Microorganisms. 2021 Feb 13;9(2):381. doi: 10.3390/microorganisms9020381.

ABSTRACT

Revealing the relationship between taxonomy and function in microbiomes is critical to discover their contribution to ecosystem functioning. However, while the relationship between taxonomic and functional diversity in bacteria and fungi is known, this is not the case for archaea. Here, we used a meta-analysis of 417 completely annotated extant and taxonomically unique archaeal genomes to predict the extent of microbiome functionality on Earth contained within archaeal genomes using accumulation curves of all known level 3 functions of KEGG Orthology. We found that intergenome redundancy as functions present in multiple genomes was inversely related to intragenome redundancy as multiple copies of a gene in one genome, implying the tradeoff between additional copies of functionally important genes or a higher number of different genes. A logarithmic model described the relationship between functional diversity and species richness better than both the unsaturated and the saturated model, which suggests a limited total number of archaeal functions in contrast to the sheer unlimited potential of bacteria and fungi. Using the global archaeal species richness estimate of 13,159, the logarithmic model predicted 4164.1 ± 2.9 KEGG level 3 functions. The non-parametric bootstrap estimate yielded a lower bound of 2994 ± 57 KEGG level 3 functions. Our approach not only highlighted similarities in functional redundancy but also the difference in functional potential of archaea compared to other domains of life.

PMID:33668634 | DOI:10.3390/microorganisms9020381

Biosensors (Basel). 2021 Feb 24;11(3):60. doi: 10.3390/bios11030060.

ABSTRACT

The aryl hydrocarbon receptor (AhR) is a highly conserved cellular sensor of a variety of environmental pollutants and dietary-, cell- and microbiota-derived metabolites with important roles in fundamental biological processes. Deregulation of the AhR pathway is implicated in several diseases, including autoimmune diseases and cancer, rendering AhR a promising target for drug development and host-directed therapy. The pharmacological intervention of AhR processes requires detailed information about the ligand binding properties to allow specific targeting of a particular signaling process without affecting the remaining. Here, we present a novel microscale thermophoresis-based approach to monitoring the binding of purified recombinant human AhR to its natural ligands in a cell-free system. This approach facilitates a precise identification and characterization of unknown AhR ligands and represents a screening strategy for the discovery of potential selective AhR modulators.

PMID:33668313 | DOI:10.3390/bios11030060

Molecules. 2021 Feb 24;26(5):1209. doi: 10.3390/molecules26051209.

ABSTRACT

Protein molecules are inherently dynamic and modulate their interactions with different molecular partners by accessing different tertiary structures under physiological conditions. Elucidating such structures remains challenging. Current momentum in deep learning and the powerful performance of generative adversarial networks (GANs) in complex domains, such as computer vision, inspires us to investigate GANs on their ability to generate physically-realistic protein tertiary structures. The analysis presented here shows that several GAN models fail to capture complex, distal structural patterns present in protein tertiary structures. The study additionally reveals that mechanisms touted as effective in stabilizing the training of a GAN model are not all effective, and that performance based on loss alone may be orthogonal to performance based on the quality of generated datasets. A novel contribution in this study is the demonstration that Wasserstein GAN strikes a good balance and manages to capture both local and distal patterns, thus presenting a first step towards more powerful deep generative models for exploring a possibly very diverse set of structures supporting diverse activities of a protein molecule in the cell.

PMID:33668217 | DOI:10.3390/molecules26051209

Redox Biol. 2021 Feb 20;41:101907. doi: 10.1016/j.redox.2021.101907. Online ahead of print.

ABSTRACT

BACKGROUND: Numerous pathologies result in multiple-organ failure, which is thought to be a direct consequence of compromised cellular bioenergetic status. Neither the nature of this phenotype nor its relevance to survival are well understood, limiting the efficacy of modern life-support.

METHODS: To explore the hypothesis that survival from critical illness relates to changes in cellular bioenergetics, we combined assessment of mitochondrial respiration with metabolomic, lipidomic and redox profiling in skeletal muscle and blood, at multiple timepoints, in 21 critically ill patients and 12 reference patients.

