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Intra-tumor heterogeneity (ITH) is a mechanism of therapeutic resistance and therefore an important clinical challenge. However, the extent, origin, and drivers of ITH across cancer types are poorly understood. To address this, we extensively characterize ITH across whole-genome sequences of 2,658 cancer samples spanning 38 cancer types. Nearly all informative samples (95.1%) contain evidence of distinct subclonal expansions with frequent branching relationships between subclones. We observe positive selection of subclonal driver mutations across most cancer types and identify cancer type-specific subclonal patterns of driver gene mutations, fusions, structural variants, and copy number alterations as well as dynamic changes in mutational processes between subclonal expansions. Our results underline the importance of ITH and its drivers in tumor evolution and provide a pan-cancer resource of comprehensively annotated subclonal events from whole-genome sequencing data.
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Heterogeneidad Genética , Neoplasias/genética , Variaciones en el Número de Copia de ADN , ADN de Neoplasias/química , ADN de Neoplasias/metabolismo , Bases de Datos Genéticas , Resistencia a Antineoplásicos/genética , Humanos , Neoplasias/patología , Polimorfismo de Nucleótido Simple , Secuenciación Completa del GenomaRESUMEN
Clostridioides difficile infection (CDI) is a major cause of healthcare-associated gastrointestinal infections1,2. The exaggerated colonic inflammation caused by C. difficile toxins such as toxin B (TcdB) damages tissues and promotes C. difficile colonization3-6, but how TcdB causes inflammation is unclear. Here we report that TcdB induces neurogenic inflammation by targeting gut-innervating afferent neurons and pericytes through receptors, including the Frizzled receptors (FZD1, FZD2 and FZD7) in neurons and chondroitin sulfate proteoglycan 4 (CSPG4) in pericytes. TcdB stimulates the secretion of the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) from neurons and pro-inflammatory cytokines from pericytes. Targeted delivery of the TcdB enzymatic domain, through fusion with a detoxified diphtheria toxin, into peptidergic sensory neurons that express exogeneous diphtheria toxin receptor (an approach we term toxogenetics) is sufficient to induce neurogenic inflammation and recapitulates major colonic histopathology associated with CDI. Conversely, mice lacking SP, CGRP or the SP receptor (neurokinin 1 receptor) show reduced pathology in both models of caecal TcdB injection and CDI. Blocking SP or CGRP signalling reduces tissue damage and C. difficile burden in mice infected with a standard C. difficile strain or with hypervirulent strains expressing the TcdB2 variant. Thus, targeting neurogenic inflammation provides a host-oriented therapeutic approach for treating CDI.
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Toxinas Bacterianas , Clostridioides difficile , Inflamación Neurogénica , Neuronas Aferentes , Pericitos , Animales , Ratones , Toxinas Bacterianas/administración & dosificación , Toxinas Bacterianas/farmacología , Péptido Relacionado con Gen de Calcitonina/antagonistas & inhibidores , Péptido Relacionado con Gen de Calcitonina/metabolismo , Clostridioides difficile/patogenicidad , Infecciones por Clostridium/microbiología , Inflamación Neurogénica/inducido químicamente , Inflamación Neurogénica/microbiología , Inflamación Neurogénica/patología , Pericitos/efectos de los fármacos , Pericitos/microbiología , Pericitos/patología , Receptores de Neuroquinina-1/metabolismo , Sustancia P/antagonistas & inhibidores , Sustancia P/metabolismo , Neuronas Aferentes/efectos de los fármacos , Neuronas Aferentes/microbiología , Neuronas Aferentes/patología , Mediadores de Inflamación/metabolismo , Ciego/efectos de los fármacos , Ciego/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Vascular remodeling is the process of structural alteration and cell rearrangement of blood vessels in response to injury and is the cause of many of the world's most afflicted cardiovascular conditions, including pulmonary arterial hypertension (PAH). Many studies have focused on the effects of vascular endothelial cells and smooth muscle cells (SMCs) during vascular remodeling, but pericytes, an indispensable cell population residing largely in capillaries, are ignored in this maladaptive process. Here, we report that hypoxia-inducible factor 2α (HIF2α) expression is increased in the lung tissues of PAH patients, and HIF2α overexpressed pericytes result in greater contractility and an impaired endothelial-pericyte interaction. Using single-cell RNAseq and hypoxia-induced pulmonary hypertension (PH) models, we show that HIF2α is a major molecular regulator for the transformation of pericytes into SMC-like cells. Pericyte-selective HIF2α overexpression in mice exacerbates PH and right ventricular hypertrophy. Temporal cellular lineage tracing shows that HIF2α overexpressing reporter NG2+ cells (pericyte-selective) relocate from capillaries to arterioles and co-express SMA. This novel insight into the crucial role of NG2+ pericytes in pulmonary vascular remodeling via HIF2α signaling suggests a potential drug target for PH.
