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Integrative multiomics can help elucidate the pathophysiology of pulmonary fibrosis (PF) associated pulmonary hypertension (PH) (PF-PH). Weighted gene co-expression network analysis (WGCNA) was performed on a transcriptomic dataset of explanted lung tissue from 116 patients with PF. Patients were stratified by pulmonary vascular resistance (PVR) and differential gene expression analysis was conducted. Gene modules were correlated with hemodynamics at the time of transplantation and tested for enrichment in the lung transcriptomics signature of an independent pulmonary arterial hypertension (PAH) cohort. We found 1,250 differentially expressed genes between high and low PVR groups. WGCNA identified that black and yellowgreen modules negatively correlated with PVR, while the tan and darkgrey modules positively correlated with PVR. Additionally, the tan module showed the strongest enrichment for an independent PAH gene signature, suggesting shared gene expression patterns between PAH and PF-PH. Pharmacotranscriptomic analysis using the Connectivity Map implicated the tan and darkgrey modules as potentially pathogenic in PF-PH, given their combined module signature demonstrated a high negative connectivity score for Treprostinil, a medication used in the treatment of PF-PH, and a high positive connectivity score for Bone morphogenetic protein loss of function. Pathway enrichment analysis revealed that inflammatory pathways and oxidative phosphorylation were downregulated, whereas epithelial mesenchymal transition was upregulated in modules associated with increased PVR. Our integrative systems biology approach to the lung transcriptome of PF with and without PH identified several PH-associated co-expression modules and gene targets with shared molecular features with PAH warranting further investigation to uncover potential new therapies for PF-PH.
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Tumor cell heterogeneity defines therapy responsiveness in neuroblastoma (NB), a cancer derived from neural crest cells. NB consists of two primary subtypes: adrenergic and mesenchymal. Adrenergic traits predominate in NB tumors, while mesenchymal features becomes enriched post-chemotherapy or after relapse. The interconversion between these subtypes contributes to NB lineage plasticity, but the underlying mechanisms driving this phenotypic switching remain unclear. Here, we demonstrate that SWI/SNF chromatin remodeling complex ATPases are essential in establishing an mesenchymal gene-permissive chromatin state in adrenergic-type NB, facilitating lineage plasticity. Targeting SWI/SNF ATPases with SMARCA2/4 dual degraders effectively inhibits NB cell proliferation, invasion, and notably, cellular plasticity, thereby preventing chemotherapy resistance. Mechanistically, depletion of SWI/SNF ATPases compacts cis-regulatory elements, diminishes enhancer activity, and displaces core transcription factors (MYCN, HAND2, PHOX2B, and GATA3) from DNA, thereby suppressing transcriptional programs associated with plasticity. These findings underscore the pivotal role of SWI/SNF ATPases in driving intrinsic plasticity and therapy resistance in neuroblastoma, highlighting an epigenetic target for combinational treatments in this cancer.
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BACKGROUND: Integrative multiomics can elucidate pulmonary arterial hypertension (PAH) pathobiology, but procuring human PAH lung samples is rare. METHODS: We leveraged transcriptomic profiling and deep phenotyping of the largest multicenter PAH lung biobank to date (96 disease and 52 control) by integration with clinicopathologic data, genome-wide association studies, Bayesian regulatory networks, single-cell transcriptomics, and pharmacotranscriptomics. RESULTS: We identified 2 potentially protective gene network modules associated with vascular cells, and we validated ASPN, coding for asporin, as a key hub gene that is upregulated as a compensatory response to counteract PAH. We found that asporin is upregulated in lungs and plasma of multiple independent PAH cohorts and correlates with reduced PAH severity. We show that asporin inhibits proliferation and transforming growth factor-ß/phosphorylated SMAD2/3 signaling in pulmonary artery smooth muscle cells from PAH lungs. We demonstrate in Sugen-hypoxia rats that ASPN knockdown exacerbated PAH and recombinant asporin attenuated PAH. CONCLUSIONS: Our integrative systems biology approach to dissect the PAH lung transcriptome uncovered asporin as a novel protective target with therapeutic potential in PAH.