RESULTS: We demonstrate an end-organ cellular phenotype in critical illness, characterized by preserved total energetic capacity, greater coupling efficiency and selectively lower capacity for complex I and fatty acid oxidation (FAO)-supported respiration in skeletal muscle, compared to health. In survivors, complex I capacity at 48 h was 27% lower than in non-survivors (p = 0.01), but tended to increase by day 7, with no such recovery observed in non-survivors. By day 7, survivors' FAO enzyme activity was double that of non-survivors (p = 0.048), in whom plasma triacylglycerol accumulated. Increases in both cellular oxidative stress and reductive drive were evident in early critical illness compared to health. Initially, non-survivors demonstrated greater plasma total antioxidant capacity but ultimately higher lipid peroxidation compared to survivors. These alterations were mirrored by greater levels of circulating total free thiol and nitrosated species, consistent with greater reductive stress and vascular inflammation, in non-survivors compared to survivors. In contrast, no clear differences in systemic inflammatory markers were observed between the two groups.

CONCLUSION: Critical illness is associated with rapid, specific and coordinated alterations in the cellular respiratory machinery, intermediary metabolism and redox response, with different trajectories in survivors and non-survivors. Unravelling the cellular and molecular foundation of human resilience may enable the development of more effective life-support strategies.

PMID:33667994 | DOI:10.1016/j.redox.2021.101907

J Glob Antimicrob Resist. 2021 Mar 2:S2213-7165(21)00054-0. doi: 10.1016/j.jgar.2021.02.022. Online ahead of print.

ABSTRACT

OBJECTIVES: Bacteroides fragilis is one of the most important human anaerobic pathogens that are often found during various clinical infections. The purpose of this study was to determine susceptibility of B. fragilis to the most common anti-anaerobic drugs at the local level and to detect genes associated with resistance to these antibiotics.

METHODS: This article describes the B. fragilis BFR_KZ01 clinical strain study. Identification of the bacteria by two modern methods: MALDI-TOF mass spectrometry and 16S rRNA gene sequencing was performed. Sensitivity to broad-spectrum antibiotics (metronidazole, meropenem, ciprofloxacin, clindamycin and tetracycline) most commonly used for intraabdominal infections treatment was studied. Mass spectra groups essential for identifying cfiA-positive strains from clinical isolates were studied using ClinProTools 3.0.22 software. The Ion Torrent PGM platform was used for the whole-genome sequencing of the studied isolates.

RESULTS: The resulting whole-genome sequence of the BFR_KZ01 strain was imported to GenBank. In total, 5300 coding sequences (CDSs) and 69 RNA genes were determined. Analysis of the whole genome data revealed that the studied strain has cfiA, nimB, tetQ and gyrA genes, which confer resistance to key drugs used in treatment of the intraabdominal infections. MALDI-TOF mass spectrometry analysis has assigned the strain BFR_KZ01 to Group II (cfiA-positive); however, BFR_KZ01 was phenotypically sensitive to meropenem (mean MIC = 1.3 mg/L).

CONCLUSIONS: To sum up, determinants of drug resistance in the BFR_KZ01 strain were identified. It was revealed that the B. fragilis strain BFR_KZ01 from Kazakhstan is multidrug-resistant, since it carries nimB, tetQ and gyrA genes, which confer resistance to metronidazole, tetracycline and ciprofloxacin.

PMID:33667704 | DOI:10.1016/j.jgar.2021.02.022

J Invest Dermatol. 2021 Mar 2:S0022-202X(21)00237-2. doi: 10.1016/j.jid.2021.02.013. Online ahead of print.

