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 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.

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 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 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.

scholarly journals Altered Expression Levels of MMP1, MMP9, MMP12, TIMP1, and IL-1βas a Risk Factor for the Elevated IOP and Optic Nerve Head Damage in the Primary Open-Angle Glaucoma Patients

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Lukasz Markiewicz ◽  
Dariusz Pytel ◽  
Bartosz Mucha ◽  
Katarzyna Szymanek ◽  
Jerzy Szaflik ◽  
...  
Keyword(s):  
Risk Factor ◽  
Aqueous Humor ◽  
Open Angle Glaucoma ◽  
Luciferase Assay ◽  
Control Group ◽  
Promoter Regions ◽  
Altered Expression ◽  
Expression Levels ◽  
The Impact

The aim of presented work was to analyze the impact of particular polymorphic changes in the promoter regions of the -1607 1G/2GMMP1, -1562 C/TMMP9, -82 A/GMMP12, -511 C/TIL-1β, and 372 T/CTIMP1genes on their expression level in POAG patients. Blood and aqueous humor samples acquired from 50 patients with POAG and 50 control subjects were used for QPCR and protein levels analysis by ELISA.In vivopromoter activity assays were carried on HTM cells using dual luciferase assay. All studied subjects underwent ophthalmic examination, including BCVA, intraocular pressure, slit-lamp examination, gonioscopy, HRT, and OCT scans. Patients with POAG are characterized by an increased mRNA expression ofMMP1,MMP9,MMP12, andIL-1βgenes as compared to the control group (P<0.001). Aqueous humor acquired from patients with POAG displayed increased protein expression of MMP1, MMP9, MMP12, and IL-1βcompared to the control group (P<0.001). Allele -1607 1G ofMMP1gene possesses only 42,91% of the -1607 2G allele transcriptional activity and allele -1562 C ofMMP9gene possesses only 21,86% of the -1562 T allele. Increased expression levels of metalloproteinases can be considered as a risk factor for the development of POAG.

scholarly journals A Pilot Study towards the Impact of Type 2 Diabetes on the Expression and Activities of Drug Metabolizing Enzymes and Transporters in Human Duodenum

2019 ◽  
Vol 20 (13) ◽  
pp. 3257 ◽  
Author(s):  
Sophie Gravel ◽  
Benoit Panzini ◽  
Francois Belanger ◽  
Jacques Turgeon ◽  
Veronique Michaud
Keyword(s):  
Type 2 Diabetes ◽  
Mrna Expression ◽  
Drug Metabolizing Enzymes ◽  
Mrna Levels ◽  
Metabolizing Enzymes ◽  
Expression Levels ◽  
The Impact ◽  
Duodenal Biopsies ◽  
Mrna Expression Levels

To characterize effects of type 2 diabetes (T2D) on mRNA expression levels for 10 Cytochromes P450 (CYP450s), two carboxylesterases, and three drug transporters (ABCB1, ABCG2, SLCO2B1) in human duodenal biopsies. To compare drug metabolizing enzyme activities of four CYP450 isoenzymes in duodenal biopsies from patients with or without T2D. mRNA levels were quantified (RT-qPCR) in human duodenal biopsies obtained from patients with (n = 20) or without (n = 16) T2D undergoing a scheduled gastro-intestinal endoscopy. CYP450 activities were determined following incubation of biopsy homogenates with probe substrates for CYP2B6 (bupropion), CYP2C9 (tolbutamide), CYP2J2 (ebastine), and CYP3A4/5 (midazolam). Covariables related to inflammation, T2D, demographic, and genetics were investigated. T2D had no major effects on mRNA levels of all enzymes and transporters assessed. Formation rates of metabolites (pmoles mg protein−1 min−1) determined by LC-MS/MS for CYP2C9 (0.48 ± 0.26 vs. 0.41 ± 0.12), CYP2J2 (2.16 ± 1.70 vs. 1.69 ± 0.93), and CYP3A (5.25 ± 3.72 vs. 5.02 ± 4.76) were not different between biopsies obtained from individuals with or without T2D (p > 0.05). No CYP2B6 specific activity was measured. TNF-α levels were higher in T2D patients but did not correlate with any changes in mRNA expression levels for drug metabolizing enzymes or transporters in the duodenum. T2D did not modulate expression or activity of tested drug metabolizing enzymes and transporters in the human duodenum. Previously reported changes in drug oral clearances in patients with T2D could be due to a tissue-specific disease modulation occurring in the liver and/or in other parts of the intestines.

