scholarly journals Flux, toxicity and protein expression costs shape genetic interaction in a metabolic pathway

2018 ◽  
Author(s):  
Harry Kemble ◽  
Catherine Eisenhauer ◽  
Alejandro Couce ◽  
Audrey Chapron ◽  
Mélanie Magnan ◽  
...  
Keyword(s):  
Protein Expression ◽  
Molecular Interactions ◽  
Metabolic Pathway ◽  
Genetic Background ◽  
Genetic Interaction ◽  
Mechanistic Model ◽  
Metabolic Genes ◽  
Simultaneous Impact ◽  
Molecular Phenotypes ◽  
The Impact

AbstractOur ability to predict the impact of mutations on traits relevant for disease and evolution remains severely limited by the dependence of their effects on the genetic background and environment. Even when molecular interactions between genes are known, it is unclear how these translate to organism-level interactions between alleles. We therefore characterized the interplay of genetic and environmental dependencies in determining fitness by quantifying ~4,000 fitness interactions between expression variants of two metabolic genes, in different environments. We detect a remarkable variety of environment-dependent interactions, and demonstrate they can be quantitatively explained by a mechanistic model accounting for catabolic flux, metabolite toxicity and expression costs. Complex fitness interactions between mutations can therefore be predicted simply from their simultaneous impact on a few connected molecular phenotypes.

scholarly journals Flux, toxicity, and expression costs generate complex genetic interactions in a metabolic pathway

2020 ◽  
Vol 6 (23) ◽  
pp. eabb2236 ◽  
Author(s):  
Harry Kemble ◽  
Catherine Eisenhauer ◽  
Alejandro Couce ◽  
Audrey Chapron ◽  
Mélanie Magnan ◽  
...  
Keyword(s):  
Molecular Interactions ◽  
Metabolic Pathway ◽  
Genetic Background ◽  
Mechanistic Model ◽  
Genetic Interactions ◽  
Expression Levels ◽  
Metabolic Genes ◽  
Simultaneous Impact ◽  
Molecular Phenotypes ◽  
The Impact

Our ability to predict the impact of mutations on traits relevant for disease and evolution remains severely limited by the dependence of their effects on the genetic background and environment. Even when molecular interactions between genes are known, it is unclear how these translate to organism-level interactions between alleles. We therefore characterized the interplay of genetic and environmental dependencies in determining fitness by quantifying ~4000 fitness interactions between expression variants of two metabolic genes, starting from various environmentally modulated expression levels. We detect a remarkable variety of interactions dependent on initial expression levels and demonstrate that they can be quantitatively explained by a mechanistic model accounting for catabolic flux, metabolite toxicity, and expression costs. Complex fitness interactions between mutations can therefore be predicted simply from their simultaneous impact on a few connected molecular phenotypes.

scholarly journals Ancient balancing selection maintains incompatible versions of a conserved metabolic pathway in yeast

2019 ◽  
Author(s):  
James Boocock ◽  
Meru J Sadhu ◽  
Joshua S Bloom ◽  
Leonid Kruglyak
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Metabolic Pathway ◽  
Genetic Interaction ◽  
Balancing Selection ◽  
Sensu Stricto ◽  
The Other ◽  
Reference Allele ◽  
Metabolic Genes ◽  
Species Cluster ◽  
Metabolic Strategies

AbstractDifferences in nutrient availability have led to the evolution of diverse metabolic strategies across species, but within species these strategies are expected to be similar. Here, we discovered that the galactose metabolic pathway in the yeast Saccharomyces cerevisiae exists in two functionally distinct, incompatible states maintained by ancient balancing selection. We identified a genetic interaction for growth in galactose among the metabolic genes GAL2, GAL1/10/7, and PGM1. We engineered strains with all allelic combinations at these loci and showed that the reference allele of PGM1 is incompatible with the alternative alleles of the other genes. We observed a strong signature of ancient balancing selection at all three loci and found that the alternative alleles diverged from the reference alleles before the birth of the Saccharomyces sensu stricto species cluster 10-20 million years ago. Strains with the alternative alleles are found primarily in galactose-rich dairy environments, and they grow faster in galactose, but slower in glucose, revealing a tradeoff on which balancing selection may have acted.

