Cell Death Dis. 2023 Jul 12;14(7):414. doi: 10.1038/s41419-023-05855-4.

ABSTRACT

The human liver has a remarkable capacity to regenerate and thus compensate over decades for fibrosis caused by toxic chemicals, drugs, alcohol, or malnutrition. To date, no protective mechanisms have been identified that help the liver tolerate these repeated injuries. In this study, we revealed dysregulation of lipid metabolism and mild inflammation as protective mechanisms by studying longitudinal multi-omic measurements of liver fibrosis induced by repeated CCl4 injections in mice (n = 45). Based on comprehensive proteomics, transcriptomics, blood- and tissue-level profiling, we uncovered three phases of early disease development-initiation, progression, and tolerance. Using novel multi-omic network analysis, we identified multi-level mechanisms that are significantly dysregulated in the injury-tolerant response. Public data analysis shows that these profiles are altered in human liver diseases, including fibrosis and early cirrhosis stages. Our findings mark the beginning of the tolerance phase as the critical switching point in liver response to repetitive toxic doses. After fostering extracellular matrix accumulation as an acute response, we observe a deposition of tiny lipid droplets in hepatocytes only in the Tolerant phase. Our comprehensive study shows that lipid metabolism and mild inflammation may serve as biomarkers and are putative functional requirements to resist further disease progression.

PMID:37438332 | DOI:10.1038/s41419-023-05855-4

Semin Cell Dev Biol. 2023 Jul 11:S1084-9521(23)00140-4. doi: 10.1016/j.semcdb.2023.07.001. Online ahead of print.

ABSTRACT

Neurons are remarkably long-lived, non-dividing cells that must maintain their functional features (e.g., electrical properties, chemical signaling) for extended periods of time - decades in humans. How neurons accomplish this incredible feat is poorly understood. Here, we review recent advances, primarily in the nematode C. elegans, that have enhanced our understanding of the molecular mechanisms that enable post-mitotic neurons to maintain their functionality across different life stages. We begin with "terminal selectors" - transcription factors necessary for the establishment and maintenance of neuronal identity. We highlight new findings on five terminal selectors (CHE-1 [Glass], UNC-3 [Collier/Ebf1-4], LIN-39 [Scr/Dfd/Hox4-5], UNC-86 [Acj6/Brn3a-c], AST-1 [Etv1/ER81]) from different transcription factor families (ZNF, COE, HOX, POU, ETS). We compare the functions of these factors in specific neuron types of C. elegans with the actions of their orthologs in other invertebrate (D. melanogaster) and vertebrate (M. musculus) systems, highlighting remarkable functional conservation. Finally, we reflect on recent findings implicating chromatin-modifying proteins, such as histone methyltransferases and Polycomb proteins, in the control of neuronal terminal identity. Altogether, these new studies on transcription factors and chromatin modifiers not only shed light on the fundamental problem of neuronal identity maintenance, but also outline mechanistic principles of gene regulation that may operate in other long-lived, post-mitotic cell types.

PMID:37438210 | DOI:10.1016/j.semcdb.2023.07.001

Plant Physiol Biochem. 2023 Jun 24;201:107857. doi: 10.1016/j.plaphy.2023.107857. Online ahead of print.

ABSTRACT

Climate change significantly impacts crop production by inducing several abiotic and biotic stresses. The increasing world population, and their food and industrial demands require focused efforts to improve crop plants to ensure sustainable food production. Among various modern biotechnological tools, microRNAs (miRNAs) are one of the fascinating tools available for crop improvement. miRNAs belong to a class of small non-coding RNAs playing crucial roles in numerous biological processes. miRNAs regulate gene expression by post-transcriptional target mRNA degradation or by translation repression. Plant miRNAs have essential roles in plant development and various biotic and abiotic stress tolerance. In this review, we provide propelling evidence from previous studies conducted around miRNAs and provide a one-stop review of progress made for breeding stress-smart future crop plants. Specifically, we provide a summary of reported miRNAs and their target genes for improvement of plant growth and development, and abiotic and biotic stress tolerance. We also highlight miRNA-mediated engineering for crop improvement and sequence-based technologies available for the identification of miRNAs associated with stress tolerance and plant developmental events.