scholarly journals The impact of genetic background and sex on the phenotype of IL-23 induced murine arthritis

2021 ◽  
Author(s):  
Emma Haley ◽  
Mederbek Matmusaev ◽  
Imtiyaz N. Hossain ◽  
Sean Davin ◽  
Tammy M. Martin ◽  
...  
Keyword(s):  
Weight Loss ◽  
Genetic Background ◽  
Skin Inflammation ◽  
Control Mechanisms ◽  
Adult Mice ◽  
Severe Arthritis ◽  
Cytokine Levels ◽  
Clinical Arthritis ◽  
Organ Specific ◽  
The Impact

AbstractBackgroundOverexpression of IL-23 in adult mice by means of hydrodynamic tail vein injection of IL-23 minicircles has been reported to result in spondyloarthritis-like disease. The impact of genetic background and sex on the disease phenotype in this model has not been investigated.MethodsWe compared male B10.RIII mice with male C57BL/6 mice, and male with female B10.RIII mice after hydrodynamic injection of IL-23 enhanced episomal vector (EEV) at 8-12 weeks of age. We monitored clinical arthritis scores, paw swelling, and body weight. Animals were euthanized after two weeks and tissues were harvested for histology, flow cytometry and gene expression analysis. Serum cytokine levels were determined by ELISA.FindingsMale B10.RIII mice developed arthritis in the forepaws and feet within 6 days after IL-23 EEV injection; they also exhibited psoriasis-like skin disease, colitis, weight loss, and osteopenia. In contrast to previous reports, we did not observe spondylitis or uveitis. Male C57BL/6 mice injected with IL-23 EEV had serum IL-23 levels comparable with B10.RIII mice and developed skin inflammation, colitis, weight loss, and osteopenia but failed to develop arthritis. Female B10.RIII mice had more severe arthritis than male B10.RIII mice but did not lose weight.ConclusionsSystemic IL-23 overexpression results in spondyloarthritis-like disease in B10.RIII mice. The development of extra-articular manifestations but absence of arthritis in C57BL/6 mice suggests organ-specific genetic control mechanisms of IL-23 driven inflammation. Discrepancies regarding the phenotype of IL-23 induced disease in different labs and the sexual dimorphism observed in this study warrant further exploration.

scholarly journals Expression of mRNAs for Pro-and Anti-Apoptotic Factors in Granulosa Cells and Follicular Fluid of Women Undergoing in Vitro Fertilization. A Pilot Study

2021 ◽  
Author(s):  
Jozsef Bodis ◽  
Endre Sulyok ◽  
Akos Varnagy ◽  
Viktória Prémusz ◽  
Krisztina Godony ◽  
...  
Keyword(s):  
Gene Expression ◽  
In Vitro Fertilization ◽  
Mrna Expression ◽  
Granulosa Cells ◽  
Follicular Fluid ◽  
Vitro Fertilization ◽  
Expression Levels ◽  
The Impact ◽  
Apoptotic Factors

Abstract BackgroundThis observational clinical study evaluated the expression levels and predictive values of some apoptosis-related genes in granulosa cells (GCs) and follicular fluid (FF) of women undergoing in vitro fertilization (IVF).Methods GCs and FF were obtained at oocyte retrieval from 31 consecutive patients with heterogeneous infertility diagnosis (age: 34.3±5.8 years, body mass index: 24.02±3.12 kg/m2, duration of infertility: 4.2±2.1 years). mRNA expression of pro-apoptotic (BAX, CASP3, CASP8) and anti-apoptotic (BCL2, AMH, AMHR, FSHR, LHR, CYP19A1) factors was determined by quantitative RT-PCR using ROCHE LightCycler 480. Results No significant difference in GC or FF mRNA expression of pro- and anti-apoptotic factors could be demonstrated between IVF patients with (9 patients) or without (22 patients) clinical pregnancy. Each transcript investigated was detected in FF, but their levels were markedly reduced and independent of those in GCs. The number of retrieved oocytes was positively associated with GC AMHR (r=0.393, p=0.029), but the day of embryo transfer was negatively associated with GC LHR (r=-0.414, p=0.020) and GC FSHR transcripts (r=-0.535, p=0.002). When pregnancy positive group was analysed separately the impact of apoptosis- related gene expressions on some selected measures of IVF success could be observed. Strong positive relationship was found between gene expression levels of pro- and anti-apoptotic factors in GCs.ConclusionOur study provides only marginal evidences for the apoptosis dependence of IVF outcome and suggests that the apoptosis process induces adaptive increases of the anti-apoptotic gene expression to attenuate apoptosis and to protect cell survival.

