Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 645
Filtrar
1.
Cell ; 186(3): 479-496.e23, 2023 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-36736300

RESUMO

Using four-dimensional whole-embryo light sheet imaging with improved and accessible computational tools, we longitudinally reconstruct early murine cardiac development at single-cell resolution. Nascent mesoderm progenitors form opposing density and motility gradients, converting the temporal birth sequence of gastrulation into a spatial anterolateral-to-posteromedial arrangement. Migrating precardiac mesoderm does not strictly preserve cellular neighbor relationships, and spatial patterns only become solidified as the cardiac crescent emerges. Progenitors undergo a mesenchymal-to-epithelial transition, with a first heart field (FHF) ridge apposing a motile juxta-cardiac field (JCF). Anchored along the ridge, the FHF epithelium rotates the JCF forward to form the initial heart tube, along with push-pull morphodynamics of the second heart field. In Mesp1 mutants that fail to make a cardiac crescent, mesoderm remains highly motile but directionally incoherent, resulting in density gradient inversion. Our practicable live embryo imaging approach defines spatial origins and behaviors of cardiac progenitors and identifies their unanticipated morphological transitions.


Assuntos
Coração , Mesoderma , Camundongos , Animais , Diferenciação Celular , Morfogênese , Embrião de Mamíferos , Mamíferos
2.
Cell ; 185(5): 794-814.e30, 2022 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-35182466

RESUMO

Congenital heart disease (CHD) is present in 1% of live births, yet identification of causal mutations remains challenging. We hypothesized that genetic determinants for CHDs may lie in the protein interactomes of transcription factors whose mutations cause CHDs. Defining the interactomes of two transcription factors haplo-insufficient in CHD, GATA4 and TBX5, within human cardiac progenitors, and integrating the results with nearly 9,000 exomes from proband-parent trios revealed an enrichment of de novo missense variants associated with CHD within the interactomes. Scoring variants of interactome members based on residue, gene, and proband features identified likely CHD-causing genes, including the epigenetic reader GLYR1. GLYR1 and GATA4 widely co-occupied and co-activated cardiac developmental genes, and the identified GLYR1 missense variant disrupted interaction with GATA4, impairing in vitro and in vivo function in mice. This integrative proteomic and genetic approach provides a framework for prioritizing and interrogating genetic variants in heart disease.


Assuntos
Fator de Transcrição GATA4/metabolismo , Cardiopatias Congênitas , Proteínas Nucleares/metabolismo , Oxirredutases/metabolismo , Fatores de Transcrição , Animais , Cardiopatias Congênitas/genética , Camundongos , Mutação , Proteômica , Proteínas com Domínio T/genética , Fatores de Transcrição/genética
3.
Cell ; 176(4): 816-830.e18, 2019 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-30595451

RESUMO

The temporal order of DNA replication (replication timing [RT]) is highly coupled with genome architecture, but cis-elements regulating either remain elusive. We created a series of CRISPR-mediated deletions and inversions of a pluripotency-associated topologically associating domain (TAD) in mouse ESCs. CTCF-associated domain boundaries were dispensable for RT. CTCF protein depletion weakened most TAD boundaries but had no effect on RT or A/B compartmentalization genome-wide. By contrast, deletion of three intra-TAD CTCF-independent 3D contact sites caused a domain-wide early-to-late RT shift, an A-to-B compartment switch, weakening of TAD architecture, and loss of transcription. The dispensability of TAD boundaries and the necessity of these "early replication control elements" (ERCEs) was validated by deletions and inversions at additional domains. Our results demonstrate that discrete cis-regulatory elements orchestrate domain-wide RT, A/B compartmentalization, TAD architecture, and transcription, revealing fundamental principles linking genome structure and function.


