PubMed

Related Articles Natural product modulators of human sensations and mood: molecular mechanisms and therapeutic potential. Chem Soc Rev. 2017 Sep 21;: Authors: Pluskal T, Weng JK Abstract Humans perceive physical information about the surrounding environment through their senses. This physical information is registered by a collection of highly evolved and finely tuned molecular sensory receptors. A multitude of bioactive, structurally diverse ligands have evolved in nature that bind these molecular receptors. The complex, dynamic interactions between the ligands and the receptors lead to changes in our sensory perception or mood. Here, we review our current knowledge of natural products and their derived analogues that interact specifically with human G protein-coupled receptors, ion channels, and nuclear hormone receptors to modulate the sensations of taste, smell, temperature, pain, and itch, as well as mood and its associated behaviour. We discuss the molecular and structural mechanisms underlying such interactions and highlight cases where subtle differences in natural product chemistry produce drastic changes in functional outcome. We also discuss cases where a single compound triggers complex sensory or behavioural changes in humans through multiple mechanistic targets. Finally, we comment on the therapeutic potential of the reviewed area of research and draw attention to recent technological developments in genomics, metabolomics, and metabolic engineering that allow us to tap the medicinal properties of natural product chemistry without taxing nature. PMID: 28933478 [PubMed - as supplied by publisher]

Related Articles Biomarkers and Imaging Findings of Anderson-Fabry Disease-What We Know Now. Diseases. 2017 Jun 11;5(2): Authors: Beirão I, Cabrita A, Torres M, Silva F, Aguiar P, Laranjeira F, Gomes AM Abstract Anderson-Fabry disease (AFD) is an X-linked lysosomal storage disorder, caused by deficiency or absence of the alpha-galactosidase A activity, with a consequent glycosphingolipid accumulation. Biomarkers and imaging findings may be useful for diagnosis, identification of an organ involvement, therapy monitoring and prognosis. The aim of this article is to review the current available literature on biomarkers and imaging findings of AFD patients. An extensive bibliographic review from PubMed, Medline and Clinical Key databases was performed by a group of experts from nephrology, neurology, genetics, cardiology and internal medicine, aiming for consensus. Lyso-GB3 is a valuable biomarker to establish the diagnosis. Proteinuria and creatinine are the most valuable to detect renal damage. Troponin I and high-sensitivity assays for cardiac troponin T can identify patients with cardiac lesions, but new techniques of cardiac imaging are essential to detect incipient damage. Specific cerebrovascular imaging findings are present in AFD patients. Techniques as metabolomics and proteomics have been developed in order to find an AFD fingerprint. Lyso-GB3 is important for evaluating the pathogenic mutations and monitoring the response to treatment. Many biomarkers can detect renal, cardiac and cerebrovascular involvement, but none of these have proved to be important to monitoring the response to treatment. Imaging features are preferred in order to find cardiac and cerebrovascular compromise in AFD patients. PMID: 28933368 [PubMed]

Related Articles Mass spectrometry methods to study protein-metabolite interactions. Expert Opin Drug Discov. 2017 Sep 21;:1-10 Authors: Guo H, Peng H, Emili A Abstract INTRODUCTION: To ​​​​understand and manipulate biochemical processes and signaling pathways, the knowledge of endogenous protein-metabolite interactions would be extremely helpful. Recent developments in precision mass spectrometry, high-throughput proteomics and sensitive metabolomic profiling are beginning to converge on a possible solution, heralding a new era of global metabolome-proteome 'interactome' studies that promise to change biomedical research and drug discovery. Areas covered: Here, we review innovative mass spectrometry-based methods and recent pioneering studies aimed at elucidating the physical associations of small molecule ligands with cellular proteins. The technologies covered belong to two main categories: tag-based and tag-free methods. We emphasize the latter in this review, and outline promising experimental workflows and key data analysis considerations involved. Expert opinion: Recent ground-breaking advances in chemical-proteomics technology and allied computational methods now make the global detection of protein-ligand engagement an increasingly attractive research problem. Despite ongoing challenges, rapid progress in the field is expected these coming next few years, leading to a refreshed systems biology research paradigm and much needed new opportunities for improving sparse drug discovery pipelines. PMID: 28933205 [PubMed - as supplied by publisher]