A form of Autoimmune Diabetes in Adults Named LADA – An Update on Essential Features and Controversies

2019 ◽  
Vol 15 (3) ◽  
pp. 172-173 ◽  
Author(s):  
Valdemar Grill ◽  
Bjørn O. Åsvold
Keyword(s):  
Genetic Background ◽  
Clinical Utility ◽  
Autoimmune Diabetes ◽  
Classical Type ◽  
Phenotypic Characteristics ◽  
Latent Autoimmune Diabetes ◽  
The Impact

Latent Autoimmune Diabetes in the Adult, LADA has been investigated less than “classical” type 1 and type 2 diabetes and the criteria for and the relevance of a LADA diagnosis has been challenged. Despite the absence of a genetic background that is exclusive to LADA, this form of diabetes displays phenotypic characteristics that distinguish it from other forms of diabetes. LADA is heterogeneous in terms of the impact of autoimmunity and lifestyle factors, something that poses problems as to therapy and follow-up perhaps particularly in those with marginal positivity. Yet, there appears to be clear clinical utility in classifying individuals as LADA.

scholarly journals Inhibition of p38 Mitogen-Activated Protein Kinase Impairs Mayaro Virus Replication in Human Dermal Fibroblasts and HeLa Cells

Viruses ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1156
Author(s):  
Madelaine Sugasti-Salazar ◽  
Yessica Y. Llamas-González ◽  
Dalkiria Campos ◽  
José González-Santamaría
Keyword(s):  
Protein Expression ◽  
Hela Cells ◽  
Plaque Assay ◽  
Dermal Fibroblasts ◽  
Dependent Manner ◽  
Human Dermal Fibroblasts ◽  
Mitogen Activated Protein ◽  
Mayaro Virus ◽  
The Impact ◽  
Dose Dependent

Mayaro virus (MAYV) hijacks the host’s cell machinery to effectively replicate. The mitogen-activated protein kinases (MAPKs) p38, JNK, and ERK1/2 have emerged as crucial cellular factors implicated in different stages of the viral cycle. However, whether MAYV uses these MAPKs to competently replicate has not yet been determined. The aim of this study was to evaluate the impact of MAPK inhibition on MAYV replication using primary human dermal fibroblasts (HDFs) and HeLa cells. Viral yields in supernatants from MAYV-infected cells treated or untreated with inhibitors SB203580, SP600125, U0126, or Losmapimod were quantified using plaque assay. Additionally, viral protein expression was analyzed using immunoblot and immunofluorescence. Knockdown of p38⍺/p38β isoforms was performed in HDFs using the PROTACs molecule NR-7h. Our data demonstrated that HDFs are highly susceptible to MAYV infection. SB203580, a p38 inhibitor, reduced MAYV replication in a dose-dependent manner in both HDFs and HeLa cells. Additionally, SB203580 significantly decreased viral E1 protein expression. Similarly, knockdown or inhibition of p38⍺/p38β isoforms with NR-7h or Losmapimod, respectively, affected MAYV replication in a dose-dependent manner. Collectively, these findings suggest that p38 could play an important role in MAYV replication and could serve as a therapeutic target to control MAYV infection.

scholarly journals Modeling Bacterial Regrowth and Trihalomethane Formation in Water Distribution Systems

Water ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 463
Author(s):  
Gopinathan R. Abhijith ◽  
Leonid Kadinski ◽  
Avi Ostfeld
Keyword(s):  
Distribution Systems ◽  
Water Distribution ◽  
Mechanistic Model ◽  
Water Distribution Systems ◽  
Sensitivity Study ◽  
Operating Conditions ◽  
Growth Rate Constant ◽  
Model Parameters ◽  
Bacterial Regrowth ◽  
The Impact