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The foundation of most food production systems underpinning global food security is the careful management of soil resources. Embedded in the concept of soil health is the impact of diverse soil-borne pests and pathogens, and phytoparasitic nematodes represent a particular challenge. Root-knot nematodes and cyst nematodes are severe threats to agriculture, accounting for annual yield losses of US$157 billion. The control of soil-borne phytoparasitic nematodes conventionally relies on the use of chemical nematicides, which can have adverse effects on the environment and human health due to their persistence in soil, plants, and water. Nematode-resistant plants offer a promising alternative, but genetic resistance is species-dependent, limited to a few crops, and breeding and deploying resistant cultivars often takes years. Novel approaches for the control of phytoparasitic nematodes are therefore required, those that specifically target these parasites in the ground whilst minimizing the impact on the environment, agricultural ecosystems, and human health. In addition to the development of next-generation, environmentally safer nematicides, promising biochemical strategies include the combination of RNA interference (RNAi) with nanomaterials that ensure the targeted delivery and controlled release of double-stranded RNA. Genome sequencing has identified more than 75 genes in root knot and cyst nematodes that have been targeted with RNAi so far. But despite encouraging results, the delivery of dsRNA to nematodes in the soil remains inefficient. In this review article, we describe the state-of-the-art RNAi approaches targeting phytoparasitic nematodes and consider the potential benefits of nanotechnology to improve dsRNA delivery.
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Nanotecnología , Nematodos , Enfermedades de las Plantas , Animales , Nematodos/fisiología , Nanotecnología/métodos , Enfermedades de las Plantas/parasitología , Enfermedades de las Plantas/prevención & control , Productos Agrícolas/parasitología , Productos Agrícolas/genética , Interferencia de ARNRESUMEN
Background: Pulmonary hypertension (PH)-induced right ventricular (RV) failure (PH-RVF) is a significant prognostic determinant of mortality and is characterized by RV hypertrophy, endothelial-to-mesenchymal transition (EndMT), fibroblast-to-myofibroblast transition (FMT), fibrosis, and extracellular matrix (ECM)-remodeling. Despite the importance of RV function in PH, the mechanistic details of PH-RVF, especially the regulatory control of RV EndMT, FMT, and fibrosis, remain unclear. The action of transcription factor Snai1 is shown to be mediated through LOXL2 recruitment, and their co-translocation to the nucleus, during EndMT progression. We hypothesize that RV EndMT and fibrosis in PH-RVF are governed by the TGFß1-Snai1-LOXL2 axis. Furthermore, targeting Snai1 could serve as a novel therapeutic strategy for PH-RVF. Methods: Adult male Sprague Dawley rats (250-300g) received either a single subcutaneous injection of Monocrotaline (MCT, 60mg/kg, n=9; followed for 30-days) or Sugen (SU5416 20mg/kg, n=9; 10% O 2 hypoxia for 3-weeks followed by normoxia for 2-weeks) or PBS (CTRL, n=9). We performed secondary bioinformatics analysis on the RV bulk RNA-Seq data from MCT, SuHx, and PAB rats and human PH-PVF. We validated EndMT and FMT and their association with Snai1 and LOXL2 in the RVs of MCT and SuHx rat models and human PH-RVF using immunofluorescence, qPCR, and Western blots. For in vivo Snai1 knockdown (Snai1-KD), MCT-rats either received Snai1-siRNA (n=7; 5nM/injection every 3-4 days; 4-injections) or scramble (SCRM-KD; n=7) through tail vein from day 14-30 after MCT. Echocardiography and catheterization were performed terminally. Bulk RNASeq and differential expression analysis were performed on Snai1- and SCRM-KD rat RVs. In vitro Snai1-KD was performed on human coronary artery endothelial cells (HCAECs) and human cardiac fibroblasts (HCFs) under hypoxia+TGFß1 for 72-hrs. Results: PH-RVF had increased RVSP and Fulton index and decreased RV fractional area change (RVFAC %). RV RNASeq demonstrated EndMT as the common top-upregulated pathway between rat (MCT, SuHx, and PAB) and human PH-RVF. Immunofluorescence using EndMT- and FMT-specific markers demonstrated increased EndMT and FMT in RV of MCT and SuHx rats and PH-RVF patients. Further, RV expression of TGFß1, Snai1, and LOXL2 was increased in MCT and SuHx. Nuclear co-localization and increased immunoreactivity, transcript, and protein levels of Snai1 and LOXL2 were observed in MCT and SuHx rats and human RVs. MCT rats treated with Snai1-siRNA demonstrated decreased Snai1 expression, RVSP, Fulton index, and increased RVFAC. Snai1-KD resulted in decreased RV-EndMT, FMT, and fibrosis via a LOXL2-dependent manner. Further, Snai1-KD inhibited hypoxia+TGFß1-induced EndMT in HCAECs and FMT in HCFs in vitro by decreasing perinuclear/nuclear Snai1+LOXL2 expression and co-localization. Conclusions: RV-specific targeting of Snai1 rescues PH-RVF by inhibiting EndMT and Fibrosis via a LOXL2-mediated mechanism.