PMID:37437345 | DOI:10.1016/j.plaphy.2023.107857

J Chem Inf Model. 2023 Jul 12. doi: 10.1021/acs.jcim.3c00574. Online ahead of print.

ABSTRACT

Due to the complex nature of noncovalent interactions and their long-range effects, analyzing protein conformations using network theory can be enlightening. Protein Structure Networks (PSNs) provide a convenient formalism to study protein structures in relation to essential properties such as key residues for structural stability, allosteric communication, and the effects of modifications of the protein. PSNs can be defined according to very different principles, and the available tools have limitations in input formats, supported models, and version control. Other outstanding problems are related to the definition of network cutoffs and the assessment of the stability of the network properties. The protein science community could benefit from a common framework to carry out these analyses and make them easier to reproduce, reuse, and evaluate. We here provide two open-source software packages, PyInteraph2 and PyInKnife2, to implement and analyze PSNs in a reproducible and documented manner. PyInteraph2 interfaces with multiple formats for protein ensembles and incorporates different network models with the possibility of integrating them into a macronetwork and performing various downstream analyses, including hubs, connected components, and several other centrality measures, and visualizes the networks or further analyzes them thanks to compatibility with Cytoscape.PyInKnife2 that supports the network models implemented in PyInteraph2. It employs a jackknife resampling approach to estimate the convergence of network properties and streamline the selection of distance cutoffs. We foresee that the modular structure of the code and the supported version control system will promote the transition to a community-driven effort, boost reproducibility, and establish common protocols in the PSN field. As developers, we will guarantee the introduction of new functionalities and maintenance, assistance, and training of new contributors.

PMID:37437128 | DOI:10.1021/acs.jcim.3c00574

Sci Adv. 2023 Jul 14;9(28):eadf9336. doi: 10.1126/sciadv.adf9336. Epub 2023 Jul 12.

ABSTRACT

Developing tissues form spatial patterns by establishing concentration gradients of diffusible signaling proteins called morphogens. The bone morphogenetic protein (BMP) morphogen pathway uses a family of extracellular modulators to reshape signaling gradients by actively "shuttling" ligands to different locations. It has remained unclear what circuits are sufficient to enable shuttling, what other patterns they can generate, and whether shuttling is evolutionarily conserved. Here, using a synthetic, bottom-up approach, we compared the spatiotemporal dynamics of different extracellular circuits. Three proteins-Chordin, Twsg, and the BMP-1 protease-successfully displaced gradients by shuttling ligands away from the site of production. A mathematical model explained the different spatial dynamics of this and other circuits. Last, combining mammalian and Drosophila components in the same system suggests that shuttling is a conserved capability. Together, these results reveal principles through which extracellular circuits control the spatiotemporal dynamics of morphogen signaling.

PMID:37436981 | DOI:10.1126/sciadv.adf9336

Inflammopharmacology. 2023 Jul 12. doi: 10.1007/s10787-023-01288-9. Online ahead of print.

ABSTRACT

BACKGROUND: Complementary ozone therapy has been identified as a revolutionary medical technique for a number of goals and ailments. At the present, it has been shown that ozone has medicinal qualities, such as antibacterial, antifungal, and antiparasitic properties. Coronavirus (SARS-CoV-2) is quickly spread over the globe. Cytokine storms and oxidative stress seem to play a substantial role in the most of acute attacks of the disease. The aim of this research was to assess the therapeutic advantages of complementary ozone therapy on the cytokine profile and antioxidant status in COVID-19 patients.