The formation of bacterial regrowth and disinfection by-products is ubiquitous in chlorinated water distribution systems (WDSs) operated with organic loads. A generic, easy-to-use mechanistic model describing the fundamental processes governing the interrelationship between chlorine, total organic carbon (TOC), and bacteria to analyze the spatiotemporal water quality variations in WDSs was developed using EPANET-MSX. The representation of multispecies reactions was simplified to minimize the interdependent model parameters. The physicochemical/biological processes that cannot be experimentally determined were neglected. The effects of source water characteristics and water residence time on controlling bacterial regrowth and Trihalomethane (THM) formation in two well-tested systems under chlorinated and non-chlorinated conditions were analyzed by applying the model. The results established that a 100% increase in the free chlorine concentration and a 50% reduction in the TOC at the source effectuated a 5.87 log scale decrement in the bacteriological activity at the expense of a 60% increase in THM formation. The sensitivity study showed the impact of the operating conditions and the network characteristics in determining parameter sensitivities to model outputs. The maximum specific growth rate constant for bulk phase bacteria was found to be the most sensitive parameter to the predicted bacterial regrowth.

scholarly journals Treadmill Running Changes Endothelial Lipase Expression: Insights from Gene and Protein Analysis in Various Striated Muscle Tissues and Serum

Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 906
Author(s):  
Agnieszka Mikłosz ◽  
Bartłomiej Łukaszuk ◽  
Adrian Chabowski ◽  
Jan Górski
Keyword(s):  
Protein Expression ◽  
Density Lipoprotein ◽  
Treadmill Running ◽  
Endothelial Lipase ◽  
Type I ◽  
Fiber Types ◽  
Gene And Protein Expression ◽  
Single Bout ◽  
The Impact ◽  
White Gastrocnemius

Endothelial lipase (EL) is an enzyme capable of HDL phospholipids hydrolysis. Its action leads to a reduction in the serum high-density lipoprotein concentration, and thus, it exerts a pro-atherogenic effect. This study examines the impact of a single bout exercise on the gene and protein expression of the EL in skeletal muscles composed of different fiber types (the soleus—mainly type I, the red gastrocnemius—mostly IIA, and the white gastrocnemius—predominantly IIX fibers), as well as the diaphragm, and the heart. Wistar rats were subjected to a treadmill run: 1) t = 30 [min], V = 18 [m/min]; 2) t = 30 [min], V = 28 [m/min]; 3) t = 120 [min], V = 18 [m/min] (designated: M30, F30, and M120, respectively). We established EL expression in the total muscle homogenates in sedentary animals. Resting values could be ordered with the decreasing EL protein expression as follows: endothelium of left ventricle > diaphragm > red gastrocnemius > right ventricle > soleus > white gastrocnemius. Furthermore, we observed that even a single bout of exercise was capable of inducing changes in the mRNA and protein level of EL, with a clearer pattern observed for the former. After 30 min of running at either exercise intensity, the expression of EL transcript in all the cardiovascular components of muscles tested, except the soleus, was reduced in comparison to the respective sedentary control. The protein content of EL varied with the intensity and/or duration of the run in the studied whole tissue homogenates. The observed differences between EL expression in vascular beds of muscles may indicate the muscle-specific role of the lipase.

scholarly journals Ageratina adenophora Inhibits Spleen Immune Function in Rats via the Loss of the FRC Network and Th1–Th2 Cell Ratio Elevation

Toxins ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 309
Author(s):  
Zhihua Ren ◽  
Pei Gao ◽  
Samuel Kumi Okyere ◽  
Yujing Cui ◽  
Juan Wen ◽  
...  
Keyword(s):  
Protein Expression ◽  
Immune Function ◽  
Tissue Sample ◽  
Th2 Cells ◽  
Sample Collection ◽  
Functional Protein ◽  
Th2 Cell ◽  
Ageratina Adenophora ◽  
Mrna And Protein Expression ◽  
The Impact