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This review examines how single-cell omics technologies, particularly single-cell RNA sequencing (scRNAseq), enhance our understanding of pulmonary arterial hypertension (PAH). PAH is a multifaceted disorder marked by pulmonary vascular remodeling, leading to high morbidity and mortality. The cellular pathobiology of this heterogeneous disease, involving various vascular and non-vascular cell types, is not fully understood. Traditional PAH studies have struggled to resolve the complexity of pathogenic cell populations. scRNAseq offers a refined perspective by detailing cellular diversity within PAH, identifying unique cell subsets, gene networks, and molecular pathways that drive the disease. We discuss significant findings from recent literature, summarizing how scRNAseq has shifted our understanding of PAH in human, rat, and mouse models. This review highlights the insights gained into cellular phenotypes, gene expression patterns, and novel molecular targets, and contemplates the challenges and prospective paths for research. We propose ways in which single-cell omics could inform future research and translational efforts to combat PAH.
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Análisis de la Célula Individual , Humanos , Animales , Análisis de la Célula Individual/métodos , Hipertensión Arterial Pulmonar/genética , Hipertensión Arterial Pulmonar/metabolismo , Hipertensión Arterial Pulmonar/fisiopatología , Hipertensión Arterial Pulmonar/patología , Análisis de Secuencia de ARN/métodos , Hipertensión Pulmonar/genética , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/patologíaRESUMEN
Rationale: Idiopathic pulmonary arterial hypertension (IPAH) is characterized by extensive pulmonary vascular remodeling caused by plexiform and obliterative lesions, media hypertrophy, inflammatory cell infiltration, and alterations of the adventitia. Objective: We sought to test the hypothesis that microscopic IPAH vascular lesions express unique molecular profiles, which collectively are different from control pulmonary arteries. Methods: We used digital spatial transcriptomics to profile the genomewide differential transcriptomic signature of key pathological lesions (plexiform, obliterative, intima+media hypertrophy, and adventitia) in IPAH lungs (n = 11) and compared these data with the intima+media hypertrophy and adventitia of control pulmonary artery (n = 5). Measurements and Main Results: We detected 8,273 transcripts in the IPAH lesions and control lung pulmonary arteries. Plexiform lesions and IPAH adventitia exhibited the greatest number of differentially expressed genes when compared with intima+media hypertrophy and obliterative lesions. Plexiform lesions in IPAH showed enrichment for 1) genes associated with transforming growth factor ß signaling and 2) mutated genes affecting the extracellular matrix and endothelial-mesenchymal transformation. Plexiform lesions and IPAH adventitia showed upregulation of genes involved in immune and IFN signaling, coagulation, and complement pathways. Cellular deconvolution indicated variability in the number of vascular and inflammatory cells between IPAH lesions, which underlies the differential transcript profiling. Conclusions: IPAH lesions express unique molecular transcript profiles enriched for pathways involving pathogenetic pathways, including genetic disease drivers, innate and acquired immunity, hypoxia sensing, and angiogenesis signaling. These data provide a rich molecular-structural framework in IPAH vascular lesions that inform novel biomarkers and therapeutic targets in this highly morbid disease.