Related Articles [Metabolomics research of medicinal plants]. Zhongguo Zhong Yao Za Zhi. 2016 Nov;41(22):4090-4095 Authors: Duan LX, Dai YT, Sun C, Chen SL Abstract Metabolomics is the comprehensively study of chemical processes involving small molecule metabolites. It is an important part of systems biology, and is widely applied in complex traditional Chinese medicine（TCM）system. Metabolites biosynthesized by medicinal plants are the effective basis for TCM. Metabolomics studies of medicinal plants will usher in a new period of vigorous development with the implementation of Herb Genome Program and the development of TCM synthetic biology. This manuscript introduces the recent research progresses of metabolomics technology and the main research contents of metabolomics studies for medicinal plants, including identification and quality evaluation for medicinal plants, cultivars breeding, stress resistance, metabolic pathways, metabolic network, metabolic engineering and synthetic biology researches. The integration of genomics, transcriptomics and metabolomics approaches will finally lay foundation for breeding of medicinal plants, R&D, quality and safety evaluation of innovative drug. PMID: 28933072 [PubMed - in process]

Related Articles Usefulness of zebrafish larvae to evaluate drug-induced functional and morphological renal tubular alterations. Arch Toxicol. 2017 Sep 20;: Authors: Gorgulho R, Jacinto R, Lopes SS, Pereira SA, Tranfield EM, Martins GG, Gualda EJ, Derks RJE, Correia AC, Steenvoorden E, Pintado P, Mayboroda OA, Monteiro EC, Morello J Abstract Prediction and management of drug-induced renal injury (DIRI) rely on the knowledge of the mechanisms of drug insult and on the availability of appropriate animal models to explore it. Zebrafish (Danio rerio) offers unique advantages for assessing DIRI because the larval pronephric kidney has a high homology with its human counterpart and it is fully mature at 3.5 days post-fertilization. Herein, we aimed to evaluate the usefulness of zebrafish larvae as a model of renal tubular toxicity through a comprehensive analysis of the renal alterations induced by the lethal concentrations for 10% of the larvae for gentamicin, paracetamol and tenofovir. We evaluated drug metabolic profile by mass spectrometry, renal function with the inulin clearance assay, the 3D morphology of the proximal convoluted tubule by two-photon microscopy and the ultrastructure of proximal convoluted tubule mitochondria by transmission electron microscopy. Paracetamol was metabolized by conjugation and oxidation with further detoxification with glutathione. Renal clearance was reduced with gentamicin and paracetamol. Proximal tubules were enlarged with paracetamol and tenofovir. All drugs induced mitochondrial alterations including dysmorphic shapes ("donuts", "pancakes" and "rods"), mitochondrial swelling, cristae disruption and/or loss of matrix granules. These results are in agreement with the tubular effects of gentamicin, paracetamol and tenofovir in man and demonstrate that zebrafish larvae might be a good model to assess functional and structural damage associated with DIRI. PMID: 28932931 [PubMed - as supplied by publisher]

Related Articles A Metabolomics-Based Strategy for the Mechanism Exploration of Traditional Chinese Medicine: Descurainia sophia Seeds Extract and Fractions as a Case Study. Evid Based Complement Alternat Med. 2017;2017:2845173 Authors: Zhou N, Sun YP, Zheng XK, Wang QH, Yang YY, Bai ZY, Kuang HX, Feng WS Abstract A UPLC-QTOF-MS based metabolomics research was conducted to explore potential biomarkers which would increase our understanding of the model and to assess the integral efficacy of Descurainia sophia seeds extract (DS-A). Additionally, DS-A was split into five fractions in descending order of polarity, which were utilized to illustrate the mechanism together. The 26 identified biomarkers were mainly related to disturbances in phenylalanine, tyrosine, tryptophan, purine, arginine, and proline metabolism. Furthermore, heat map, hierarchical cluster analysis (HCA), and correlation network diagram of biomarkers perturbed by modeling were all conducted. The results of heat map and HCA suggested that fat oil fraction could reverse the abnormal metabolism in the model to some extent; meanwhile the metabolic inhibitory effect produced by the other four fractions helped to relieve cardiac load and compensate the insufficient energy supplement induced by the existing heart and lung injury in model rats. Briefly, the split fractions interfered with the model from different aspects and ultimately constituted the overall effects of extract. In conclusion, the metabolomics method, combined with split fractions of extract, is a powerful approach for illustrating pathologic changes of Chinese medicine syndrome and action mechanisms of traditional Chinese medicine. PMID: 28932251 [PubMed]