ABSTRACT

IL-9 producing T cells are present in healthy skin as well as in the cutaneous lesions of inflammatory diseases and cancers. However, the roles of IL-9 in human skin during homeostasis and in the pathogenesis of inflammatory disorders remain obscure. In this study, we examined the roles of IL-9 in metabolic reprogramming of human primary keratinocytes (HPKs). High-throughput quantitative proteomics revealed that IL-9 signalling in HPKs disrupts the electron transport chain (ETC) by downregulating multiple ETC proteins. NMR-based metabolomics demonstrated that IL-9 also reduced the production of tricarboxylic acid (TCA) cycle intermediates in HPKs. Integration of multi-omics data with systems level analysis using the constraint based MitoCore model predicted marked IL-9-dependent effects on central carbohydrate metabolism, particularly in relation to the glycolytic switch. Stable isotope metabolomic and biochemical assays confirmed increased glucose consumption and redirection of metabolic flux towards lactate by IL-9. Functionally, IL-9 inhibited reactive oxygen species (ROS) production by IFNγ and promoted HPK survival by inhibiting apoptosis. In conclusion, our data reveal IL-9 as a master regulator of keratinocyte metabolic reprogramming and survival.

PMID:33667432 | DOI:10.1016/j.jid.2021.02.013

J Mol Cell Cardiol. 2021 Mar 2:S0022-2828(21)00051-1. doi: 10.1016/j.yjmcc.2021.02.014. Online ahead of print.

ABSTRACT

Despite clinical observations of cardiotoxicity among cancer patients treated with tyrosine kinase inhibitors (TKIs), the molecular mechanisms by which these drugs affect the heart remain largely unknown. Mechanistic understanding of TKI-induced cardiotoxicity has been limited in part due to the complexity of tyrosine kinase signaling pathways and the multi-targeted nature of many of these drugs. TKI treatment has been associated with reactive oxygen species generation, mitochondrial dysfunction, and apoptosis in cardiomyocytes. To gain insight into the mechanisms mediating TKI-induced cardiotoxicity, this study constructs and validates a computational model of cardiomyocyte apoptosis, integrating intrinsic apoptotic and tyrosine kinase signaling pathways. The model predicts high levels of apoptosis in response to sorafenib, sunitinib, ponatinib, trastuzumab, and gefitinib, and lower levels of apoptosis in response to nilotinib and erlotinib, with the highest level of apoptosis induced by sorafenib. Knockdown simulations identified AP1, ASK1, JNK, MEK47, p53, and ROS as positive functional regulators of sorafenib-induced apoptosis of cardiomyocytes. Overexpression simulations identified Akt, IGF1, PDK1, and PI3K among the negative functional regulators of sorafenib-induced cardiomyocyte apoptosis. A combinatorial screen of the positive and negative regulators of sorafenib-induced apoptosis revealed ROS knockdown coupled with overexpression of FLT3, FGFR, PDGFR, VEGFR, or KIT as a particularly potent combination in reducing sorafenib-induced apoptosis Network simulations of combinatorial treatment with sorafenib and the antioxidant N-acetyl cysteine (NAC) suggest that NAC may protect cardiomyocytes from sorafenib-induced apoptosis.

PMID:33667419 | DOI:10.1016/j.yjmcc.2021.02.014

Cell. 2021 Mar 4;184(5):1142-1155. doi: 10.1016/j.cell.2021.02.020.

ABSTRACT

The characterization of cancer genomes has provided insight into somatically altered genes across tumors, transformed our understanding of cancer biology, and enabled tailoring of therapeutic strategies. However, the function of most cancer alleles remains mysterious, and many cancer features transcend their genomes. Consequently, tumor genomic characterization does not influence therapy for most patients. Approaches to understand the function and circuitry of cancer genes provide complementary approaches to elucidate both oncogene and non-oncogene dependencies. Emerging work indicates that the diversity of therapeutic targets engendered by non-oncogene dependencies is much larger than the list of recurrently mutated genes. Here we describe a framework for this expanded list of cancer targets, providing novel opportunities for clinical translation.

PMID:33667368 | DOI:10.1016/j.cell.2021.02.020

Annu Rev Plant Biol. 2021 Mar 5. doi: 10.1146/annurev-arplant-081320-090914. Online ahead of print.