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Hipertensión Pulmonar , Remodelación Vascular , Ratones , Humanos , Animales , Pericitos/metabolismo , Células Endoteliales/metabolismo , Hipertensión Pulmonar/genética , Hipertensión Pulmonar/metabolismo , Hipoxia/genética , Hipoxia/metabolismo , PulmónRESUMEN
Cancer develops through a process of somatic evolution1,2. Sequencing data from a single biopsy represent a snapshot of this process that can reveal the timing of specific genomic aberrations and the changing influence of mutational processes3. Here, by whole-genome sequencing analysis of 2,658 cancers as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA)4, we reconstruct the life history and evolution of mutational processes and driver mutation sequences of 38 types of cancer. Early oncogenesis is characterized by mutations in a constrained set of driver genes, and specific copy number gains, such as trisomy 7 in glioblastoma and isochromosome 17q in medulloblastoma. The mutational spectrum changes significantly throughout tumour evolution in 40% of samples. A nearly fourfold diversification of driver genes and increased genomic instability are features of later stages. Copy number alterations often occur in mitotic crises, and lead to simultaneous gains of chromosomal segments. Timing analyses suggest that driver mutations often precede diagnosis by many years, if not decades. Together, these results determine the evolutionary trajectories of cancer, and highlight opportunities for early cancer detection.
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Evolución Molecular , Genoma Humano/genética , Neoplasias/genética , Reparación del ADN/genética , Dosificación de Gen , Genes Supresores de Tumor , Variación Genética , Humanos , Mutagénesis Insercional/genéticaRESUMEN
Efficient homing of infused hematopoietic stem and progenitor cells (HSPCs) into the bone marrow (BM) is the prerequisite for successful hematopoietic stem cell transplantation. However, only a small part of infused HSPCs find their way to the BM niche. A better understanding of the mechanisms that facilitate HSPC homing will help to develop strategies to improve the initial HSPC engraftment and subsequent hematopoietic regeneration. Here, we show that irradiation upregulates the endomucin expression of endothelial cells in vivo and in vitro. Furthermore, depletion of endomucin in irradiated endothelial cells with short interfering RNA (siRNA) increases the HSPC-endothelial cell adhesion in vitro. To abrogate the endomucin of BM sinusoidal endothelial cells (BM-SECs) in vivo, we develop a siRNA-loaded bovine serum albumin nanoparticle for targeted delivery. Nanoparticle-mediated siRNA delivery successfully silences endomucin expression in BM-SECs and improves HSPC homing during transplantation. These results reveal that endomucin plays a critical role in HSPC homing during transplantation and that gene-based manipulation of BM-SEC endomucin in vivo can be exploited to improve the efficacy of HSPC transplantation.