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Arteria Pulmonar , Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Arteria Pulmonar/patología , Remodelación Vascular/genética , Perfilación de la Expresión Génica/métodos , Hipertensión Arterial Pulmonar/genética , Transcriptoma/genética , Hipertensión Pulmonar Primaria Familiar/genética , Hipertensión Pulmonar Primaria Familiar/fisiopatologíaRESUMEN
MYCN activates canonical MYC targets involved in ribosome biogenesis, protein synthesis, and represses neuronal differentiation genes to drive oncogenesis in neuroblastoma (NB). How MYCN orchestrates global gene expression remains incompletely understood. Our study finds that MYCN binds promoters to up-regulate canonical MYC targets but binds to both enhancers and promoters to repress differentiation genes. MYCN binding also increases H3K4me3 and H3K27ac on canonical MYC target promoters and decreases H3K27ac on neuronal differentiation gene enhancers and promoters. WDR5 facilitates MYCN promoter binding to activate canonical MYC target genes, whereas MYCN recruits G9a to enhancers to repress neuronal differentiation genes. Targeting both MYCN's active and repressive transcriptional activities using both WDR5 and G9a inhibitors synergistically suppresses NB growth. We demonstrate that MYCN cooperates with WDR5 and G9a to orchestrate global gene transcription. The targeting of both these cofactors is a novel therapeutic strategy to indirectly target the oncogenic activity of MYCN.
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Transformación Celular Neoplásica , Proteínas Nucleares , Humanos , Proteínas Nucleares/metabolismo , Proteína Proto-Oncogénica N-Myc/genética , Proteína Proto-Oncogénica N-Myc/metabolismo , Histona Metiltransferasas/genética , Línea Celular Tumoral , Transformación Celular Neoplásica/genética , Carcinogénesis/genética , Regulación Neoplásica de la Expresión Génica , Transcripción Genética , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismoRESUMEN
The loss of the soil fumigant methyl bromide (MeBr) and adoption of soil fumigant alternatives has been challenging for farmers, particularly for those crops in which pathogens previously controlled by MeBr have emerged as significant problems, but it has resulted in some unanticipated benefits for the scientific community and the environment. Applauded as one of the most effective environmental agreements to date, the universally accepted Montreal Protocol on Ozone Depleting Substances has had a significant impact on the environment, reducing the release of halogenated compounds from anthropogenic sources enough to mitigate global warming by an estimated 1.1°C by 2021. The funding associated with various MeBr transition programs has increased collaboration across scientific disciplines, commodity groups, industry, and regulatory agencies. Chemical alternatives and improved application strategies, including the development of gas-retentive agricultural films, coupled with sound efficacy data and grower ingenuity have resulted in the sustained production of many of the impacted crops; although there has been some loss of acreage and value, particularly for Florida fumigated crops, for some, value has continued to increase, allowing production to continue. The loss of a single, broad-spectrum tool for pest control has led to a deeper understanding of the specific pest complexes impacting these at-risk crops, as well as the development of new, biologically based management tools for their control while increasing our understanding of the role of the soil microbiome in pest control and crop production.
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Fumigación , Hidrocarburos Bromados , Suelo , Suelo/química , Productos Agrícolas/microbiología , Agricultura , Enfermedades de las Plantas/prevención & control , Enfermedades de las Plantas/microbiologíaRESUMEN
Gene expression is under tight regulation from the chromatin structure that regulates gene accessibility by the transcription machinery to protein degradation. At the transcript level, this regulation falls on RNA-binding proteins (RBPs). RBPs are a large and diverse class of proteins involved in all aspects of a transcript's lifecycle: splicing and maturation, localization, stability, and translation. In the past few years, our understanding of the role of RBPs in cardiovascular diseases has expanded. Here, we discuss the general structure and function of RBPs and the latest discoveries of their role in pulmonary and systemic cardiovascular diseases.
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Enfermedades Cardiovasculares , Humanos , Enfermedades Cardiovasculares/genética , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Empalme del ARNRESUMEN
MYCN activates canonical MYC targets involved in ribosome biogenesis, protein synthesis and represses neuronal differentiation genes to drive oncogenesis in neuroblastoma (NB). How MYCN orchestrates global gene expression remains incompletely understood. Our study finds that MYCN binds promoters to up-regulate canonical MYC targets but binds to both enhancers and promoters to repress differentiation genes. MYCN-binding also increases H3K4me3 and H3K27ac on canonical MYC target promoters and decreases H3K27ac on neuronal differentiation gene enhancers and promoters. WDR5 is needed to facilitate MYCN promoter binding to activate canonical MYC target genes, whereas MYCN recruits G9a to enhancers to repress neuronal differentiation genes. Targeting both MYCN's active and repressive transcriptional activities using both WDR5 and G9a inhibitors synergistically suppresses NB growth. We demonstrate that MYCN cooperates with WDR5 and G9a to orchestrate global gene transcription. The targeting of both these cofactors is a novel therapeutic strategy to indirectly target the oncogenic activity of MYCN.