METHODS: The statistical sample of this study included two hundred patients with COVID-19. One hundred COVID-19 patients (treatment group) received 240 ml of the patient's blood and an equal volume of O2/O3 gas at a concentration of 35-50 μg/ml daily, which gradually increased in concentration, and were kept for 5-10 days and one hundred patients (control group) received standard treatment. The secretion levels of IL-6, TNF-α, IL-1β, IL-10 cytokines, SOD, CAT and GPx were compared between control patients (standard treatment) and standard treatment plus intervention (ozone) before and after treatment.

RESULTS: The findings indicated a significant decrease in the level of IL-6, TNF-α, IL-1β in group receiving complementary ozone therapy in compared with control group. Furthermore, a significant increase was found in the level of IL-10 cytokine. Moreover, SOD, CAT and GPx levels revealed a significant increase in complementary ozone therapy group compared to control group.

CONCLUSIONS: Our results revealed that complementary ozone therapy can be used as a medicinal complementary therapy to reduce and control inflammatory cytokines and oxidative stress status in patients with COVID-19 as revealed its antioxidant and anti-inflammatory effects.

PMID:37436523 | DOI:10.1007/s10787-023-01288-9

J Bone Miner Res. 2023 Jul 12. doi: 10.1002/jbmr.4882. Online ahead of print.

ABSTRACT

Genome-wide association studies (GWASs) have advanced our understanding of the genetics of osteoporosis; however, the challenge has been converting associations to causal genes. Studies have utilized transcriptomics data to link disease-associated variants to genes, but few population transcriptomics datasets have been generated on bone at the single-cell level. To address this challenge, we profiled the transcriptomes of bone marrow-derived stromal cells (BMSCs) cultured under osteogenic conditions from five Diversity Outbred (DO) mice using single-cell RNA-seq (scRNA-seq). The goal of the study was to determine if BMSCs could serve as a model to generate cell-type specific transcriptomic profiles of mesenchymal lineage cells from large populations of mice to inform genetic studies. By enriching for mesenchymal lineage cells in vitro, coupled with pooling of multiple samples and downstream genotype deconvolution, we demonstrate the scalability of this model for population-level studies. We demonstrate that dissociation of BMSCs from a heavily mineralized matrix had little effect on viability or their transcriptomic signatures. Furthermore, we show that BMSCs cultured under osteogenic conditions are diverse and consist of cells with characteristics of mesenchymal progenitors, marrow adipogenic lineage precursors (MALPs), osteoblasts, osteocyte-like cells, and immune cells. Importantly, all cells were similar from a transcriptomic perspective to cells isolated in vivo. We employed scRNA-seq analytical tools to confirm the biological identity of profiled cell-types. SCENIC was used to reconstruct gene regulatory networks (GRNs) and we showed that cell-types show GRNs expected of osteogenic and pre-adipogenic lineage cells. Further, CELLECT analysis showed that osteoblasts, osteocyte-like cells, and MALPs captured a significant component of bone mineral density (BMD) heritability. Together, these data suggest that BMSCs cultured under osteogenic conditions coupled with scRNA-seq can be used as a scalable and biologically-informative model to generate cell-type specific transcriptomic profiles of mesenchymal lineage cells in large populations. This article is protected by copyright. All rights reserved.

PMID:37436066 | DOI:10.1002/jbmr.4882

Elife. 2023 Jul 12;12:e84881. doi: 10.7554/eLife.84881. Online ahead of print.