Assuntos
Período de Replicação do DNA/fisiologia , Replicação do DNA/genética , Replicação do DNA/fisiologia , Animais , Fator de Ligação a CCCTC/genética , Fator de Ligação a CCCTC/metabolismo , Cromatina , DNA/genética , Período de Replicação do DNA/genética , Células-Tronco Embrionárias , Elementos Facilitadores Genéticos/genética , Mamíferos/genética , Mamíferos/metabolismo , Camundongos , Proteínas Repressoras/metabolismo , Análise Espaço-Temporal
4.
Cell ; 175(1): 38-40, 2018 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-30241613

RESUMO

TAD boundaries are insulators of genomic neighborhoods. In this issue, Sun et al. show that disease-associated tandem repeats are located to TAD boundaries and affect their insulation. The findings have important implications for TAD function and mechanisms underlying diseases such as fragile X syndrome and Huntington's disease.


Assuntos
Cromatina , Síndrome do Cromossomo X Frágil/genética , Genoma , Genômica , Humanos , Repetições de Microssatélites
5.
Nat Immunol ; 21(5): 513-524, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32284594

RESUMO

Oxidative stress is a central part of innate immune-induced neurodegeneration. However, the transcriptomic landscape of central nervous system (CNS) innate immune cells contributing to oxidative stress is unknown, and therapies to target their neurotoxic functions are not widely available. Here, we provide the oxidative stress innate immune cell atlas in neuroinflammatory disease and report the discovery of new druggable pathways. Transcriptional profiling of oxidative stress-producing CNS innate immune cells identified a core oxidative stress gene signature coupled to coagulation and glutathione-pathway genes shared between a microglia cluster and infiltrating macrophages. Tox-seq followed by a microglia high-throughput screen and oxidative stress gene network analysis identified the glutathione-regulating compound acivicin, with potent therapeutic effects that decrease oxidative stress and axonal damage in chronic and relapsing multiple sclerosis models. Thus, oxidative stress transcriptomics identified neurotoxic CNS innate immune populations and may enable discovery of selective neuroprotective strategies.


Assuntos
Encefalomielite Autoimune Experimental/genética , Perfilação da Expressão Gênica/métodos , Microglia/fisiologia , Esclerose Múltipla/genética , Inflamação Neurogênica/genética , Animais , Antioxidantes/uso terapêutico , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/tratamento farmacológico , Feminino , Redes Reguladoras de Genes , Ensaios de Triagem em Larga Escala , Humanos , Imunidade Inata , Isoxazóis/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Esclerose Múltipla/tratamento farmacológico , Inflamação Neurogênica/tratamento farmacológico , Estresse Oxidativo , Análise de Sequência de RNA , Análise de Célula Única
7.
Cell ; 169(5): 930-944.e22, 2017 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-28525758

RESUMO

The molecular mechanisms underlying folding of mammalian chromosomes remain poorly understood. The transcription factor CTCF is a candidate regulator of chromosomal structure. Using the auxin-inducible degron system in mouse embryonic stem cells, we show that CTCF is absolutely and dose-dependently required for looping between CTCF target sites and insulation of topologically associating domains (TADs). Restoring CTCF reinstates proper architecture on altered chromosomes, indicating a powerful instructive function for CTCF in chromatin folding. CTCF remains essential for TAD organization in non-dividing cells. Surprisingly, active and inactive genome compartments remain properly segregated upon CTCF depletion, revealing that compartmentalization of mammalian chromosomes emerges independently of proper insulation of TADs. Furthermore, our data support that CTCF mediates transcriptional insulator function through enhancer blocking but not as a direct barrier to heterochromatin spreading. Beyond defining the functions of CTCF in chromosome folding, these results provide new fundamental insights into the rules governing mammalian genome organization.


Assuntos
Cromossomos de Mamíferos/química , Animais , Fator de Ligação a CCCTC , Ciclo Celular , Cromatina/metabolismo , Cromossomos de Mamíferos/genética , Cromossomos de Mamíferos/metabolismo , Células-Tronco Embrionárias/metabolismo , Regulação da Expressão Gênica , Ácidos Indolacéticos/farmacologia , Camundongos , Proteínas Repressoras/metabolismo , Transcrição Gênica
8.
Cell ; 164(5): 999-1014, 2016 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-26875865