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Introduction: Originally regarded as garnish greens, microgreens are increasingly valued for their nutritional profile, including their mineral content. Methods: A study was conducted under controlled environmental conditions utilizing a selection of seventeen microgreen species belonging to seven different botanical families to investigate the genetic variation of macro- and micro-minerals and nitrate (NO3 -) content. Plants were grown in a soilless system using a natural fiber mat as the substrate. After germination, microgreens were fertigated with a modified half-strength Hoagland solution prepared using deionized water and without adding microelements. At harvest (10 to 19 days after sowing, based on the species), yield components were measured and dry tissue samples were analyzed for the concentration of total nitrogen (N), NO3 -, P, K, Ca, Mg, S, Na, Fe, Zn, Mn, Cu, and B. Results and discussion: Genotypic variations were observed for all of the examined parameters. Nitrogen and K were the principal macronutrients accounting for 38.4% and 33.8% of the total macro-minerals concentration, respectively, followed in order by Ca, P, S, and Mg. Except for sunflower (Helianthus annuus L.), all the tested species accumulated high (1,000-2,500 mg kg-1 FW) or very high (>2,500 mg kg-1 FW) NO3 - levels. Eight of the studied species had a K concentration above 300 mg 100 g-1 FW and could be considered as a good dietary source of K. On the other hand, scallion (Allium fistulosum L.), red cabbage (Brassica oleracea L. var. capitata), amaranth (Amaranthus tricolor L.), and Genovese basil (Ocinum basilicum L.) microgreens were a good source of Ca. Among micro-minerals, the most abundant was Fe followed by Zn, Mn, B, and Cu. Sunflower, scallion, and shiso (Perilla frutescens (L.) Britton) were a good source of Cu. Moreover, sunflower was a good source of Zn, whereas none of the other species examined could be considered a good source of Fe and Zn, suggesting that supplementary fertilization may be required to biofortify microgreens with essential microminerals. In conclusion, the tested microgreens can be a good source of minerals showing a high potential to address different dietary needs; however, their yield potential and mineral profile are largely determined by the genotype.
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Myocardial fibrosis and calcification associate with adverse outcomes in nonischemic heart failure. Cardiac fibroblasts (CF) transition into myofibroblasts (MF) and osteogenic fibroblasts (OF) to promote myocardial fibrosis and calcification. However, common upstream mechanisms regulating both CF-to-MF transition and CF-to-OF transition remain unknown. microRNAs are promising targets to modulate CF plasticity. Our bioinformatics revealed downregulation of miR-129-5p and upregulation of its targets small leucine-rich proteoglycan Asporin (ASPN) and transcription factor SOX9 as common in mouse and human heart failure (HF). We experimentally confirmed decreased miR-129-5p and enhanced SOX9 and ASPN expression in CF in human hearts with myocardial fibrosis and calcification. miR-129-5p repressed both CF-to-MF and CF-to-OF transition in primary CF, as did knockdown of SOX9 and ASPN. Sox9 and Aspn are direct targets of miR-129-5p that inhibit downstream ß-catenin expression. Chronic Angiotensin II infusion downregulated miR-129-5p in CF in WT and TCF21-lineage CF reporter mice, and it was restored by miR-129-5p mimic. Importantly, miR-129-5p mimic not only attenuated progression of myocardial fibrosis, calcification marker expression, and SOX9 and ASPN expression in CF but also restored diastolic and systolic function. Together, we demonstrate miR-129-5p/ASPN and miR-129-5p/SOX9 as potentially novel dysregulated axes in CF-to-MF and CF-to-OF transition in myocardial fibrosis and calcification and the therapeutic relevance of miR-129-5p.
