scholarly journals Inhibition of NPC1L1 disrupts adaptive responses of drug‐tolerant persister cells to chemotherapy

2022 ◽  
Author(s):  
Zhe Zhang ◽  
Siyuan Qin ◽  
Yan Chen ◽  
Li Zhou ◽  
Mei Yang ◽  
...  
Keyword(s):  
Adaptive Responses ◽  
Persister Cells

scholarly journals Nitrogen starvation induces persister cell formation inEscherichia coli

2018 ◽  
Author(s):  
Daniel R. Brown
Keyword(s):  
Stress Responses ◽  
Nitrogen Starvation ◽  
Cell Formation ◽  
Nitrogen Regulation ◽  
Adaptive Responses ◽  
Persister Cells ◽  
E Coli ◽  
Secondary Messenger ◽  
Regulatory Cascade ◽  
Expression Of Genes

AbstractTo cope with fluctuations in their environment bacteria have evolved multiple adaptive stress responses. One such response is the nitrogen regulation stress response, which allows bacteria such asEscherichia colito cope with and overcome conditions of nitrogen limitation. This response is directed by the two-component system NtrBC, where NtrC acts as the major transcriptional regulator to activate the expression of genes to mount the response. Recently we showed that NtrC directly regulates the expression of therelAgene, the major (p)ppGpp synthetase inE. coli, coupling the nitrogen regulation stress and stringent responses. As elevated levels of (p)ppGpp have been implicated in the formation persister cells, here we investigated whether nitrogen starvation promotes their formation and whether the NtrC-RelA regulatory cascade plays a role in this. The results reveal that both nitrogen starvedE. coliform a higher percentage of persister cells than non-starved cells, and that both NtrC and RelA are important for this process. This provides novel insights into how the formation of persisters can be promoted in response to a nutritional stress.ImportanceBacteria often reside in environments where nutrient availability is scarce and therefore they have evolved adaptive responses to rapidly cope with conditions of feast and famine. Understanding the mechanisms that underpin the regulation of how bacteria cope with this stress is a fundamentally important question in the wider context of understanding the biology of the bacterial cell and bacterial pathogenesis. Two major adaptive mechanisms to cope with starvation are the nitrogen regulation (ntr) stress and stringent responses. Here I describe how these bacterial stress responses are coordinated under conditions of nitrogen starvation to promote the formation of antibiotic tolerant persister cells by elevating levels of the secondary messenger (p)ppGpp.

scholarly journals Nitrogen Starvation Induces Persister Cell Formation inEscherichia coli

2018 ◽  
Vol 201 (3) ◽  
Author(s):  
Daniel R. Brown
Keyword(s):  
Stress Responses ◽  
Nitrogen Starvation ◽  
Cell Formation ◽  
Nitrogen Regulation ◽  
Adaptive Responses ◽  
Persister Cells ◽  
Content Type ◽  
E Coli ◽  
Secondary Messenger ◽  
Regulatory Cascade

ABSTRACTTo cope with fluctuations in their environment, bacteria have evolved multiple adaptive stress responses. One such response is the nitrogen regulation stress response, which allows bacteria, such asEscherichia coli, to cope with and overcome conditions of nitrogen limitation. This response is directed by the two-component system NtrBC, where NtrC acts as the major transcriptional regulator to activate the expression of genes to mount the response. Recently, my colleagues and I showed that NtrC directly regulates the expression of therelAgene, the major (p)ppGpp synthetase inE. coli, coupling the nitrogen regulation stress and stringent responses. As elevated levels of (p)ppGpp have been implicated in the formation of persister cells, here, I investigated whether nitrogen starvation promotes their formation and whether the NtrC-RelA regulatory cascade plays a role. The results reveal that nitrogen-starvedE. colisynthesizes (p)ppGpp and forms a higher percentage of persister cells than nonstarved cells and that both NtrC and RelA are important for these processes. This study provides novel insights into how the formation of persisters can be promoted in response to a nutritional stress.IMPORTANCEBacteria often reside in environments where nutrient availability is scarce; therefore, they have evolved adaptive responses to rapidly cope with conditions of feast and famine. Understanding the mechanisms that underpin the regulation of how bacteria cope with this stress is a fundamentally important question in the wider context of understanding the biology of the bacterial cell and bacterial pathogenesis. Two major adaptive mechanisms to cope with starvation are the nitrogen regulation (ntr) stress and stringent responses. Here, I describe how these bacterial stress responses are coordinated under conditions of nitrogen starvation to promote the formation of antibiotic-tolerant persister cells by elevating levels of the secondary messenger (p)ppGpp.