RESUMO

Transcription factors (TFs) are thought to function with partners to achieve specificity and precise quantitative outputs. In the developing heart, heterotypic TF interactions, such as between the T-box TF TBX5 and the homeodomain TF NKX2-5, have been proposed as a mechanism for human congenital heart defects. We report extensive and complex interdependent genomic occupancy of TBX5, NKX2-5, and the zinc finger TF GATA4 coordinately controlling cardiac gene expression, differentiation, and morphogenesis. Interdependent binding serves not only to co-regulate gene expression but also to prevent TFs from distributing to ectopic loci and activate lineage-inappropriate genes. We define preferential motif arrangements for TBX5 and NKX2-5 cooperative binding sites, supported at the atomic level by their co-crystal structure bound to DNA, revealing a direct interaction between the two factors and induced DNA bending. Complex interdependent binding mechanisms reveal tightly regulated TF genomic distribution and define a combinatorial logic for heterotypic TF regulation of differentiation.


Assuntos
Fator de Transcrição GATA4/metabolismo , Proteínas de Homeodomínio/metabolismo , Miocárdio/citologia , Organogênese , Proteínas com Domínio T/metabolismo , Fatores de Transcrição/metabolismo , Animais , Diferenciação Celular , Cristalografia por Raios X , Embrião de Mamíferos/metabolismo , Proteína Homeobox Nkx-2.5 , Proteínas de Homeodomínio/genética , Camundongos , Camundongos Transgênicos , Modelos Moleculares , Miocárdio/metabolismo , Regiões Promotoras Genéticas , Domínios e Motivos de Interação entre Proteínas , Proteínas com Domínio T/genética , Fatores de Transcrição/genética
9.
Mol Cell ; 83(15): 2624-2640, 2023 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-37419111

RESUMO

The four-dimensional nucleome (4DN) consortium studies the architecture of the genome and the nucleus in space and time. We summarize progress by the consortium and highlight the development of technologies for (1) mapping genome folding and identifying roles of nuclear components and bodies, proteins, and RNA, (2) characterizing nuclear organization with time or single-cell resolution, and (3) imaging of nuclear organization. With these tools, the consortium has provided over 2,000 public datasets. Integrative computational models based on these data are starting to reveal connections between genome structure and function. We then present a forward-looking perspective and outline current aims to (1) delineate dynamics of nuclear architecture at different timescales, from minutes to weeks as cells differentiate, in populations and in single cells, (2) characterize cis-determinants and trans-modulators of genome organization, (3) test functional consequences of changes in cis- and trans-regulators, and (4) develop predictive models of genome structure and function.


Assuntos
Núcleo Celular , Genoma , Genoma/genética , Núcleo Celular/genética , Núcleo Celular/metabolismo , Cromatina/metabolismo
10.
Cell ; 160(6): 1072-86, 2015 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-25768904

RESUMO

The mechanisms by which transcription factor haploinsufficiency alters the epigenetic and transcriptional landscape in human cells to cause disease are unknown. Here, we utilized human induced pluripotent stem cell (iPSC)-derived endothelial cells (ECs) to show that heterozygous nonsense mutations in NOTCH1 that cause aortic valve calcification disrupt the epigenetic architecture, resulting in derepression of latent pro-osteogenic and -inflammatory gene networks. Hemodynamic shear stress, which protects valves from calcification in vivo, activated anti-osteogenic and anti-inflammatory networks in NOTCH1(+/+), but not NOTCH1(+/-), iPSC-derived ECs. NOTCH1 haploinsufficiency altered H3K27ac at NOTCH1-bound enhancers, dysregulating downstream transcription of more than 1,000 genes involved in osteogenesis, inflammation, and oxidative stress. Computational predictions of the disrupted NOTCH1-dependent gene network revealed regulatory nodes that, when modulated, restored the network toward the NOTCH1(+/+) state. Our results highlight how alterations in transcription factor dosage affect gene networks leading to human disease and reveal nodes for potential therapeutic intervention.