ABSTRACT

For HIV virions to become infectious, the immature lattice of Gag polyproteins attached to the virion membrane must be cleaved. Cleavage cannot initiate without the protease formed by the homo-dimerization of domains linked to Gag. However, only 5% of the Gag polyproteins, termed Gag-Pol, carry this protease domain, and they are embedded within the structured lattice. The mechanism of Gag-Pol dimerization is unknown. Here, we use spatial stochastic computer simulations of the immature Gag lattice as derived from experimental structures, showing that dynamics of the lattice on the membrane is unavoidable due to the missing 1/3 of the spherical protein coat. These dynamics allow for Gag-Pol molecules carrying the protease domains to detach and reattach at new places within the lattice. Surprisingly, dimerization timescales of minutes or less are achievable for realistic binding energies and rates despite retaining most of the large-scale lattice structure. We derive a formula allowing extrapolation of timescales as a function of interaction free energy and binding rate, thus predicting how additional stabilization of the lattice would impact dimerization times. We further show that during assembly, dimerization of Gag-Pol is highly likely and therefore must be actively suppressed to prevent early activation. By direct comparison to recent biochemical measurements within budded virions, we find that only moderately stable hexamer contacts (-12kBT<∆G<-8kBT) retain both the dynamics and lattice structures that are consistent with experiment. These dynamics are likely essential for proper maturation, and our models quantify and predict lattice dynamics and protease dimerization timescales that define a key step in understanding formation of infectious viruses.

PMID:37435945 | DOI:10.7554/eLife.84881

J Biomol Tech. 2023 Jun 2;34(2):3fc1f5fe.9b78d780. doi: 10.7171/3fc1f5fe.9b78d780. eCollection 2023 Jul 1.

ABSTRACT

Despite the advantages of fewer missing values by collecting fragment ion data on all analytes in the sample as well as the potential for deeper coverage, the adoption of data-independent acquisition (DIA) in proteomics core facility settings has been slow. The Association of Biomolecular Resource Facilities conducted a large interlaboratory study to evaluate DIA performance in proteomics laboratories with various instrumentation. Participants were supplied with generic methods and a uniform set of test samples. The resulting 49 DIA datasets act as benchmarks and have utility in education and tool development. The sample set consisted of a tryptic HeLa digest spiked with high or low levels of 4 exogenous proteins. Data are available in MassIVE MSV000086479. Additionally, we demonstrate how the data can be analyzed by focusing on 2 datasets using different library approaches and show the utility of select summary statistics. These data can be used by DIA newcomers, software developers, or DIA experts evaluating performance with different platforms, acquisition settings, and skill levels.

PMID:37435391 | PMC:PMC10332336 | DOI:10.7171/3fc1f5fe.9b78d780

Transfus Med Hemother. 2023 Mar 8;50(3):174-183. doi: 10.1159/000529744. eCollection 2023 Jun.

ABSTRACT

BACKGROUND: Blood transfusion is a life-saving intervention for millions of recipients worldwide. Over the last 15 years, the advent of high-throughput, affordable omics technologies - including genomics, proteomics, lipidomics, and metabolomics - has allowed transfusion medicine to revisit the biology of blood donors, stored blood products, and transfusion recipients.

SUMMARY: Omics approaches have shed light on the genetic and non-genetic factors (environmental or other exposures) impacting the quality of stored blood products and efficacy of transfusion events, based on the current Food and Drug Administration guidelines (e.g., hemolysis and post-transfusion recovery for stored red blood cells). As a treasure trove of data accumulates, the implementation of machine learning approaches promises to revolutionize the field of transfusion medicine, not only by advancing basic science. Indeed, computational strategies have already been used to perform high-content screenings of red blood cell morphology in microfluidic devices, generate in silico models of erythrocyte membrane to predict deformability and bending rigidity, or design systems biology maps of the red blood cell metabolome to drive the development of novel storage additives.

KEY MESSAGE: In the near future, high-throughput testing of donor genomes via precision transfusion medicine arrays and metabolomics of all donated products will be able to inform the development and implementation of machine learning strategies that match, from vein to vein, donors, optimal processing strategies (additives, shelf life), and recipients, realizing the promise of personalized transfusion medicine.

PMID:37434999 | PMC:PMC10331163 | DOI:10.1159/000529744

Front Microbiol. 2023 Jun 26;14:1176751. doi: 10.3389/fmicb.2023.1176751. eCollection 2023.