ABSTRACT

All aspects of transcription and its regulation involve dynamic events. However, capturing these dynamic events in gene regulatory networks (GRNs) offers both a promise and a challenge. The promise is that capturing and modeling the dynamic changes in GRNs will allow us to understand how organisms adapt to a changing environment. The ability to mount a rapid transcriptional response to environmental changes is especially important in nonmotile organisms such as plants. The challenge is to capture these dynamic, genome-wide events and model them in GRNs. In this review, we cover recent progress in capturing dynamic interactions of transcription factors with their targets-at both the local and genome-wide levels-and using them to learn how GRNs operate as a function of time. We also discuss recent advances that employ time-based machine learning approaches to forecast gene expression at future time points, a key goal of systems biology. Expected final online publication date for the Annual Review of Plant Biology, Volume 72 is May 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

PMID:33667112 | DOI:10.1146/annurev-arplant-081320-090914

Med J (Ft Sam Houst Tex). 2021 Jan-Mar;(PB 8-21-01/02/03):37-49.

ABSTRACT

SARS-CoV-2 has highlighted the requirement for a drastic change in pandemic response. While cases continue to rise, there is an urgent need to deploy sensitive and rapid testing in order to identify potential outbreaks before there is an opportunity for further community spread. Currently, reverse transcription quantitative polymerase chain reaction (RT-qPCR) is considered the gold standard for diagnosing an active infection, using a nasopharyngeal swab; however, it can take days after symptoms develop to properly identify and trace the infection. While many civilian jobs can be performed remotely, the Department of Defense (DOD) is by nature a very fluid organization which requires in-person interaction and a physical presence to maintain effectiveness. In this commentary, we examine several current and emergent technologies and their ability to identify both active and previous SARS-CoV-2 infection, possibly in those without symptoms. Further, we will explore an ongoing study at the Air Force Research Laboratory, utilizing Reverse Transcription Loop-mediated isothermal amplification (RT-LAMP), next-generation sequencing, and the presence of SARS-CoV-2 antibodies through Lateral Flow Immunoassays. The ability to identify SARS-CoV-2 through volatile organic compound biomarker identification will also be explored. By exploring and validating multiple testing strategies, and contributing to Operation Warp Speed, the DOD is postured to respond to SARS-CoV-2, and future pandemics.

PMID:33666911

Rice (N Y). 2021 Mar 5;14(1):25. doi: 10.1186/s12284-021-00467-y.

ABSTRACT

SDG711 is a histone H3K27me2/3 transmethylase in rice, a homolog of CLF in Arabidopsis, and plays key roles in regulating flowering time and panicle development. In this work, we investigated the role of SDG711 in rice seed development. Overexpression and downregulation of SDG711 lead to a decrease and increase in the expression level of genes related to starch accumulation, resulting in smaller seeds or even seed abortion. ChIP assay showed that SDG711-mediated H3K27me3 changed significantly in genes related to endosperm development, and SDG711 can directly bind to the gene body region of several starch synthesis genes and amylase genes. In addition, H3K4me3 and H3K9ac modifications also cooperate with H3K27me3 to regulate the development of the endosperm. Our results suggest that the crosstalk between SDG711-mediated H3K27me3 and H3K4me3, and H3K9ac are involved in starch accumulation to control normal seed development.

PMID:33666740 | DOI:10.1186/s12284-021-00467-y

Elife. 2021 Mar 5;10:e58394. doi: 10.7554/eLife.58394. Online ahead of print.

ABSTRACT

Chromatin dynamics are mediated by remodeling enzymes and play crucial roles in gene regulation, as established in a paradigmatic model, the S. cerevisiae PHO5 promoter. However, effective nucleosome dynamics, i.e. trajectories of promoter nucleosome configurations, remain elusive. Here, we infer such dynamics from the integration of published single-molecule data capturing multi-nucleosome configurations for repressed to fully active PHO5 promoter states with other existing histone turnover and new chromatin accessibility data. We devised and systematically investigated a new class of 'regulated on-off-slide' models simulating global and local nucleosome (dis)assembly and sliding. Only seven of 68145 models agreed well with all data. All seven models involve sliding and the known central role of the N-2 nucleosome, but regulate promoter state transitions by modulating just one assembly rather than disassembly process. This is consistent with but challenges common interpretations of previous observations at the PHO5 promoter and suggests chromatin opening by binding competition.

