LINC01106 and explore its potential molecular mechanism in CRC. Based on the data of online database GEPIA, we determined that LINC01106 was expressed at a high level in colon adenocarcinoma (COAD) tissues compared to normal colon tissues. More importantly, high level of LINC01106 had negative correlation with the overall survival of COAD patients. Additionally, we also determined the low level of LINC01106 in normal colon tissues based on UCSC database. Through qRT-PCR, we identified that LINC01106 was highly expressed in CRC tissues compared to adjacent normal ones. Similarly, we detected the expression of LINC01106 and confirmed that LINC01106 was expressed higher in CRC cells than that in normal cells. Subsequently, LINC01106 was mainly distributed in the cytoplasm. LINC01106 induced the proliferation, migration, and stem-like phenotype of CRC cells. Mechanistically, cytoplasmic LINC01106 positively modulated Gli4 in CRC cells by serving as a miR-449b-5p sponge. Furthermore, nuclear LINC01106 could activate the transcription of Gli1 and Gli2 through recruiting FUS to Gli1 and Gli2 promoters. Mechanism of investigation unveiled that Gli2 was a transcription activator of LINC01106. In conclusion, Gli2-induced upregulation of LINC01106 aggravates CRC progression through upregulating Gli2, Gli2, and Gli4.

scholarly journals Multiscale Distribution and Bioaccumulation Analysis of Clofazimine Reveals a Massive Immune System-Mediated Xenobiotic Sequestration Response

2012 ◽  
Vol 57 (3) ◽  
pp. 1218-1230 ◽  
Author(s):  
Jason Baik ◽  
Kathleen A. Stringer ◽  
Gerta Mane ◽  
Gus R. Rosania
Keyword(s):  
Immune System ◽  
Acute Phase Response ◽  
Chemotherapeutic Agent ◽  
Interleukin 1 ◽  
Model Organism ◽  
Mycobacterial Infection ◽  
Major Fraction ◽  
Living Organisms ◽  
Lymphatic Organs

ABSTRACTChronic exposure to some well-absorbed but slowly eliminated xenobiotics can lead to their bioaccumulation in living organisms. Here, we studied the bioaccumulation and distribution of clofazimine, a riminophenazine antibiotic used to treat mycobacterial infection. Using mice as a model organism, we performed a multiscale, quantitative analysis to reveal the sites of clofazimine bioaccumulation during chronic, long-term exposure. Remarkably, between 3 and 8 weeks of dietary administration, clofazimine massively redistributed from adipose tissue to liver and spleen. During this time, clofazimine concentration in fat and serum significantly decreased, while the mass of clofazimine in spleen and liver increased by >10-fold. These changes were paralleled by the accumulation of clofazimine in the resident macrophages of the lymphatic organs, with as much as 90% of the clofazimine mass in spleen sequestered in intracellular crystal-like drug inclusions (CLDIs). The amount of clofazimine associated with CLDIs of liver and spleen macrophages disproportionately increased and ultimately accounted for a major fraction of the total clofazimine in the host. After treatment was discontinued, clofazimine was retained in spleen while its concentrations decreased in blood and other organs. Immunologically, clofazimine bioaccumulation induced a local, monocyte-specific upregulation of various chemokines and receptors. However, interleukin-1 receptor antagonist was also upregulated, and the acute-phase response pathways and oxidant capacity decreased or remained unchanged, marking a concomitant activation of an anti-inflammatory response. These experiments indicate an inducible, immune system-dependent, xenobiotic sequestration response affecting the atypical pharmacokinetics of a small molecule chemotherapeutic agent.

scholarly journals Interbacterial signaling via Burkholderia contact-dependent growth inhibition system proteins

2016 ◽  
Vol 113 (29) ◽  
pp. 8296-8301 ◽  
Author(s):  
Erin C. Garcia ◽  
Andrew I. Perault ◽  
Sara A. Marlatt ◽  
Peggy A. Cotter
Keyword(s):  
Growth Inhibition ◽  
Biofilm Formation ◽  
Cell Communication ◽  
Model Organism ◽  
Protein Toxin ◽  
Naturally Occurring ◽  
Catalytically Active ◽  
Dependent Growth ◽  
Underlying Mechanisms ◽  
Contact Dependent Growth Inhibition

In prokaryotes and eukaryotes, cell–cell communication and recognition of self are critical to coordinate multicellular functions. Although kin and kind discrimination are increasingly appreciated to shape naturally occurring microbe populations, the underlying mechanisms that govern these interbacterial interactions are insufficiently understood. Here, we identify a mechanism of interbacterial signal transduction that is mediated by contact-dependent growth inhibition (CDI) system proteins. CDI systems have been characterized by their ability to deliver a polymorphic protein toxin into the cytoplasm of a neighboring bacterium, resulting in growth inhibition or death unless the recipient bacterium produces a corresponding immunity protein. Using the model organism Burkholderia thailandensis, we show that delivery of a catalytically active CDI system toxin to immune (self) bacteria results in gene expression and phenotypic changes within the recipient cells. Termed contact-dependent signaling (CDS), this response promotes biofilm formation and other community-associated behaviors. Engineered strains that are isogenic with B. thailandensis, except the DNA region encoding the toxin and immunity proteins, did not display CDS, whereas a strain of Burkholderia dolosa producing a nearly identical toxin-immunity pair induced signaling in B. thailandensis. Our data indicate that bcpAIOB loci confer dual benefits; they direct antagonism toward non-self bacteria and promote cooperation between self bacteria, with self being defined by the bcpAIOB allele and not by genealogic relatedness.

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