ABSTRACT

Determining which microorganisms are active within soil communities remains a major technical endeavor in microbial ecology research. One promising method to accomplish this is coupling bioorthogonal non-canonical amino acid tagging (BONCAT) with fluorescence activated cell sorting (FACS) which sorts cells based on whether or not they are producing new proteins. Combined with shotgun metagenomic sequencing (Seq), we apply this method to profile the diversity and potential functional capabilities of both active and inactive microorganisms in a biocrust community after being resuscitated by a simulated rain event. We find that BONCAT-FACS-Seq is capable of discerning the pools of active and inactive microorganisms, especially within hours of applying the BONCAT probe. The active and inactive components of the biocrust community differed in species richness and composition at both 4 and 21 h after the wetting event. The active fraction of the biocrust community is marked by taxa commonly observed in other biocrust communities, many of which play important roles in species interactions and nutrient transformations. Among these, 11 families within the Firmicutes are enriched in the active fraction, supporting previous reports indicating that the Firmicutes are key early responders to biocrust wetting. We highlight the apparent inactivity of many Actinobacteria and Proteobacteria through 21 h after wetting, and note that members of the Chitinophagaceae, enriched in the active fraction, may play important ecological roles following wetting. Based on the enrichment of COGs in the active fraction, predation by phage and other bacterial members, as well as scavenging and recycling of labile nutrients, appear to be important ecological processes soon after wetting. To our knowledge, this is the first time BONCAT-FACS-Seq has been applied to biocrust samples, and therefore we discuss the potential advantages and shortcomings of coupling metagenomics to BONCAT to intact soil communities such as biocrust. In all, by pairing BONCAT-FACS and metagenomics, we are capable of highlighting the taxa and potential functions that typifies the microbes actively responding to a rain event.

PMID:37434715 | PMC:PMC10330726 | DOI:10.3389/fmicb.2023.1176751

Eur J Pharmacol. 2023 Jul 9:175883. doi: 10.1016/j.ejphar.2023.175883. Online ahead of print.

ABSTRACT

BACKGROUND: Lung adenocarcinoma (LUAD) has high morbidity and is prone to recurrence. TIMELESS (TIM), which regulates circadian rhythms in Drosophila, is highly expressed in various tumors. Its role in LUAD has gained attention, but the detailed function and mechanism have not been clarified completely at present.

METHODS: Tumor samples from patients with LUAD patient data from public databases were used to confirm the relationship of TIM expression with lung cancer. LUAD cell lines were used and siRNA of TIM was adopted to knock down TIM expression in LUAD cells, and further cell proliferation, migration and colony formation were analyzed. By using Western blot and qPCR, we detected the influence of TIM on epidermal growth factor receptor (EGFR), sphingosine kinase 1 (SPHK1) and AMP-activated protein kinase (AMPK). With proteomics analysis, we comprehensively inspected the different changed proteins influenced by TIM and did global bioinformatic analysis.

RESULTS: We found that TIM expression was elevated in LUAD and that this high expression was positively correlated with more advanced tumor pathological stages and shorter overall and disease-free survival. TIM knockdown inhibited EGFR activation and also AKT/mTOR phosphorylation. We also clarified that TIM regulated the activation of SPHK1 in LUAD cells. And with SPHK1 siRNA to knock down the expression level of SPHK1, we found that EGFR activation were inhibited greatly too. Quantitative proteomics techniques combined with bioinformatics analysis clarified the global molecular mechanisms regulated by TIM in LUAD. The results of proteomics suggested that mitochondrial translation elongation and termination were altered, which were closely related to the process of mitochondrial oxidative phosphorylation. We further confirmed that TIM knockdown reduced ATP content and promoted AMPK activation in LUAD cells.

CONCLUSIONS: Our study revealed that siTIM could inhibited EGFR activation through activating AMPK and inhibiting SPHK1 expression, as well as influencing mitochondrial function and alter the ATP level; TIM's high expression in LUAD is an important factor and a potential key target in LUAD.