Related Articles Non-invasive real time monitoring of yeast volatilome by PTR-ToF-MS. Metabolomics. 2017;13(10):118 Authors: Khomenko I, Stefanini I, Cappellin L, Cappelletti V, Franceschi P, Cavalieri D, Märk TD, Biasioli F Abstract INTRODUCTION: Producing a wide range of volatile secondary metabolites Saccharomyces cerevisiae influences wine, beer, and bread sensory quality and hence selection of strains based on their volatilome becomes pivotal. A rapid on-line method for volatilome assessing of strains growing on standard solid media is still missing. OBJECTIVES: Methodologically, the aim of this study was to demonstrate the automatic, real-time, direct, and non-invasive monitoring of yeast volatilome in order to rapidly produce a robust large data set encompassing measurements relative to many strains, replicates and time points. The fundamental scope was to differentiate volatilomes of genetically similar strains of oenological relevance during the whole growing process. METHOD: Six different S. cerevisiae strains (four meiotic segregants of a natural strain and two laboratory strains) inoculated onto a solid medium have been monitored on-line by Proton Transfer Reaction-Time-of-Flight-Mass Spectrometry for 11 days every 4 h (3540 time points). FastGC PTR-ToF-MS was performed during the stationary phase on the 5th day. RESULTS: More than 300 peaks have been extracted from the average spectra associated to each time point, 70 have been tentatively identified. Univariate and multivariate analyses have been performed on the data matrix (3640 measurements × 70 peaks) highlighting the volatilome evolution and strain-specific features. Laboratory strains with opposite mating type, and meiotic segregants of the same natural strain showed significantly different profiles. CONCLUSIONS: The described set-up allows the on-line high-throughput screening of yeast volatilome of S. cerevisiae strains and the identification of strain specific features and new metabolic pathways, discriminating also genetically similar strains, thus revealing a novel method for strain phenotyping, identification, and quality control. PMID: 28932179 [PubMed]

Related Articles Identification of sequence variants influencing immunoglobulin levels. Nat Genet. 2017 Aug;49(8):1182-1191 Authors: Jonsson S, Sveinbjornsson G, de Lapuente Portilla AL, Swaminathan B, Plomp R, Dekkers G, Ajore R, Ali M, Bentlage AEH, Elmér E, Eyjolfsson GI, Gudjonsson SA, Gullberg U, Gylfason A, Halldorsson BV, Hansson M, Holm H, Johansson Å, Johnsson E, Jonasdottir A, Ludviksson BR, Oddsson A, Olafsson I, Olafsson S, Sigurdardottir O, Sigurdsson A, Stefansdottir L, Masson G, Sulem P, Wuhrer M, Wihlborg AK, Thorleifsson G, Gudbjartsson DF, Thorsteinsdottir U, Vidarsson G, Jonsdottir I, Nilsson B, Stefansson K Abstract Immunoglobulins are the effector molecules of the adaptive humoral immune system. In a genome-wide association study of 19,219 individuals, we found 38 new variants and replicated 5 known variants associating with IgA, IgG or IgM levels or with composite immunoglobulin traits, accounted for by 32 loci. Variants at these loci also affect the risk of autoimmune diseases and blood malignancies and influence blood cell development. Notable associations include a rare variant at RUNX3 decreasing IgA levels by shifting isoform proportions (rs188468174[C>T]: P = 8.3 × 10(-55), β = -0.90 s.d.), a rare in-frame deletion in FCGR2B abolishing IgG binding to the encoded receptor (p.Asn106del: P = 4.2 × 10(-8), β = 1.03 s.d.), four IGH locus variants influencing class switching, and ten new associations with the HLA region. Our results provide new insight into the regulation of humoral immunity. PMID: 28628107 [PubMed - indexed for MEDLINE]