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Cardiomiopatías , Insuficiencia Cardíaca , MicroARNs , Humanos , Ratones , Animales , MicroARNs/genética , MicroARNs/metabolismo , Cardiomiopatías/metabolismo , Fibroblastos/metabolismo , Insuficiencia Cardíaca/metabolismo , Fibrosis , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Factor de Transcripción SOX9/genética , Factor de Transcripción SOX9/metabolismoRESUMEN
BACKGROUND: Pulmonary hypertension (PH) is associated with aberrant sympathoexcitation leading to right ventricular failure (RVF), arrhythmias, and death. Microglial activation and neuroinflammation have been implicated in sympathoexcitation in experimental PH. We recently reported the first evidence of thoracic spinal cord (TSC) neuroinflammation in PH rats. Here, we hypothesize that PH is associated with increased cardiopulmonary afferent signaling leading to TSC-specific neuroinflammation and sympathoexcitation. Furthermore, inhibition of TSC neuroinflammation rescues experimental PH and RVF. METHODS: We performed transcriptomic analysis and its validation on the TSC of monocrotaline (n=8) and Sugen hypoxia (n=8) rat models of severe PH-RVF. A group of monocrotaline rats received either daily intrathecal microglial activation inhibitor minocycline (200 µg/kg per day, n=5) or PBS (n=5) from day 14 through 28. Echocardiography and right ventricle-catheterization were performed terminally. Real-time quantitative reverse transcription PCR, immunolocalization, microglia+astrocyte quantification, and terminal deoxynucleotidyl transferase dUTP nick end labeling were assessed. Plasma catecholamines were measured by ELISA. Human spinal cord autopsy samples (Control n=3; pulmonary arterial hypertension n=3) were assessed to validate preclinical findings. RESULTS: Increased cardiopulmonary afferent signaling was demonstrated in preclinical and clinical PH. Our findings delineated common dysregulated genes and pathways highlighting neuroinflammation and apoptosis in the remodeled TSC and highlighted increased sympathoexcitation in both rat models. Moreover, we validated significantly increased microglial and astrocytic activation and CX3CL1 expression in TSC of human pulmonary arterial hypertension. Finally, amelioration of TSC neuroinflammation by minocycline in monocrotaline rats inhibited microglial activation, decreased proinflammatory cytokines, sympathetic nervous system activation and significantly attenuated PH and RVF. CONCLUSIONS: Targeting neuroinflammation and associated molecular pathways and genes in the TSC may yield novel therapeutic strategies for PH and RVF.
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Hipertensión Pulmonar , Hipertensión Arterial Pulmonar , Humanos , Ratas , Animales , Ratas Sprague-Dawley , Minociclina/farmacología , Minociclina/uso terapéutico , Enfermedades Neuroinflamatorias , Monocrotalina , Hipertensión Pulmonar Primaria Familiar , Médula Espinal , Modelos Animales de EnfermedadRESUMEN
Pulmonary arterial hypertension (PAH) remains an incurable and often fatal disease despite currently available therapies. Multiomics systems biology analysis can shed new light on PAH pathobiology and inform translational research efforts. Using RNA sequencing on the largest PAH lung biobank to date (96 disease and 52 control), we aim to identify gene co-expression network modules associated with PAH and potential therapeutic targets. Co-expression network analysis was performed to identify modules of co-expressed genes which were then assessed for and prioritized by importance in PAH, regulatory role, and therapeutic potential via integration with clinicopathologic data, human genome-wide association studies (GWAS) of PAH, lung Bayesian regulatory networks, single-cell RNA-sequencing data, and pharmacotranscriptomic profiles. We identified a co-expression module of 266 genes, called the pink module, which may be a response to the underlying disease process to counteract disease progression in PAH. This module was associated not only with PAH severity such as increased PVR and intimal thickness, but also with compensated PAH such as lower number of hospitalizations, WHO functional class and NT-proBNP. GWAS integration demonstrated the pink module is enriched for PAH-associated genetic variation in multiple cohorts. Regulatory network analysis revealed that BMPR2 regulates the main target of FDA-approved riociguat, GUCY1A2, in the pink module. Analysis of pathway enrichment and pink hub genes (i.e. ANTXR1 and SFRP4) suggests the pink module inhibits Wnt signaling and epithelial-mesenchymal transition. Cell type deconvolution showed the pink module correlates with higher vascular cell fractions (i.e. myofibroblasts). A pharmacotranscriptomic screen discovered ubiquitin-specific peptidases (USPs) as potential therapeutic targets to mimic the pink module signature. Our multiomics integrative study uncovered a novel gene subnetwork associated with clinicopathologic severity, genetic risk, specific vascular cell types, and new therapeutic targets in PAH. Future studies are warranted to investigate the role and therapeutic potential of the pink module and targeting USPs in PAH.