PMID:37433364 | DOI:10.1016/j.ejphar.2023.175883

BMC Microbiol. 2023 Jul 11;23(1):182. doi: 10.1186/s12866-023-02931-9.

ABSTRACT

BACKGROUND: It has been demonstrated in the literature that a dysbiotic microbiome could have a negative impact on the host immune system and promote disease onset or exacerbation. Co-occurrence networks have been widely adopted to identify biomarkers and keystone taxa in the pathogenesis of microbiome-related diseases. Despite the promising results that network-driven approaches have led to in various human diseases, there is a dearth of research pertaining to key taxa that contribute to the pathogenesis of lung cancer. Therefore, our primary goal in this study is to explore co-existing relationships among members of the lung microbial community and any potential gained or lost interactions in lung cancer.

RESULTS: Using integrative and network-based approaches, we integrated four studies assessing the microbiome of lung biopsies of cancer patients. Differential abundance analyses showed that several bacterial taxa are different between tumor and tumor-adjacent normal tissues (FDR adjusted p-value < 0.05). Four, fifteen, and twelve significantly different associations were found at phylum, family, and genus levels. Diversity analyses suggested reduced alpha diversity in the tumor microbiome. However, beta diversity analysis did not show any discernible pattern between groups. In addition, four distinct modules of bacterial families were detected by the DBSCAN clustering method. Finally, in the co-occurrence network context, Actinobacteria, Firmicutes, Bacteroidetes, and Chloroflexi at the phylum level and Bifidobacterium, Massilia, Sphingobacterium, and Ochrobactrum at the genus level showed the highest degree of rewiring.

CONCLUSIONS: Despite the absence of statistically significant differences in the relative abundance of certain taxa between groups, it is imperative not to overlook them for further exploration. This is because they may hold pivotal central roles in the broader network of bacterial taxa (e.g., Bifidobacterium and Massilia). These findings emphasize the importance of a network analysis approach for studying the lung microbiome since it could facilitate identifying key microbial taxa in lung cancer pathogenesis. Relying exclusively on differentially abundant taxa may not be enough to fully grasp the complex interplay between lung cancer and the microbiome. Therefore, a network-based approach can offer deeper insights and a more comprehensive understanding of the underlying mechanisms.

PMID:37434142 | DOI:10.1186/s12866-023-02931-9

Nat Methods. 2023 Jul;20(7):971-972. doi: 10.1038/s41592-023-01910-2.

NO ABSTRACT

PMID:37433997 | DOI:10.1038/s41592-023-01910-2

Sci Rep. 2023 Jul 11;13(1):11225. doi: 10.1038/s41598-023-38444-8.

ABSTRACT

Depression is a common mental disease, with some patients exhibiting ideas and behaviors such as self-harm and suicide. The drugs currently used to treat depression have not achieved good results. It has been reported that metabolites produced by intestinal microbiota affect the development of depression. In this study, core targets and core compounds were screened by specific algorithms in the database, and three-dimensional structures of these compounds and proteins were simulated by molecular docking and molecular dynamics software to further study the influence of intestinal microbiota metabolites on the pathogenesis of depression. By analyzing the RMSD gyration radius and RMSF, it was finally determined that NR1H4 had the best binding effect with genistein. Finally, according to Lipinski's five rules, equol, genistein, quercetin and glycocholic acid were identified as effective drugs for the treatment of depression. In conclusion, the intestinal microbiota can affect the development of depression through the metabolites equol, genistein and quercetin, which act on the critical targets of DPP4, CYP3A4, EP300, MGAM and NR1H4.

PMID:37433869 | DOI:10.1038/s41598-023-38444-8

Nat Commun. 2023 Jul 11;14(1):4100. doi: 10.1038/s41467-023-38816-8.