Related Articles An integrative analysis of tissue-specific transcriptomic and metabolomic responses to short-term dietary methionine restriction in mice. PLoS One. 2017;12(5):e0177513 Authors: Ghosh S, Forney LA, Wanders D, Stone KP, Gettys TW Abstract Dietary methionine restriction (MR) produces a coordinated series of transcriptional responses in peripheral tissues that limit fat accretion, remodel lipid metabolism in liver and adipose tissue, and improve overall insulin sensitivity. Hepatic sensing of reduced methionine leads to induction and release of fibroblast growth factor 21 (FGF21), which acts centrally to increase sympathetic tone and activate thermogenesis in adipose tissue. FGF21 also has direct effects in adipose to enhance glucose uptake and oxidation. However, an understanding of how the liver senses and translates reduced dietary methionine into these transcriptional programs remains elusive. A comprehensive systems biology approach integrating transcriptomic and metabolomic readouts in MR-treated mice confirmed that three interconnected mechanisms (fatty acid transport and oxidation, tricarboxylic acid cycle, and oxidative phosphorylation) were activated in MR-treated inguinal adipose tissue. In contrast, the effects of MR in liver involved up-regulation of anti-oxidant responses driven by the nuclear factor, erythroid 2 like 2 transcription factor, NFE2L2. Metabolomic analysis provided evidence for redox imbalance, stemming from large reductions in the master anti-oxidant molecule glutathione coupled with disproportionate increases in ophthalmate and its precursors, glutamate and 2-aminobutyrate. Thus, cysteine and its downstream product, glutathione, emerge as key early hepatic signaling molecules linking dietary MR to its metabolic phenotype. PMID: 28520765 [PubMed - indexed for MEDLINE]

Related Articles TSPAN5, ERICH3 and selective serotonin reuptake inhibitors in major depressive disorder: pharmacometabolomics-informed pharmacogenomics. Mol Psychiatry. 2016 Dec;21(12):1717-1725 Authors: Gupta M, Neavin D, Liu D, Biernacka J, Hall-Flavin D, Bobo WV, Frye MA, Skime M, Jenkins GD, Batzler A, Kalari K, Matson W, Bhasin SS, Zhu H, Mushiroda T, Nakamura Y, Kubo M, Wang L, Kaddurah-Daouk R, Weinshilboum RM Abstract Millions of patients suffer from major depressive disorder (MDD), but many do not respond to selective serotonin reuptake inhibitor (SSRI) therapy. We used a pharmacometabolomics-informed pharmacogenomics research strategy to identify genes associated with metabolites that were related to SSRI response. Specifically, 306 MDD patients were treated with citalopram or escitalopram and blood was drawn at baseline, 4 and 8 weeks for blood drug levels, genome-wide single nucleotide polymorphism (SNP) genotyping and metabolomic analyses. SSRI treatment decreased plasma serotonin concentrations (P<0.0001). Baseline and plasma serotonin concentration changes were associated with clinical outcomes (P<0.05). Therefore, baseline and serotonin concentration changes were used as phenotypes for genome-wide association studies (GWAS). GWAS for baseline plasma serotonin concentrations revealed a genome-wide significant (P=7.84E-09) SNP cluster on chromosome four 5' of TSPAN5 and a cluster across ERICH3 on chromosome one (P=9.28E-08) that were also observed during GWAS for change in serotonin at 4 (P=5.6E-08 and P=7.54E-07, respectively) and 8 weeks (P=1.25E-06 and P=3.99E-07, respectively). The SNPs on chromosome four were expression quantitative trait loci for TSPAN5. Knockdown (KD) and overexpression (OE) of TSPAN5 in a neuroblastoma cell line significantly altered the expression of serotonin pathway genes (TPH1, TPH2, DDC and MAOA). Chromosome one SNPs included two ERICH3 nonsynonymous SNPs that resulted in accelerated proteasome-mediated degradation. In addition, ERICH3 and TSPAN5 KD and OE altered media serotonin concentrations. Application of a pharmacometabolomics-informed pharmacogenomic research strategy, followed by functional validation, indicated that TSPAN5 and ERICH3 are associated with plasma serotonin concentrations and may have a role in SSRI treatment outcomes. PMID: 26903268 [PubMed - indexed for MEDLINE]