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The COVID-19 pandemic has been characterised by sequential variant-specific waves shaped by viral, individual human and population factors. SARS-CoV-2 variants are defined by their unique combinations of mutations and there has been a clear adaptation to more efficient human infection since the emergence of this new human coronavirus in late 2019. Here, we use machine learning models to identify shared signatures, i.e., common underlying mutational processes and link these to the subset of mutations that define the variants of concern (VOCs). First, we examined the global SARS-CoV-2 genomes and associated metadata to determine how viral properties and public health measures have influenced the magnitude of waves, as measured by the number of infection cases, in different geographic locations using regression models. This analysis showed that, as expected, both public health measures and virus properties were associated with the waves of regional SARS-CoV-2 reported infection numbers and this impact varies geographically. We attribute this to intrinsic differences such as vaccine coverage, testing and sequencing capacity and the effectiveness of government stringency. To assess underlying evolutionary change, we used non-negative matrix factorisation and observed three distinct mutational signatures, unique in their substitution patterns and exposures from the SARS-CoV-2 genomes. Signatures 1, 2 and 3 were biased to CâT, TâC/AâG and GâT point mutations. We hypothesise assignments of these mutational signatures to the host antiviral molecules APOBEC, ADAR and ROS respectively. We observe a shift amidst the pandemic in relative mutational signature activity from predominantly Signature 1 changes to an increasingly high proportion of changes consistent with Signature 2. This could represent changes in how the virus and the host immune response interact and indicates how SARS-CoV-2 may continue to generate variation in the future. Linkage of the detected mutational signatures to the VOC-defining amino acids substitutions indicates the majority of SARS-CoV-2's evolutionary capacity is likely to be associated with the action of host antiviral molecules rather than virus replication errors.
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COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/genética , COVID-19/genética , Pandemias , Mutación , Antivirales/farmacologíaRESUMEN
BACKGROUND: Pulmonary hypertension (PH) is a common complication of systemic sclerosis (SSc) and a leading cause of mortality among patients with this disease. PH can also occur as an idiopathic condition (idiopathic pulmonary arterial hypertension). Investigation of transcriptomic alterations in vascular populations is critical to elucidating cellular mechanisms underlying pathobiology of SSc-associated and idiopathic PH. METHODS: We analyzed single-cell RNA sequencing profiles of endothelial and perivascular mesenchymal populations from explanted lung tissue of patients with SSc-associated PH (n=16), idiopathic pulmonary arterial hypertension (n=3), and healthy controls (n=15). Findings were validated by immunofluorescence staining of explanted human lung tissue. RESULTS: Three disease-associated endothelial populations emerged. Two angiogenic endothelial cell (EC) subtypes markedly expanded in SSc-associated PH lungs: tip ECs expressing canonical tip markers PGF and APLN and phalanx ECs expressing genes associated with vascular development, endothelial barrier integrity, and Notch signaling. Gene regulatory network analysis suggested enrichment of Smad1 (SMAD family member 1) and PPAR-γ (peroxisome proliferator-activated receptor-γ) regulon activities in these 2 populations, respectively. Mapping of potential ligand-receptor interactions highlighted Notch, apelin-APJ (apelin receptor), and angiopoietin-Tie (tyrosine kinase with immunoglobulin-like and EGF-like domains 1) signaling pathways between angiogenic ECs and perivascular cells. Transitional cells, expressing both endothelial and pericyte/smooth muscle cell markers, provided evidence for the presence of endothelial-to-mesenchymal transition. Transcriptional programs associated with arterial endothelial dysfunction implicated VEGF-A (vascular endothelial growth factor-A), TGF-ß1 (transforming growth factor beta-1), angiotensin, and TNFSF12 (tumor necrosis factor ligand superfamily member 12)/TWEAK (TNF-related weak inducer of apoptosis) in the injury/remodeling phenotype of PH arterial ECs. CONCLUSIONS: These data provide high-resolution insights into the complexity and plasticity of the pulmonary endothelium in SSc-associated PH and idiopathic pulmonary arterial hypertension and provide direct molecular insights into soluble mediators and transcription factors driving PH vasculopathy.