ABSTRACT

Beginning in May 2022, Mpox virus spread rapidly in high-income countries through close human-to-human contact primarily amongst communities of gay, bisexual and men who have sex with men (GBMSM). Behavioural change arising from increased knowledge and health warnings may have reduced the rate of transmission and modified Vaccinia-based vaccination is likely to be an effective longer-term intervention. We investigate the UK epidemic presenting 26-week projections using a stochastic discrete-population transmission model which includes GBMSM status, rate of formation of new sexual partnerships, and clique partitioning of the population. The Mpox cases peaked in mid-July; our analysis is that the decline was due to decreased transmission rate per infected individual and infection-induced immunity among GBMSM, especially those with the highest rate of new partners. Vaccination did not cause Mpox incidence to turn over, however, we predict that a rebound in cases due to behaviour reversion was prevented by high-risk group-targeted vaccination.

PMID:37433797 | DOI:10.1038/s41467-023-38816-8

Plant Cell. 2023 Jul 11:koad196. doi: 10.1093/plcell/koad196. Online ahead of print.

ABSTRACT

Changes in cytosolic calcium (Ca2+) concentration are among the earliest reactions to a multitude of stress cues. While a plethora of Ca2+-permeable channels may generate distinct Ca2+ signatures and contribute to response specificities, the mechanisms by which Ca2+ signatures are decoded are poorly understood. Here we developed a genetically encoded FRET (Förster resonance energy transfer)-based reporter that visualizes the conformational changes in Ca2+-dependent protein kinases (CDPKs/CPKs). We focused on two CDPKs with distinct Ca2+-sensitivities, highly Ca2+-sensitive Arabidopsis (Arabidopsis thaliana) AtCPK21 and rather Ca2+-insensitive AtCPK23, to report conformational changes accompanying kinase activation. In tobacco (Nicotiana tabacum) pollen tubes, which naturally display coordinated spatial and temporal Ca2+ fluctuations, CPK21-FRET, but not CPK23-FRET, reported oscillatory emission ratio changes mirroring cytosolic Ca2+ changes, pointing to the isoform-specific Ca2+-sensitivity and reversibility of the conformational change. In Arabidopsis guard cells, CPK21-FRET-monitored conformational dynamics suggest that CPK21 serves as a decoder of signal-specific Ca2+ signatures in response to abscisic acid and the flagellin peptide flg22. Based on these data, CDPK-FRET is a powerful approach for tackling real-time live-cell Ca2+ decoding in a multitude of plant developmental and stress responses.

PMID:37433056 | DOI:10.1093/plcell/koad196

Cardiovasc Res. 2023 Jul 11:cvad107. doi: 10.1093/cvr/cvad107. Online ahead of print.

ABSTRACT

BACKGROUND: Myocardial infarction is a major cause of death worldwide. Effective treatments are required to improve recovery of cardiac function following myocardial infarction, with the aim of improving patient outcomes and preventing progression to heart failure. The perfused but hypocontractile region bordering an infarct is functionally distinct from the remote surviving myocardium and is a determinant of adverse remodelling and cardiac contractility. Expression of the transcription factor RUNX1 is increased in the border zone 1-day after myocardial infarction, suggesting potential for targeted therapeutic intervention.

OBJECTIVE: This study sought to investigate whether an increase in RUNX1 in the border zone can be therapeutically targeted to preserve contractility following MI.

METHODS AND RESULTS: Here we demonstrate that Runx1 drives reductions in cardiomyocyte contractility, calcium handling, mitochondrial density, and expression of genes important for oxidative phosphorylation. Both tamoxifen-inducible Runx1-deficient and essential co-factor Cbfβ-deficient cardiomyocyte-specific mouse models demonstrated that antagonising RUNX1 function preserves the expression of genes important for oxidative phosphorylation following myocardial infarction. Antagonising RUNX1 expression via short-hairpin RNA interference preserved contractile function following myocardial infarction. Equivalent effects were obtained with a small molecule inhibitor (Ro5-3335) that reduces RUNX1 function by blocking its interaction with CBFβ.