21 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2017/09/21PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

17 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2017/09/20PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

18 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2017/09/19PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

18 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2017/09/19PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Toxic responses of Perna viridis hepatopancreas exposed to DDT, benzo(a)pyrene and their mixture uncovered by iTRAQ-based proteomics and NMR-based metabolomics. Aquat Toxicol. 2017 Sep 11;192:48-57 Authors: Song Q, Zhou H, Han Q, Diao X Abstract Dichlorodiphenyltrichloroethane (DDT) and benzo(a)pyrene (BaP) are environmental estrogens (EEs) that are ubiquitous in the marine environment. In the present study, we integrated isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomic and nuclear magnetic resonance (NMR)-based metabolomic approaches to explore the toxic responses of green mussel hepatopancreas exposed to DDT (10μg/L), BaP (10μg/L) and their mixture. The metabolic responses indicated that BaP primarily disturbed energy metabolism and osmotic regulation in the hepatopancreas of the male green mussel P. viridis. Both DDT and the mixture of DDT and BaP perturbed the energy metabolism and osmotic regulation in P. viridis. The proteomic responses revealed that BaP affected the proteins involved in energy metabolism, material transformation, cytoskeleton, stress responses, reproduction and development in green mussels. DDT exposure could change the proteins involved in primary metabolism, stress responses, cytoskeleton and signal transduction. However, the mixture of DDT and BaP altered proteins associated with material and energy metabolism, stress responses, signal transduction, reproduction and development, cytoskeleton and apoptosis. This study showed that iTRAQ-based proteomic and NMR-based metabolomic approaches could effectively elucidate the essential molecular mechanism of disturbances in hepatopancreas function of green mussels exposed to environmental estrogens. PMID: 28917945 [PubMed - as supplied by publisher]

Gas chromatographic-mass spectrometric analysis of urinary volatile organic metabolites: Optimization of the HS-SPME procedure and sample storage conditions. Talanta. 2018 Jan 01;176:537-543 Authors: Živković Semren T, Brčić Karačonji I, Safner T, Brajenović N, Tariba Lovaković B, Pizent A Abstract Non-targeted metabolomics research of human volatile urinary metabolome can be used to identify potential biomarkers associated with the changes in metabolism related to various health disorders. To ensure reliable analysis of urinary volatile organic metabolites (VOMs) by gas chromatography-mass spectrometry (GC-MS), parameters affecting the headspace-solid phase microextraction (HS-SPME) procedure have been evaluated and optimized. The influence of incubation and extraction temperatures and times, coating fibre material and salt addition on SPME efficiency was investigated by multivariate optimization methods using reduced factorial and Doehlert matrix designs. The results showed optimum values for temperature to be 60°C, extraction time 50min, and incubation time 35min. The proposed conditions were applied to investigate urine samples' stability regarding different storage conditions and freeze-thaw processes. The sum of peak areas of urine samples stored at 4°C, -20°C, and -80°C up to six months showed a time dependent decrease over time although storage at -80°C resulted in a slight non-significant reduction comparing to the fresh sample. However, due to the volatile nature of the analysed compounds, more than two cycles of freezing/thawing of the sample stored for six months at -80°C should be avoided whenever possible. PMID: 28917787 [PubMed - in process]

Towards personalized medicine of colorectal cancer. Crit Rev Oncol Hematol. 2017 Oct;118:70-78 Authors: Aziz MA, Yousef Z, Saleh AM, Mohammad S, Al Knawy B Abstract Efforts in colorectal cancer (CRC) research aim to improve early detection and treatment for metastatic stages which could translate into better prognosis of this disease. One of the major challenges that hinder these efforts is the heterogeneous nature of CRC and involvement of diverse molecular pathways. New large-scale 'omics' technologies are making it possible to generate, analyze and interpret biological data from molecular determinants of CRC. The developments of sophisticated computational analyses would allow information from different omics platforms to be integrated, thus providing new insights into the biology of CRC. Together, these technological advances and an improved mechanistic understanding might allow CRC to be clinically managed at the level of the individual patient. This review provides an account of the current challenges in CRC management and an insight into how new technologies could allow the development of personalized medicine for CRC. PMID: 28917272 [PubMed - in process]