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The identification and role of endothelial progenitor cells in pulmonary arterial hypertension (PAH) remain controversial. Single-cell omics analysis can shed light on endothelial progenitor cells and their potential contribution to PAH pathobiology. We aim to identify endothelial cells that may have stem/progenitor potential in rat lungs and assess their relevance to PAH. Differential expression, gene set enrichment, cell-cell communication, and trajectory reconstruction analyses were performed on lung endothelial cells from single-cell RNA sequencing of Sugen-hypoxia, monocrotaline, and control rats. Relevance to human PAH was assessed in multiple independent blood and lung transcriptomic data sets. Rat lung endothelial cells were visualized by immunofluorescence in situ, analyzed by flow cytometry, and assessed for tubulogenesis in vitro. A subpopulation of endothelial cells (endothelial arterial type 2 [EA2]) marked by Tm4sf1 (transmembrane 4 L six family member 1), a gene strongly implicated in cancer, harbored a distinct transcriptomic signature enriched for angiogenesis and CXCL12 signaling. Trajectory analysis predicted that EA2 has a less differentiated state compared with other endothelial subpopulations. Analysis of independent data sets revealed that TM4SF1 is downregulated in lungs and endothelial cells from patients and PAH models, is a marker for hematopoietic stem cells, and is upregulated in PAH circulation. TM4SF1+CD31+ rat lung endothelial cells were visualized in distal pulmonary arteries, expressed hematopoietic marker CD45, and formed tubules in coculture with lung fibroblasts. Our study uncovered a novel Tm4sf1-marked subpopulation of rat lung endothelial cells that may have stem/progenitor potential and demonstrated its relevance to PAH. Future studies are warranted to further elucidate the role of EA2 and Tm4sf1 in PAH.
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Células Progenitoras Endoteliales , Hipertensión Arterial Pulmonar , Animales , Humanos , Ratas , Antígenos de Superficie/metabolismo , Modelos Animales de Enfermedad , Endotelio , Hipertensión Pulmonar Primaria Familiar/metabolismo , Monocrotalina , Proteínas de Neoplasias/metabolismo , Hipertensión Arterial Pulmonar/metabolismo , Arteria Pulmonar/metabolismoRESUMEN
Main effect models contend that perceived social support benefits mental health in the presence and the absence of stressful events, whereas stress-buffering models contend that perceived social support benefits mental health especially when individuals are facing stressful events. We tested these models of how perceived social support impacts mental health during the COVID-19 pandemic and evaluated whether characteristics of everyday social interactions statistically mediated this association - namely, (a) received support, the visible and deliberate assistance provided by others, and (b) pleasantness, the extent to which an interaction is positive, flows easily, and leads individuals to feel understood and validated. 591 United States adults completed a 3-week ecological momentary assessment protocol sampling characteristics of their everyday social interactions that was used to evaluate between-person average values and within-person daily fluctuations in everyday social interaction characteristics. Global measures of perceived social support and pandemic-related stressors were assessed at baseline. Psychiatric symptoms of depression and anxiety were assessed at baseline, at the end of each day of ecological momentary assessment, and at 3-week follow-up. Consistent with a main effect model, higher baseline perceived social support predicted decreases in psychiatric symptoms at 3-week follow-up (ß = -.09, p = .001). Contrary to a stress-buffering model, we did not find an interaction of pandemic-stressors × perceived social support. The main effect of perceived social support on mental health was mediated by the pleasantness of everyday social interactions, but not by received support in everyday social interactions. We found evidence for both main effects and stress-buffering effects of within-person fluctuations in interaction pleasantness on daily changes in mental health. Results suggest the importance of everyday social interaction characteristics, especially their pleasantness, in linking perceived social support and mental health.