scholarly journals Prospective mental imagery in depression: Impact on reward processing and reward-motivated behaviour

2021 ◽  
Vol 3 (2) ◽  
Author(s):  
Fritz Renner ◽  
Jessica Werthmann ◽  
Andreas Paetsch ◽  
Hannah E. Bär ◽  
Max Heise ◽  
...  
Keyword(s):  
Mental Imagery ◽  
Mechanistic Model ◽  
Reward Processing ◽  
Future Research ◽  
Clinical Implementation ◽  
Cognitive Behavioural ◽  
Behavioural Therapies ◽  
Processing Motivation ◽  
Reward Motivation ◽  
The Impact

Background Mental imagery has long been part of cognitive behavioural therapies. More recently, a resurgence of interest has emerged for prospective mental imagery, i.e. future-directed imagery-based thought, and its relation to reward processing, motivation and behaviour in the context of depression. Method We conducted a selective review on the role of prospective mental imagery and its impact on reward processing and reward-motivated behaviour in depression. Results Based on the current literature, we propose a conceptual mechanistic model of prospective mental imagery. Prospective mental imagery of engaging in positive activities can increase reward anticipation and reward motivation, which can transfer to increased engagement in reward-motivated behaviour and more experiences of reward, thereby decreasing depressive symptoms. We suggest directions for future research using multimodal assessments to measure the impact of prospective mental imagery from its basic functioning in the lab to real-world and clinical implementation. Conclusion Prospective mental imagery has the potential to improve treatment for depression where the aim is to increase reward-motivated behaviours. Future research should investigate how exactly and for whom prospective mental imagery works.

scholarly journals Intra- and inter-specific variations of gene expression levels in yeast are largely neutral

2016 ◽  
Author(s):  
Jian-Rong Yang ◽  
Calum Maclean ◽  
Chungoo Park ◽  
Huabin Zhao ◽  
Jianzhi Zhang
Keyword(s):  
Gene Expression ◽  
Genome Sequence ◽  
Large Fraction ◽  
General Role ◽  
Expression Levels ◽  
Genome Wide ◽  
Sequence Variations ◽  
Expression Evolution ◽  
Molecular Phenotypes ◽  
Gene Expression Levels

ABSTRACTIt is commonly, although not universally, accepted that most intra- and inter-specific genome sequence variations are more or less neutral, whereas a large fraction of organism-level phenotypic variations are adaptive. Gene expression levels are molecular phenotypes that bridge the gap between genotypes and corresponding organism-level phenotypes. Yet, it is unknown whether natural variations in gene expression levels are mostly neutral or adaptive. Here we address this fundamental question by genome-wide profiling and comparison of gene expression levels in nine yeast strains belonging to three closely related Saccharomyces species and originating from five different ecological environments. We find that the transcriptome-based clustering of the nine strains approximates the genome sequence-based phylogeny irrespective of their ecological environments. Remarkably, only ∼0.5% of genes exhibit similar expression levels among strains from a common ecological environment, no greater than that among strains with comparable phylogenetic relationships but different environments. These and other observations strongly suggest that most intra- and inter-specific variations in yeast gene expression levels result from the accumulation of random mutations rather than environmental adaptations. This finding has profound implications for understanding the driving force of gene expression evolution, genetic basis of phenotypic adaptation, and general role of stochasticity in evolution.

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