Time after time: support for memory accounts of temporal preparation.

2019 ◽  
Author(s):  
Joe Butler ◽  
Samuel Ngabo ◽  
Marcus Missal
Keyword(s):  
Response Times ◽  
Reaction Times ◽  
Evidence Base ◽  
Higher Order ◽  
Order Effects ◽  
Previous Trial ◽  
Adaptive Responses ◽  
Temporal Preparation ◽  
Subsequent Trial ◽  
Higher Order Effects

Complex biological systems build up temporal expectations to facilitate adaptive responses to environmental events, in order to minimise costs associated with incorrect responses, and maximise the benefits of correct responses. In the lab, this is clearly demonstrated in tasks which show faster response times when the period between warning (S1) and target stimulus (S2) on the previous trial was short and slower when the previous trial foreperiod was long. The mechanisms driving such higher order effects in temporal preparation paradigms are still under debate, with key theories proposing that either i) the foreperiod leads to automatic modulation of the arousal system which influences responses on the subsequent trial, or ii) that exposure to a foreperiod results in the creation of a memory trace which is used to guide responses on the subsequent trial. Here we provide data which extends the evidence base for the memory accounts, by showing that previous foreperiod exposures are cumulative with reaction times shortening after repeated exposures; whilst also demonstrate that the higher order effects associated with a foreperiod remain active for several trials.

Nitric Oxide is a Key Molecule Serving as a Bridge between Radiation-Induced Bystander and Adaptive Responses

2011 ◽  
Vol 4 (2) ◽  
pp. 126-134 ◽  
Author(s):  
Hideki Matsumoto ◽  
Masanori Tomita ◽  
Kensuke Otsuka ◽  
Masanori Hatashita ◽  
Nobuyuki Hamada
Keyword(s):  
Nitric Oxide ◽  
Adaptive Responses ◽  
Radiation Induced

Kinase Targets for Mycolic Acid Biosynthesis in Mycobacterium tuberculosis

2019 ◽  
Vol 12 (1) ◽  
pp. 27-49 ◽  
Author(s):  
Shahinda S.R. Alsayed ◽  
Chau C. Beh ◽  
Neil R. Foster ◽  
Alan D. Payne ◽  
Yu Yu ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Enzymatic Activity ◽  
Bacterial Pathogen ◽  
Building Blocks ◽  
Mycolic Acid ◽  
Adaptive Responses ◽  
Mycolic Acids ◽  
Hydroxylated Fatty Acids

Background:Mycolic acids (MAs) are the characteristic, integral building blocks for the mycomembrane belonging to the insidious bacterial pathogen Mycobacterium tuberculosis (M.tb). These C60-C90 long α-alkyl-β-hydroxylated fatty acids provide protection to the tubercle bacilli against the outside threats, thus allowing its survival, virulence and resistance to the current antibacterial agents. In the post-genomic era, progress has been made towards understanding the crucial enzymatic machineries involved in the biosynthesis of MAs in M.tb. However, gaps still remain in the exact role of the phosphorylation and dephosphorylation of regulatory mechanisms within these systems. To date, a total of 11 serine-threonine protein kinases (STPKs) are found in M.tb. Most enzymes implicated in the MAs synthesis were found to be phosphorylated in vitro and/or in vivo. For instance, phosphorylation of KasA, KasB, mtFabH, InhA, MabA, and FadD32 downregulated their enzymatic activity, while phosphorylation of VirS increased its enzymatic activity. These observations suggest that the kinases and phosphatases system could play a role in M.tb adaptive responses and survival mechanisms in the human host. As the mycobacterial STPKs do not share a high sequence homology to the human’s, there have been some early drug discovery efforts towards developing potent and selective inhibitors.Objective:Recent updates to the kinases and phosphatases involved in the regulation of MAs biosynthesis will be presented in this mini-review, including their known small molecule inhibitors.Conclusion:Mycobacterial kinases and phosphatases involved in the MAs regulation may serve as a useful avenue for antitubercular therapy.