PMID:33666171 | DOI:10.7554/eLife.58394

iScience. 2021 Feb 9;24(3):102169. doi: 10.1016/j.isci.2021.102169. eCollection 2021 Mar 19.

ABSTRACT

Ulcerative colitis (UC) is a chronic inflammatory bowel disease, characterized by relapsing and remitting colon mucosal inflammation. For patients suffering from UC, a higher risk of colon cancer has been widely recognized. Here, we found that Elf4 -/- mice developed colon tumors with 3 cycles of dextran sulfate sodium salt (DSS) treatment alone. We further showed that ELF4 suppression was prevalent in both patients with UC and DSS-induced mice models, and this suppression was caused by promoter region methylation. ELF4, upon PARylation by PARP1, transcriptionally regulated multiple DNA damage repair machinery components. Consistently, ELF4 deficiency leads to more severe DNA damage both in vitro and in vivo. Oral administration of montmorillonite powder can prevent the reduction of ELF4 in DSS-induced colitis models and lower the risk of colon tumor development during azoxymethane (AOM) and DSS induced colitis-associated cancer (CAC). These data provided additional mechanism of CAC initiation and supported the "epigenetic priming model of tumor initiation".

PMID:33665583 | PMC:PMC7907480 | DOI:10.1016/j.isci.2021.102169

iScience. 2021 Feb 4;24(3):102144. doi: 10.1016/j.isci.2021.102144. eCollection 2021 Mar 19.

ABSTRACT

Despite the recent availability of complete genome sequences of tumors from thousands of patients, isolating disease-causing (driver) non-coding mutations from the plethora of somatic variants remains challenging, and only a handful of validated examples exist. By integrating whole-genome sequencing, genetic data, and allele-specific gene expression from TCGA, we identified 320 somatic non-coding mutations that affect gene expression in cis (FDR<0.25). These mutations cluster into 47 cis-regulatory elements that modulate expression of their subject genes through diverse molecular mechanisms. We further show that these mutations have hallmark features of non-coding drivers; namely, that they preferentially disrupt transcription factor binding motifs, are associated with a selective advantage, increased oncogene expression and decreased tumor suppressor expression.

PMID:33665563 | PMC:PMC7903341 | DOI:10.1016/j.isci.2021.102144

iScience. 2021 Feb 3;24(3):102127. doi: 10.1016/j.isci.2021.102127. eCollection 2021 Mar 19.

ABSTRACT

Consuming addictive drugs is often initially pleasurable, but escalating drug intake eventually recruits physiological anti-reward systems called opponent processes that cause tolerance and withdrawal symptoms. Opponent processes are fundamental for the addiction process, but their physiological basis is not fully characterized. Here, we propose an opponent processes mechanism centered on the endocrine stress response, the hypothalamic-pituitary-adrenal (HPA) axis. We focus on alcohol addiction, where the HPA axis is activated and secretes β-endorphin, causing euphoria and analgesia. Using a mathematical model, we show that slow changes in the functional mass of HPA glands act as an opponent process for β-endorphin secretion. The model explains hormone dynamics in alcohol addiction and experiments on alcohol preference in rodents. The opponent process is based on fold-change detection (FCD) where β-endorphin responses are relative rather than absolute; FCD confers vulnerability to addiction but has adaptive roles for learning. Our model suggests gland mass changes as potential targets for intervention in addiction.

PMID:33665551 | PMC:PMC7903339 | DOI:10.1016/j.isci.2021.102127

iScience. 2021 Jan 29;24(2):102120. doi: 10.1016/j.isci.2021.102120. eCollection 2021 Feb 19.