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BACKGROUND: Patients with Crohn's disease (CD) have a high likelihood of being sarcopenic. Several studies have shown a positive correlation between sarcopenia measured as skeletal muscle index (SMI) and poor surgical outcomes in patients with CD. Our primary aim was to correlate SMI with the psoas muscle index (PMI), an easier measurement of sarcopenia. Secondary aim was to correlate SMI and PMI with clinical outcomes in a cohort of CD patients requiring surgery. METHODS: A retrospective cohort study of CD patients who underwent surgery at a public health service from January 2010 to December 2019. Using computed tomography and magnetic resonance enterography studies, skeletal muscle area was measured at the third lumbar vertebra level. SMI and PMI were calculated and correlated. Correlation between SMI and PMI with surgical outcomes was performed. RESULTS: Seventy-six patients were included. Median length of stay (LOS) was 6 days (IQR, 5 to 9). Eleven patients (14.5%) required ICU admission, nine patients (11.8%) required TPN and thirteen patients (17.1%) had complications. The prevalence of sarcopenia was 63.2% based on the SMI threshold of 52.4 and 38.5 cm2 /m2 for men and women, respectively. A positive correlation between SMI and PMI was found (r = 0.72, P < 0.0001). Sarcopenia status based on reported thresholds for SMI and for PMI showed no significant correlation with outcomes (LOS, ICU admission and complications). CONCLUSIONS: SMI and PMI show good correlation but there is insufficient evidence to suggest that sarcopenia status using either measurement has a significant impact on predicting clinical outcomes.
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Enfermedad de Crohn , Sarcopenia , Masculino , Humanos , Femenino , Sarcopenia/complicaciones , Sarcopenia/diagnóstico por imagen , Sarcopenia/epidemiología , Enfermedad de Crohn/complicaciones , Enfermedad de Crohn/cirugía , Enfermedad de Crohn/patología , Estudios Retrospectivos , Músculos Psoas/diagnóstico por imagen , Músculo Esquelético/patología , Tomografía Computarizada por Rayos X/métodosRESUMEN
Background: Pulmonary hypertension (PH) leads to right ventricular (RV) hypertrophy and failure (RVF). The precise mechanisms of the metabolic basis of maladaptive PH-induced RVF (PH-RVF) are yet to be fully elucidated. Here we performed a comparative analysis of RV-metabolic reprogramming in MCT and Su/Hx rat models of severe PH-RVF using targeted metabolomics and multi-omics. Methods: Male Sprague Dawley rats (250-300 gm; n = 15) were used. Rats received subcutaneous monocrotaline (60 mg/kg; MCT; n = 5) and followed for ~30-days or Sugen (20 mg/kg; Su/Hx; n = 5) followed by hypoxia (10% O2; 3-weeks) and normoxia (2-weeks). Controls received saline (Control; n = 5). Serial echocardiography was performed to assess cardiopulmonary hemodynamics. Terminal RV-catheterization was performed to assess PH. Targeted metabolomics was performed on RV tissue using UPLC-MS. RV multi-omics analysis was performed integrating metabolomic and transcriptomic datasets using Joint Pathway Analysis (JPA). Results: MCT and Su/Hx rats developed severe PH, RV-hypertrophy and decompensated RVF. Targeted metabolomics of RV of MCT and Su/Hx rats detected 126 and 125 metabolites, respectively. There were 28 and 24 metabolites significantly altered in RV of MCT and Su/Hx rats, respectively, including 11 common metabolites. Common significantly upregulated metabolites included aspartate and GSH, whereas downregulated metabolites included phosphate, α-ketoglutarate, inositol, glutamine, 5-Oxoproline, hexose phosphate, creatine, pantothenic acid and acetylcarnitine. JPA highlighted common genes and metabolites from key pathways such as glycolysis, fatty acid metabolism, oxidative phosphorylation, TCA cycle, etc. Conclusions: Comparative analysis of metabolic reprogramming of RV from MCT and Su/Hx rats reveals common and distinct metabolic signatures which may serve as RV-specific novel therapeutic targets for PH-RVF.