The objective of this study was to determine the impact of Ageratina adenophora (A. adenophora) on splenic immune function in a rat model. Rats were fed with 10 g/100 g normal feed and an experimental feed, which was composed of 3:7 A. adenophora powder and normal feed for 60 days. On days 14, 28, and 60, subsets of rats (n = 8 rats/group/time point) were selected for blood and spleen tissue sample collection. The results showed that the proportion of CD3+ T cells in the spleen was decreased at day 60 (vs. control). Also, mRNA and protein expression of chemokines CCL21 and CCL19 and functional protein gp38 in spleen decreased significantly versus the control at day 60. In addition, ER-TR7 antigen protein expression was also decreased at day 60. Levels of T-helper (Th)1 cells significantly increased, whereas those of Th2 cells decreased significantly versus the control at day 60 in spleen. The finding revealed that A. adenophora could affect splenic immune function in rats by altering the fibroblast reticulocyte (FRC) network, as well as by causing an imbalance in Th1/Th2 cell ratios. This research provides new insights into potential mechanisms of spleen immunotoxicity due to exposures to A. Adenophora.

scholarly journals Landscape condition influences energetics, reproduction, and stress biomarkers in grizzly bears

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Abbey E. Wilson ◽  
Dan Wismer ◽  
Gordon Stenhouse ◽  
Nicholas C. Coops ◽  
David M. Janz
Keyword(s):  
Protein Expression ◽  
Physiological Function ◽  
A Priori ◽  
Food Resources ◽  
Information Criteria ◽  
Complement C3 ◽  
Grizzly Bears ◽  
Theoretic Approach ◽  
Protein Food ◽  
The Impact

AbstractEnvironmental change has been shown to influence mammalian distribution, habitat use, and behavior; however, few studies have investigated the impact on physiological function. This study aimed to determine the influence of landscape condition on the expression of target proteins related to energetics, reproduction, and stress in grizzly bears. We hypothesized that changes in landscape condition explains protein expression. Skin biopsies were collected from free-ranging grizzly bears in Alberta, Canada from 2013–2019 (n = 86 individuals). We used an information theoretic approach to develop 11 a priori candidate generalized linear mixed models to explain protein expression. We compared models using Akaike Information Criteria (AICc) weights and averaged models with ΔAICc < 2 for each protein. Food resources, represented by increased distance to coal mines and decreased crown closure, positively influenced energetic proteins (adiponectin and alpha-1-acid glycoprotein). Proteins related to reproduction (ceruloplasmin and serpin B5) were positively associated with increased wetland and upland food resources in addition to movement, but negatively associated with increased distance to roads. One stress related protein, complement C3, was positively influenced by increased percent conifer. Given the need to detect emerging threats to wildlife, we suggest the assessment of physiological function will lead to improved monitoring of species in rapidly changing landscapes.

scholarly journals The impact of indole-3-lactic acid on immature intestinal innate immunity and development: a transcriptomic analysis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Wuyang Huang ◽  
Ky Young Cho ◽  
Di Meng ◽  
W. Allan Walker
Keyword(s):  
Lactic Acid ◽  
Mechanistic Model ◽  
Transcriptomic Analysis ◽  
Dependent Manner ◽  
Protective Effects ◽  
Very Preterm Infants ◽  
Anti Inflammatory ◽  
The Impact

AbstractAn excessive intestinal inflammatory response may have a role in the pathogenesis of necrotizing enterocolitis (NEC) in very preterm infants. Indole-3-lactic acid (ILA) of breastmilk tryptophan was identified as the anti-inflammatory metabolite involved in probiotic conditioned media from Bifidobacteria longum subsp infantis. This study aimed to explore the molecular endocytic pathways involved in the protective ILA effect against inflammation. H4 cells, Caco-2 cells, C57BL/6 pup and adult mice were used to compare the anti-inflammatory mechanisms between immature and mature enterocytes in vitro and in vivo. The results show that ILA has pleiotropic protective effects on immature enterocytes including anti-inflammatory, anti-viral, and developmental regulatory potentials in a region-dependent and an age-dependent manner. Quantitative transcriptomic analysis revealed a new mechanistic model in which STAT1 pathways play an important role in IL-1β-induced inflammation and ILA has a regulatory effect on STAT1 pathways. These studies were validated by real-time RT-qPCR and STAT1 inhibitor experiments. Different protective reactions of ILA between immature and mature enterocytes indicated that ILA’s effects are developmentally regulated. These findings may be helpful in preventing NEC for premature infants.

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