ABSTRACT

Classically, hematopoietic stem cell (HSC) differentiation is assumed to occur via progenitor compartments of decreasing plasticity and increasing maturity in a specific, hierarchical manner. The classical hierarchy has been challenged in the past by alternative differentiation pathways. We abstracted experimental evidence into 10 differentiation hierarchies, each comprising 7 cell type compartments. By fitting ordinary differential equation models with realistic waiting time distributions to time-resolved data of differentiating HSCs from 10 healthy human donors, we identified plausible lineage hierarchies and rejected others. We found that, for most donors, the classical model of hematopoiesis is preferred. Surprisingly, multipotent lymphoid progenitor differentiation into granulocyte-monocyte progenitors is plausible in 90% of samples. An in silico analysis confirmed that, even for strong noise, the classical model can be identified robustly. Our computational approach infers differentiation hierarchies in a personalized fashion and can be used to gain insights into kinetic alterations of diseased hematopoiesis.

PMID:33665548 | PMC:PMC7897991 | DOI:10.1016/j.isci.2021.102120

Front Vet Sci. 2021 Feb 16;8:630989. doi: 10.3389/fvets.2021.630989. eCollection 2021.

ABSTRACT

Bovine tuberculosis (bTB) has yet to be eradicated in Brazil. Herds of cattle and buffalo are important sources of revenue to people living in the banks of the Amazon River basin. A better understanding of Mycobacterium bovis (M. bovis) populational structure and transmission dynamics affecting these animals can significantly contribute in efforts to improve their sanitary status. Herein, we sequenced the whole genome of 22 M. bovis isolates (15 from buffalo and 7 from cattle) from 10 municipalities in the region of the Lower Amazon River Basin in Brazil and performed phylogenomic analysis and Single Nucleotide Polymorphism (SNP)-based transmission inference to evaluate population structure and transmission networks. Additionally, we compared these genomes to others obtained in unrelated studies in the Marajó Island (n = 15) and worldwide (n = 128) to understand strain diversity in the Amazon and to infer M. bovis lineages. Our results show a higher genomic diversity of M. bovis genomes obtained in the Lower Amazon River region when compared to the Marajó Island, while no significant difference was observed between M. bovis genomes obtained from cattle and buffalo (p ≥ 0.05). This high genetic diversity is reflected by the weak phylogenetic clustering of M. bovis from the Lower Amazon River region based on geographic proximity and in the detection of only two putative transmission clusters in the region. One of these clusters is the first description of inter-species transmission between cattle and buffalo in the Amazon, bringing implications to the bTB control program. Surprisingly, two M. bovis lineages were detected in our dataset, namely Lb1 and Lb3, constituting the first description of Lb1 in South America. Most of the strains of this study (13/22) and all 15 strains of the Marajó Island carried no clonal complex marker, suggesting that the recent lineage classification better describe the diversity of M. bovis in the Amazon.

PMID:33665220 | PMC:PMC7921743 | DOI:10.3389/fvets.2021.630989

Front Vet Sci. 2021 Feb 16;8:630164. doi: 10.3389/fvets.2021.630164. eCollection 2021.

ABSTRACT

Anxiety is a physio-psychological state anticipating an imminent threat. In social mammals it is behaviorally expressed via displacement activities and buffered via affiliation. Anxiety research on domestic pigs (Sus scrofa) has mostly focused on abnormal/stereotypic behavior associated with intensive farming. We investigated how anxiety is expressed and modulated in semi-free ranging pigs, in natural habitats. Owing to pigs' socio-cognitive complexity, we posited that displacement activities, if such, would increase after a (stressful) intra-group aggression (Prediction 1), be reduced by affiliation (Prediction 2) and influenced by individual/contextual factors (Prediction 3). From 224 videos recorded on adult individuals (Mean ± SD/subject: 4.84 ± 1.85 h) at the "Ethical Farm Parva Domus" (Turin, Italy), we extracted possible displacement activities (vacuum-chewing, scratching/body-rubbing, head/body-shaking, and yawning) in four 3-min conditions: before (BA) and after aggression events, in the absence (AA) or presence (AP) of post-aggression affiliation, and a matched-control (no event; MC). We conducted a minute-by-minute analysis in AE/AA and assessed the effect of subjects' involvement in a conflict (aggressor, aggression's recipient, bystander). All activities were higher in AA than in BA condition-thus being anxiety markers-and all of them decreased to baseline levels in AP, faster compared to AE. Hence, anxiety behavior in pigs was socially buffered. Intriguingly, anxiety behavior was expressed significantly more by bystanders than opponents, which suggests that pigs may be able to anticipate imminent threats. By highlighting how anxiety is managed under extensive farming, this study contributes to the understanding of pig welfare and biology.