scholarly journals Metabolic response of Botryococcus braunii to high bicarbonate dosages and other conditions: analysis of photosynthetic performance, productivity, and lipidomic profile

2021 ◽  
Author(s):  
Néstor David Giraldo ◽  
Sandra Marcela Correa ◽  
Andrés Arbeláez ◽  
Felix L. Figueroa ◽  
Rigoberto Ríos-Estepa ◽  
...  
Keyword(s):  
Nutrient Limitation ◽  
Metabolic Response ◽  
Neutral Lipids ◽  
Biomass Productivity ◽  
Botryococcus Braunii ◽  
Photosynthetic Performance ◽  
Lipid Productivity ◽  
Cellular Growth ◽  
Adaptive Responses ◽  
Nitrogen And Phosphorus

AbstractIn this study the metabolic responses of Botryococcus braunii were analyzed upon different inorganic carbon dosages and nutrient limitation conditions in terms of lipid and biomass productivity, as well as photosynthetic performance. The nutritional schemes evaluated included different levels of sodium bicarbonate and nitrogen and phosphorus starvation, which were contrasted against standard cultures fed with CO2. Bicarbonate was found to be an advantageous carbon source since high dosages caused a significant increase in biomass and lipid productivity, in addition to an enhanced photosynthetic quantum yield and neutral lipids abundance. This contrasts to the commonly used approach of microalgae nutrient limitation, which leads to high lipid accumulation at the expense of impaired cellular growth, causing a decline in overall lipid productivity. The lipidome analysis served to hypothesize about the influence of the nutritional context on B. braunii structural and storage lipid metabolism, besides the adaptive responses exhibited by cells that underwent nutrient stress.

scholarly journals Adaptive metabolic and inflammatory responses identified using accelerated aging metrics are linked to adverse outcomes in severe SARS-CoV-2 infection

2021 ◽  
Author(s):  
Alejandro Márquez-Salinas ◽  
Carlos A Fermín-Martínez ◽  
Neftalí Eduardo Antonio-Villa ◽  
Arsenio Vargas-Vázquez ◽  
Enrique C. Guerra ◽  
...  
Keyword(s):  
Critical Illness ◽  
Proportional Hazards ◽  
Inflammatory Responses ◽  
Age Groups ◽  
Accelerated Aging ◽  
Cox Proportional Hazards ◽  
Adverse Outcomes ◽  
Adaptive Responses ◽  
Predictive Capacity ◽  
Risk Of Death

Abstract Background Chronological age (CA) is a predictor of adverse COVID-19 outcomes; however, CA alone does not capture individual responses to SARS-CoV-2 infection. Here, we evaluated the influence of aging metrics PhenoAge and PhenoAgeAccel to predict adverse COVID-19 outcomes. Furthermore, we sought to model adaptive metabolic and inflammatory responses to severe SARS-CoV-2 infection using individual PhenoAge components. Methods In this retrospective cohort study, we assessed cases admitted to a COVID-19 reference center in Mexico City. PhenoAge and PhenoAgeAccel were estimated using laboratory values at admission. Cox proportional hazards models were fitted to estimate risk for COVID-19 lethality and adverse outcomes (ICU admission, intubation, or death). To explore reproducible patterns which model adaptive responses to SARS-CoV-2 infection, we used k-means clustering using PhenoAge components. Results We included 1068 subjects of whom 222 presented critical illness and 218 died. PhenoAge was a better predictor of adverse outcomes and lethality compared to CA and SpO2 and its predictive capacity was sustained for all age groups. Patients with responses associated to PhenoAgeAccel>0 had higher risk of death and critical illness compared to those with lower values (log-rank p<0.001). Using unsupervised clustering we identified four adaptive responses to SARS-CoV-2 infection: 1) Inflammaging associated with CA, 2) metabolic dysfunction associated with cardio-metabolic comorbidities, 3) unfavorable hematological response, and 4) response associated with favorable outcomes. Conclusions Adaptive responses related to accelerated aging metrics are linked to adverse COVID-19 outcomes and have unique and distinguishable features. PhenoAge is a better predictor of adverse outcomes compared to CA.

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