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Neovascularización Patológica , Esclerodermia Sistémica , Remodelación Vascular , Humanos , Esclerodermia Sistémica/genética , Esclerodermia Sistémica/patología , Esclerodermia Sistémica/metabolismo , Esclerodermia Sistémica/complicaciones , Masculino , Femenino , Persona de Mediana Edad , Hipertensión Pulmonar Primaria Familiar/metabolismo , Hipertensión Pulmonar Primaria Familiar/genética , Hipertensión Pulmonar Primaria Familiar/fisiopatología , Hipertensión Pulmonar Primaria Familiar/patología , Estudios de Casos y Controles , Células Endoteliales/metabolismo , Células Endoteliales/patología , Arteria Pulmonar/metabolismo , Arteria Pulmonar/patología , Arteria Pulmonar/fisiopatología , Transcriptoma , Transducción de Señal , Adulto , Análisis de la Célula Individual , Pulmón/metabolismo , Pulmón/irrigación sanguínea , Pulmón/patología , Redes Reguladoras de Genes , AngiogénesisRESUMEN
BACKGROUND: Epsin endocytic adaptor proteins are implicated in the progression of atherosclerosis; however, the underlying molecular mechanisms have not yet been fully defined. In this study, we determined how epsins enhance endothelial-to-mesenchymal transition (EndoMT) in atherosclerosis and assessed the efficacy of a therapeutic peptide in a preclinical model of this disease. METHODS: Using single-cell RNA sequencing combined with molecular, cellular, and biochemical analyses, we investigated the role of epsins in stimulating EndoMT using knockout in Apoe-/- and lineage tracing/proprotein convertase subtilisin/kexin type 9 serine protease mutant viral-induced atherosclerotic mouse models. The therapeutic efficacy of a synthetic peptide targeting atherosclerotic plaques was then assessed in Apoe-/- mice. RESULTS: Single-cell RNA sequencing and lineage tracing revealed that epsins 1 and 2 promote EndoMT and that the loss of endothelial epsins inhibits EndoMT marker expression and transforming growth factor-ß signaling in vitro and in atherosclerotic mice, which is associated with smaller lesions in the Apoe-/- mouse model. Mechanistically, the loss of endothelial cell epsins results in increased fibroblast growth factor receptor-1 expression, which inhibits transforming growth factor-ß signaling and EndoMT. Epsins directly bind ubiquitinated fibroblast growth factor receptor-1 through their ubiquitin-interacting motif, which results in endocytosis and degradation of this receptor complex. Consequently, administration of a synthetic ubiquitin-interacting motif-containing peptide atheroma ubiquitin-interacting motif peptide inhibitor significantly attenuates EndoMT and progression of atherosclerosis. CONCLUSIONS: We conclude that epsins potentiate EndoMT during atherogenesis by increasing transforming growth factor-ß signaling through fibroblast growth factor receptor-1 internalization and degradation. Inhibition of EndoMT by reducing epsin-fibroblast growth factor receptor-1 interaction with a therapeutic peptide may represent a novel treatment strategy for atherosclerosis.
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Aterosclerosis , Factor de Crecimiento Transformador beta , Ratones , Animales , Factores de Crecimiento de Fibroblastos , Apolipoproteínas E , Aterosclerosis/genética , Receptores de Factores de Crecimiento de Fibroblastos , Factores de Crecimiento Transformadores , UbiquitinasRESUMEN
Neonates with congenital diaphragmatic hernia (CDH) frequently require cardiopulmonary bypass and systemic anticoagulation. We previously demonstrated that even subtherapeutic heparin impairs lung growth and function in a murine model of compensatory lung growth (CLG). The direct thrombin inhibitors (DTIs) bivalirudin and argatroban preserved growth in this model. Although DTIs are increasingly used for systemic anticoagulation clinically, patients with CDH may still receive heparin. In this experiment, lung endothelial cell proliferation was assessed following treatment with heparin-alone or mixed with increasing concentrations of bivalirudin or argatroban. The effects of subtherapeutic heparin with or without DTIs in the CLG model were also investigated. C57BL/6J mice underwent left pneumonectomy and subcutaneous implantation of osmotic pumps. Pumps were preloaded with normal saline, bivalirudin, or argatroban; treated animals received daily intraperitoneal low-dose heparin. In vitro, heparin-alone decreased endothelial cell proliferation and increased apoptosis. The effect of heparin on proliferation, but not apoptosis, was reversed by the addition of bivalirudin and argatroban. In vivo, low-dose heparin decreased lung volume compared with saline-treated controls. All three groups that received heparin demonstrated decreased lung function on pulmonary function testing and impaired exercise performance on treadmill tolerance testing. These findings correlated with decreases in alveolarization, vascularization, angiogenic signaling, and gene expression in the heparin-exposed groups. Together, these data suggest that bivalirudin and argatroban fail to reverse the inhibitory effects of subtherapeutic heparin on lung growth and function. Clinical studies on the impact of low-dose heparin with DTIs on CDH outcomes are warranted.NEW & NOTEWORTHY Infants with pulmonary hypoplasia frequently require cardiopulmonary bypass and systemic anticoagulation. We investigate the effects of simultaneous exposure to heparin and direct thrombin inhibitors (DTIs) on lung growth and pulmonary function in a murine model of compensatory lung growth (CGL). Our data suggest that DTIs fail to reverse the inhibitory effects of subtherapeutic heparin on lung growth and function. Clinical studies on the impact of heparin with DTIs on clinical outcomes are thus warranted.