PMID:33665219 | PMC:PMC7921160 | DOI:10.3389/fvets.2021.630164

Front Bioeng Biotechnol. 2021 Feb 16;8:536957. doi: 10.3389/fbioe.2020.536957. eCollection 2020.

ABSTRACT

Temporal multi-omics data can provide information about the dynamics of disease development and therapeutic response. However, statistical analysis of high-dimensional time-series data is challenging. Here we develop a novel approach to model temporal metabolomic and transcriptomic data by combining machine learning with metabolic models. ADAPT (Analysis of Dynamic Adaptations in Parameter Trajectories) performs metabolic trajectory modeling by introducing time-dependent parameters in differential equation models of metabolic systems. ADAPT translates structural uncertainty in the model, such as missing information about regulation, into a parameter estimation problem that is solved by iterative learning. We have now extended ADAPT to include both metabolic and transcriptomic time-series data by introducing a regularization function in the learning algorithm. The ADAPT learning algorithm was (re)formulated as a multi-objective optimization problem in which the estimation of trajectories of metabolic parameters is constrained by the metabolite data and refined by gene expression data. ADAPT was applied to a model of hepatic lipid and plasma lipoprotein metabolism to predict metabolic adaptations that are induced upon pharmacological treatment of mice by a Liver X receptor (LXR) agonist. We investigated the excessive accumulation of triglycerides (TG) in the liver resulting in the development of hepatic steatosis. ADAPT predicted that hepatic TG accumulation after LXR activation originates for 80% from an increased influx of free fatty acids. The model also correctly estimated that TG was stored in the cytosol rather than transferred to nascent very-low density lipoproteins. Through model-based integration of temporal metabolic and gene expression data we discovered that increased free fatty acid influx instead of de novo lipogenesis is the main driver of LXR-induced hepatic steatosis. This study illustrates how ADAPT provides estimates for biomedically important parameters that cannot be measured directly, explaining (side-)effects of pharmacological treatment with LXR agonists.

PMID:33665185 | PMC:PMC7921164 | DOI:10.3389/fbioe.2020.536957

Nat Chem Biol. 2021 Mar 4. doi: 10.1038/s41589-021-00742-5. Online ahead of print.

ABSTRACT

The discovery of effective therapeutic treatments for cancer via cell differentiation instead of antiproliferation remains a great challenge. Cyclin-dependent kinase 2 (CDK2) inactivation, which overcomes the differentiation arrest of acute myeloid leukemia (AML) cells, may be a promising method for AML treatment. However, there is no available selective CDK2 inhibitor. More importantly, the inhibition of only the enzymatic function of CDK2 would be insufficient to promote notable AML differentiation. To further validate the role and druggability of CDK2 involved in AML differentiation, a suitable chemical tool is needed. Therefore, we developed first-in-class CDK2-targeted proteolysis-targeting chimeras (PROTACs), which promoted rapid and potent CDK2 degradation in different cell lines without comparable degradation of other targets, and induced remarkable differentiation of AML cell lines and primary patient cells. These data clearly demonstrated the practicality and importance of PROTACs as alternative tools for verifying CDK2 protein functions.

PMID:33664520 | DOI:10.1038/s41589-021-00742-5