CONCLUSIONS: Our results confirm the translational potential of RUNX1 as a novel therapeutic target in myocardial infarction, with wider opportunities for use across a range of cardiac diseases where RUNX1 drives adverse cardiac remodelling.

PMID:37433039 | DOI:10.1093/cvr/cvad107

Elife. 2023 Jul 11;12:e84969. doi: 10.7554/eLife.84969. Online ahead of print.

ABSTRACT

A key problem in development is to understand how genes turn on or off at the right place and right time during embryogenesis. Such decisions are made by non-coding sequences called 'enhancers'. Much of our models of how enhancers work rely on the assumption that genes are activated de novo as stable domains across embryonic tissues. Such view has been strengthened by the intensive landmark studies of the early patterning of the anterior-posterior (AP) axis of the Drosophila embryo, where indeed gene expression domains seem to arise more or less stably. However, careful analysis of gene expression patterns in other model systems (including the AP patterning in vertebrates and short-germ insects like the beetle Tribolium castaneum) painted a different, very dynamic view of gene regulation, where genes are oftentimes expressed in a wavelike fashion. How such gene expression waves are mediated at the enhancer level is so far unclear. Here we establish the AP patterning of the short-germ beetle Tribolium as a model system to study dynamic and temporal pattern formation at the enhancer level. To that end, we established an enhancer prediction system in Tribolium based on time- and tissue-specific ATAC-seq and an enhancer live reporter system based on MS2 tagging. Using this experimental framework, we discovered several Tribolium enhancers, and assessed the spatiotemporal activities of some of them in live embryos. We found our data consistent with a model in which the timing of gene expression during embryonic pattern formation is mediated by a balancing act between enhancers that induce rapid changes in gene expression patterns (that we call 'dynamic enhancers') and enhancers that stabilizes gene expression patterns (that we call 'static enhancers'). However, more data is needed for a strong support for this or any other alternative models.

PMID:37432987 | DOI:10.7554/eLife.84969

Adv Wound Care (New Rochelle). 2023 Jul 11. doi: 10.1089/wound.2023.0036. Online ahead of print.

ABSTRACT

OBJECTIVE: Pseudomonas aeruginosa is an opportunistic pathogen that can establish chronic infections and form biofilm in wounds. Because the wound environment is largely devoid of oxygen, P. aeruginosa may rely on anaerobic metabolism, such as nitrate respiration, to survive in wounds. While nitrate reductase (Nar) typically reduces nitrate to nitrite, it can also reduce chlorate to chlorite which is a toxic oxidizing agent. Therefore, chlorate can act as a pro-drug to specifically eradicate hypoxic/anoxic, nitrate-respiring P. aeruginosa populations, which are often tolerant to conventional antibiotic treatments.

APPROACH: Using a diabetic mouse model for chronic wounds, we tested the role that anaerobic nitrate respiration plays in supporting chronic P. aeruginosa infections.

RESULTS: P. aeruginosa forms biofilm deep within the wound where the environment is anoxic. Daily treatment of P. aeruginosa-infected wounds with chlorate supported wound healing. Chlorate treatment was as effective as treatment with ciprofloxacin (a conventional antibiotic that targets both oxic and hypoxic/anoxic P. aeruginosa populations). Chlorate-treated wounds showed markers of good-quality wound healing, including well-formed granulation tissue, reepitheliazation and microvessel development. Loss- and gain-of-function experiments showed that P. aeruginosa requires nitrate respiration to establish a chronic wound infection and form biofilms.

INNOVATION: We show that the small molecule chlorate, kills the opportunistic pathogen, Pseudomonas aeruginosa, by targeting a form of anaerobic metabolism called nitrate respiration.

CONCLUSION: Chlorate holds promise as a treatment to combat diverse bacterial infections where oxygen is limiting and/or where pathogens grow as biofilms because many other pathogens have nitrate reductases and survive using anaerobic metabolism.

PMID:37432895 | DOI:10.1089/wound.2023.0036