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Antitrombinas , Arginina/análogos & derivados , Heparina , Ácidos Pipecólicos , Sulfonamidas , Humanos , Animales , Ratones , Heparina/farmacología , Heparina/uso terapéutico , Antitrombinas/farmacología , Antitrombinas/uso terapéutico , Anticoagulantes/uso terapéutico , Neumonectomía , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Hirudinas/farmacología , Fibrinolíticos , Pulmón/metabolismo , Fragmentos de Péptidos/farmacología , Proteínas Recombinantes/farmacología , Trombina/farmacología , Trombina/metabolismoRESUMEN
In the field of pulmonary hypertension (PH), a well-established protocol to induce severe angioproliferation in rats (SuHx) involves combining the VEGF-R inhibitor Sugen 5416 (SU5416) with 3 wk of hypoxia (Hx). In addition, injecting monocrotaline (MCT) into rats can induce inflammation and shear stress in the pulmonary vasculature, leading to neointima-like remodeling. However, the SuHx protocol in mice is still controversial, with some studies suggesting it yields higher and reversible PH than Hx alone, possibly due to species-dependent hypoxic responses. To establish an alternative rodent model of PH, we hypothesized mice would be more sensitive to hemodynamic changes secondary to shear stress compared with Hx. We attempted to induce severe and irreversible PH in mice by combining SU5416 or monocrotaline pyrrole (MCTP) injection with pneumonectomy (PNx). However, our experiments showed SU5416 administered to mice at various time points after PNx did not result in severe PH. Similarly, mice injected with MCTP after PNx (MPNx) showed no difference in right ventricular systolic pressure or exacerbated pulmonary vascular remodeling compared with PNx alone. These findings collectively demonstrate that C57/B6 mice do not develop severe and persistent PH when PNx is combined with either SU5416 or MCTP.NEW & NOTEWORTHY We attempted to establish a mouse model of severe and irreversible pulmonary hypertension by substituting hypoxia with pulmonary overcirculation. To do so, we treated mice with either SU5416 or monocrotaline pyrrole after pneumonectomy and performed hemodynamic evaluations for PH. Despite this "two-hit" protocol, mice did not exhibit signs of severe pulmonary hypertension or exacerbated pulmonary vascular remodeling compared with PNx alone.
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Hipertensión Pulmonar , Indoles , Ratones Endogámicos C57BL , Monocrotalina , Neumonectomía , Pirroles , Animales , Monocrotalina/análogos & derivados , Pirroles/farmacología , Hipertensión Pulmonar/patología , Hipertensión Pulmonar/inducido químicamente , Indoles/farmacología , Ratones , Masculino , Modelos Animales de Enfermedad , Hipoxia/patología , Remodelación Vascular/efectos de los fármacos , Pulmón/patología , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Hemodinámica/efectos de los fármacosRESUMEN
Acute myeloid leukemia (AML) is a malignant hematologic disease caused by gene mutations and genomic rearrangements in hematologic progenitors. The PHF6 (PHD finger protein 6) gene is highly conserved and located on the X chromosome in humans and mice. We found that PHF6 was highly expressed in AML cells with MLL rearrangement and was related to the shortened survival time of AML patients. In our study, we knocked out the Phf6 gene at different disease stages in the AML mice model. Moreover, we knocked down PHF6 by shRNA in two AML cell lines and examined the cell growth, apoptosis, and cell cycle. We found that PHF6 deletion significantly inhibited the proliferation of leukemic cells and prolonged the survival time of AML mice. Interestingly, the deletion of PHF6 at a later stage of the disease displayed a better anti-leukemia effect. The expressions of genes related to cell differentiation were increased, while genes that inhibit cell differentiation were decreased with PHF6 knockout. It is very important to analyze the maintenance role of PHF6 in AML, which is different from its tumor-suppressing function in T-cell acute lymphoblastic leukemia (T-ALL). Our study showed that inhibiting PHF6 expression may be a potential therapeutic strategy targeting AML patients.