Related Articles Informatics for Nutritional Genetics and Genomics. Adv Exp Med Biol. 2017;1005:143-166 Authors: Gao Y, Chen J Abstract While traditional nutrition science is focusing on nourishing population, modern nutrition is aiming at benefiting individual people. The goal of modern nutritional research is to promote health, prevent diseases, and improve performance. With the development of modern technologies like bioinformatics, metabolomics, and molecular genetics, this goal is becoming more attainable. In this chapter, we will discuss the new concepts and technologies especially in informatics and molecular genetics and genomics, and how they have been implemented to change the nutrition science and lead to the emergence of new branches like nutrigenomics, nutrigenetics, and nutritional metabolomics. PMID: 28916932 [PubMed - in process]

Related Articles Digging into the low molecular weight peptidome with the OligoNet web server. Sci Rep. 2017 Sep 15;7(1):11692 Authors: Liu Y, Forcisi S, Lucio M, Harir M, Bahut F, Deleris-Bou M, Krieger-Weber S, Gougeon RD, Alexandre H, Schmitt-Kopplin P Abstract Bioactive peptides play critical roles in regulating many biological processes. Recently, natural short peptides biomarkers are drawing significant attention and are considered as "hidden treasure" of drug candidates. High resolution and high mass accuracy provided by mass spectrometry (MS)-based untargeted metabolomics would enable the rapid detection and wide coverage of the low-molecular-weight peptidome. However, translating unknown masses (<1 500 Da) into putative peptides is often limited due to the lack of automatic data processing tools and to the limit of peptide databases. The web server OligoNet responds to this challenge by attempting to decompose each individual mass into a combination of amino acids out of metabolomics datasets. It provides an additional network-based data interpretation named "Peptide degradation network" (PDN), which unravels interesting relations between annotated peptides and generates potential functional patterns. The ab initio PDN built from yeast metabolic profiling data shows a great similarity with well-known metabolic networks, and could aid biological interpretation. OligoNet allows also an easy evaluation and interpretation of annotated peptides in systems biology, and is freely accessible at https://daniellyz200608105.shinyapps.io/OligoNet/ . PMID: 28916823 [PubMed - in process]

Related Articles Functional screening in human cardiac organoids reveals a metabolic mechanism for cardiomyocyte cell cycle arrest. Proc Natl Acad Sci U S A. 2017 Sep 15;: Authors: Mills RJ, Titmarsh DM, Koenig X, Parker BL, Ryall JG, Quaife-Ryan GA, Voges HK, Hodson MP, Ferguson C, Drowley L, Plowright AT, Needham EJ, Wang QD, Gregorevic P, Xin M, Thomas WG, Parton RG, Nielsen LK, Launikonis BS, James DE, Elliott DA, Porrello ER, Hudson JE Abstract The mammalian heart undergoes maturation during postnatal life to meet the increased functional requirements of an adult. However, the key drivers of this process remain poorly defined. We are currently unable to recapitulate postnatal maturation in human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs), limiting their potential as a model system to discover regenerative therapeutics. Here, we provide a summary of our studies, where we developed a 96-well device for functional screening in human pluripotent stem cell-derived cardiac organoids (hCOs). Through interrogation of >10,000 organoids, we systematically optimize parameters, including extracellular matrix (ECM), metabolic substrate, and growth factor conditions, that enhance cardiac tissue viability, function, and maturation. Under optimized maturation conditions, functional and molecular characterization revealed that a switch to fatty acid metabolism was a central driver of cardiac maturation. Under these conditions, hPSC-CMs were refractory to mitogenic stimuli, and we found that key proliferation pathways including β-catenin and Yes-associated protein 1 (YAP1) were repressed. This proliferative barrier imposed by fatty acid metabolism in hCOs could be rescued by simultaneous activation of both β-catenin and YAP1 using genetic approaches or a small molecule activating both pathways. These studies highlight that human organoids coupled with higher-throughput screening platforms have the potential to rapidly expand our knowledge of human biology and potentially unlock therapeutic strategies. PMID: 28916735 [PubMed - as supplied by publisher]