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The Hamiltonian, which determines the evolution of a quantum system, is fundamental in quantum physics. Therefore, it is crucial to implement high-precision generation and measurement of the Hamiltonian in a practical quantum system. Here, we experimentally demonstrate ultrahigh-precision Hamiltonian parameter estimation with a significant quantum advantage in a superconducting circuit via sequential control. We first observe the commutation relation for noncommuting operations determined by the system Hamiltonian, both with and without adding quantum control, verifying the commuting property of controlled noncommuting operations. Based on this control-induced commuting property, we further demonstrate Hamiltonian parameter estimation for polar and azimuth angles in superconducting circuits, achieving ultrahigh metrological gains in measurement precision exceeding the standard quantum limit by up to 16.0 and 16.1 dB at N=100, respectively.
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This study focuses on an improved leaching process through the combination of pressurized conditions and direct filtration of acid leaching slurry, which is conductive to improving the filterability of acid leaching systems and the extraction rates of Ti, Al, and Mg components. The effects of sulfuric acid concentration, reaction temperature, particle size of materials, acid-slag ratio, and reaction time on the leaching efficiency were systematically investigated. The results showed that pressurization significantly enhances the filtration efficiency of the reaction slurry. Under the same filtration time, the filtration efficiency increased from 46% under ordinary pressure to 78% under pressurized conditions. Moreover, under the optimal reaction conditions, the extraction rates of Ti, Al, and Mg components were more than 88.21%, 97.8%, and 96.31%, respectively. Additionally, XRD and FTIR showed that titanium oxide sulfate hydrate crystals were produced in the acid-leached residues when the reaction temperature exceeded 190 °C, thereby reducing the extraction rate of Ti component. And the XRD pattern shows that when the reaction temperature is maintained at 190 °C and the reaction time is extended to 150 min, titanium oxide sulfate hydrate crystals will be formed to reduce the extraction rate of the Ti component. In summary, this study not only provides important theoretical support for the resource utilization of high-titanium blast furnace slag but also offers a feasible solution for efficient extraction and convenient filtration, thus holding significant academic and practical implications.
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OBJECTIVE: To retrospectively analyze the clinical characteristics of 193 Chinese patients with McCune-Albright syndrome (MAS). METHODS: By using keywords "McCune-Albright syndrome", "Albright syndrome", or " fibrous dysplasia " as the search terms, 193 cases of MAS reported in China from January 1990 to November 2022 from the Wanfang data, CNKI, VIP, PubMed, and Embase databases were obtained, and their clinical data was retrospectively analyzed. Intergroup comparisons were carried out by using t test, Mann-Whitney U test, and X2 test. RESULTS: The 193 MAS patients had included 42 males and 151 females, with the median first-visit age of females being younger than males. The typical triad group had accounted for 46.1% of patients, and the middle first-visit and diagnosis age was younger than the atypical group. The primary reason for first-visit in males of MAS was fibrous dysplasia (FD), whilst that in females of MAS was peripheral precocious puberty (PPP). FD has occurred in 84.5% of the patients, with an average age of onset age being 6.1 years old, and 90% was ≤ 16 years of age. Endocrine hyperfunction was found in 79.3% of the patients, with a higher proportion in females compared with males (P < 0.05). Pituitary involvement was seen in 21.8% of the patients, and the incidence of craniofacial FD and cranial nerve compression was significantly higher in those with elevated growth hormone (GH) than without (P < 0.05). Café-au-Lait Spots were noted in 86.5% of the patients, and 28.3% (28/99) had located on the different side of FD. CONCLUSION: Most MAS patients had atypical manifestations and multi-systemic involvement. It is more common and occurs earlier in females. The most common reasons for initial diagnosis in male and female patients were FD and PPP, respectively. Patients with elevated GH should be examined for cranial nerve compression.
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Displasia Fibrosa Poliostótica , Humanos , Displasia Fibrosa Poliostótica/genética , Masculino , Femenino , Niño , Adolescente , China , Preescolar , Adulto , Estudios Retrospectivos , Adulto Joven , Lactante , Pueblo Asiatico/genética , Persona de Mediana Edad , Pueblos del Este de AsiaRESUMEN
INTRODUCTION: Pulmonary arterial hypertension (PAH) is characterised by loss of microvessels. The Wnt pathways control pulmonary angiogenesis but their role in PAH is incompletely understood. We hypothesised that Wnt activation in pulmonary microvascular endothelial cells (PMVECs) is required for pulmonary angiogenesis, and its loss contributes to PAH. METHODS: Lung tissue and PMVECs from healthy and PAH patients were screened for Wnt production. Global and endothelial-specific Wnt7a -/- mice were generated and exposed to chronic hypoxia and Sugen-hypoxia (SuHx). RESULTS: Healthy PMVECs demonstrated >6-fold Wnt7a expression during angiogenesis that was absent in PAH PMVECs and lungs. Wnt7a expression correlated with the formation of tip cells, a migratory endothelial phenotype critical for angiogenesis. PAH PMVECs demonstrated reduced vascular endothelial growth factor (VEGF)-induced tip cell formation as evidenced by reduced filopodia formation and motility, which was partially rescued by recombinant Wnt7a. We discovered that Wnt7a promotes VEGF signalling by facilitating Y1175 tyrosine phosphorylation in vascular endothelial growth factor receptor 2 (VEGFR2) through receptor tyrosine kinase-like orphan receptor 2 (ROR2), a Wnt-specific receptor. We found that ROR2 knockdown mimics Wnt7a insufficiency and prevents recovery of tip cell formation with Wnt7a stimulation. While there was no difference between wild-type and endothelial-specific Wnt7a -/- mice under either chronic hypoxia or SuHx, global Wnt7a +/- mice in hypoxia demonstrated higher pulmonary pressures and severe right ventricular and lung vascular remodelling. Similar to PAH, Wnt7a +/- PMVECs exhibited an insufficient angiogenic response to VEGF-A that improved with Wnt7a. CONCLUSIONS: Wnt7a promotes VEGF signalling in lung PMVECs and its loss is associated with an insufficient VEGF-A angiogenic response. We propose that Wnt7a deficiency contributes to progressive small vessel loss in PAH.
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Hipertensión Arterial Pulmonar , Ratones , Animales , Hipertensión Arterial Pulmonar/complicaciones , Factor A de Crecimiento Endotelial Vascular/metabolismo , Células Endoteliales/metabolismo , Hipertensión Pulmonar Primaria Familiar/metabolismo , Hipoxia/metabolismoRESUMEN
The high cost of noble Pd/Pt required for the oxygen reduction reaction (ORR) in the cathode restricts the wide applications of fuel cells. In this study, the synthesis of a novel Pd3 CuFe0.5 aerogel electrocatalyst is successfully demonstrated using self-assembly and lyophilization techniques, employing a mild reducing agent. The resulting aerogel electrocatalyst exhibits a distinctive 3D network structure, possessing a substantial BET-specific surface area of 75.19 m2 g-1 . It is worth noting that the optimized Pd3 CuFe0.5 aerogel demonstrates exceptional ORR performance with a high half-wave potential of 0.92 V versus RHE, a significant limiting current density of 7.6 mA cm-2 , and the excellent electrocatalytic stability, superior to the reported noble metal electrocatalysts, with the ORR activity decays only 4.9% after 16 000 s. In addition, the Pd3 CuFe0.5 aerogel electrocatalyst shows superior cycling stability for ≈120 h at a charge/discharge current density of 10 mA cm-2 , indicating its promising application in fuel cells. Furthermore, the resulting composite aerogel possesses excellent hydrogen evolution reaction and ethanol oxidation reaction activity. The density functional theory calculations show that the partial oxidation of Pd3 CuFe0.5 aerogel leads to a negative shift of the d-band center, which energetically optimizes the binding strength of *O intermediates, therefore accelerating the ORR activity.
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Nucleation and growth of minerals has broad implications in the geological, environmental and materials sciences. Recent developments in fast X-ray nanotomography have enabled imaging of crystal growth in solutions in situ with a resolution of tens of nanometres, far surpassing optical microscopy. Here, a low-cost, custom-designed aqueous flow cell dedicated to the study of heterogeneous nucleation and growth of minerals in aqueous environments is shown. To gauge the effects of radiation damage from the imaging process on growth reactions, radiation-induced morphological changes of barite crystals (hundreds of nanometres to â¼1â µm) that were pre-deposited on the wall of the flow cell were investigated. Under flowing solution, minor to major crystal dissolution was observed when the tomography scan frequency was increased from every 30â min to every 5â min (with a 1â min scan duration). The production of reactive radicals from X-ray induced water radiolysis and decrease of pH close to the surface of barite are likely responsible for the observed dissolution. The flow cell shown here can possibly be adopted to study a wide range of other chemical reactions in solutions beyond crystal nucleation and growth where the combination of fast flow and fast scan can be used to mitigate the radiation effects.
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Noncoding RNAs (ncRNAs) play crucial roles in many biological processes. Experimental methods for identifying ncRNA-protein interactions (NPIs) are always costly and time-consuming. Many computational approaches have been developed as alternative ways. In this work, we collected five benchmarking datasets for predicting NPIs. Based on these datasets, we evaluated and compared the prediction performances of existing machine-learning based methods. Graph neural network (GNN) is a recently developed deep learning algorithm for link predictions on complex networks, which has never been applied in predicting NPIs. We constructed a GNN-based method, which is called Noncoding RNA-Protein Interaction prediction using Graph Neural Networks (NPI-GNN), to predict NPIs. The NPI-GNN method achieved comparable performance with state-of-the-art methods in a 5-fold cross-validation. In addition, it is capable of predicting novel interactions based on network information and sequence information. We also found that insufficient sequence information does not affect the NPI-GNN prediction performance much, which makes NPI-GNN more robust than other methods. As far as we can tell, NPI-GNN is the first end-to-end GNN predictor for predicting NPIs. All benchmarking datasets in this work and all source codes of the NPI-GNN method have been deposited with documents in a GitHub repo (https://github.com/AshuiRUA/NPI-GNN).
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Aprendizaje Profundo , Proteínas/metabolismo , ARN no Traducido/metabolismo , Programas Informáticos , Benchmarking , Conjuntos de Datos como Asunto , Humanos , Internet , Unión Proteica , Proteínas/genética , ARN no Traducido/genética , Sensibilidad y EspecificidadRESUMEN
With the development of high-throughput sequencing technology, the genomic sequences increased exponentially over the last decade. In order to decode these new genomic data, machine learning methods were introduced for genome annotation and analysis. Due to the requirement of most machines learning methods, the biological sequences must be represented as fixed-length digital vectors. In this representation procedure, the physicochemical properties of k-tuple nucleotides are important information. However, the values of the physicochemical properties of k-tuple nucleotides are scattered in different resources. To facilitate the studies on genomic sequences, we developed the first comprehensive database, namely KNIndex (https://knindex.pufengdu.org), for depositing and visualizing physicochemical properties of k-tuple nucleotides. Currently, the KNIndex database contains 182 properties including one for mononucleotide (DNA), 169 for dinucleotide (147 for DNA and 22 for RNA) and 12 for trinucleotide (DNA). KNIndex database also provides a user-friendly web-based interface for the users to browse, query, visualize and download the physicochemical properties of k-tuple nucleotides. With the built-in conversion and visualization functions, users are allowed to display DNA/RNA sequences as curves of multiple physicochemical properties. We wish that the KNIndex will facilitate the related studies in computational biology.