Assuntos
Epigênese Genética , Redes Reguladoras de Genes , Receptor Notch1/genética , Células Endoteliais/metabolismo , Feminino , Haploinsuficiência , Código das Histonas , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Inflamação/metabolismo , Masculino , Osteogênese , Linhagem , Receptor Notch1/metabolismo , Estresse Mecânico , Transcrição Gênica
11.
Genes Dev ; 36(11-12): 652-663, 2022 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-35835508

RESUMO

Congenital heart defects (CHDs) are among the most common birth defects, but their etiology has long been mysterious. In recent decades, the development of a variety of experimental models has led to a greater understanding of the molecular basis of CHDs. In this review, we contrast mouse models of CHD, which maintain the anatomical arrangement of the heart, and human cellular models of CHD, which are more likely to capture human-specific biology but lack anatomical structure. We also discuss the recent development of cardiac organoids, which are a promising step toward more anatomically informative human models of CHD.


Assuntos
Cardiopatias Congênitas , Organoides , Animais , Modelos Animais de Doenças , Coração , Cardiopatias Congênitas/genética , Humanos , Camundongos
12.
Genes Dev ; 35(21-22): 1401-1402, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34725128

RESUMO

In this issue of Genes & Development, Amândio and colleagues (pp. 1490-1509) dissect the function of a cluster of several CTCF binding sites in the HoxD cluster by iterative deletions in mice. They found additive functions for some, and intriguingly found that some sites function as insulators, while others function as anchors for enhancer-promoter interactions. These functions vary depending on developmental context. The work provides new insights into the roles played by CTCF in regulating developmental patterns and 3D chromatin organization.


Assuntos
Cromatina , Elementos Facilitadores Genéticos , Animais , Sítios de Ligação/genética , Fator de Ligação a CCCTC/genética , Fator de Ligação a CCCTC/metabolismo , Cromatina/genética , Elementos Facilitadores Genéticos/genética , Proteínas de Homeodomínio , Camundongos , Regiões Promotoras Genéticas/genética
13.
Nature ; 602(7895): 129-134, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35082446

RESUMO

Differentiation proceeds along a continuum of increasingly fate-restricted intermediates, referred to as canalization1,2. Canalization is essential for stabilizing cell fate, but the mechanisms that underlie robust canalization are unclear. Here we show that the BRG1/BRM-associated factor (BAF) chromatin-remodelling complex ATPase gene Brm safeguards cell identity during directed cardiogenesis of mouse embryonic stem cells. Despite the establishment of a well-differentiated precardiac mesoderm, Brm-/- cells predominantly became neural precursors, violating germ layer assignment. Trajectory inference showed a sudden acquisition of a non-mesodermal identity in Brm-/- cells. Mechanistically, the loss of Brm prevented de novo accessibility of primed cardiac enhancers while increasing the expression of neurogenic factor POU3F1, preventing the binding of the neural suppressor REST and shifting the composition of BRG1 complexes. The identity switch caused by the Brm mutation was overcome by increasing BMP4 levels during mesoderm induction. Mathematical modelling supports these observations and demonstrates that Brm deletion affects cell fate trajectory by modifying saddle-node bifurcations2. In the mouse embryo, Brm deletion exacerbated mesoderm-deleted Brg1-mutant phenotypes, severely compromising cardiogenesis, and reveals an in vivo role for Brm. Our results show that Brm is a compensable safeguard of the fidelity of mesoderm chromatin states, and support a model in which developmental canalization is not a rigid irreversible path, but a highly plastic trajectory.


Assuntos
Diferenciação Celular , Linhagem da Célula , Mesoderma/citologia , Mesoderma/metabolismo , Miócitos Cardíacos/citologia , Fatores de Transcrição/metabolismo , Animais , Proteína Morfogenética Óssea 4/metabolismo , Cromatina/genética , Cromatina/metabolismo , Montagem e Desmontagem da Cromatina , DNA Helicases/metabolismo , Embrião de Mamíferos , Epigênese Genética , Feminino , Regulação da Expressão Gênica , Masculino , Camundongos , Miocárdio/metabolismo , Neurogênese , Neurônios/citologia , Neurônios/metabolismo , Proteínas Nucleares/metabolismo , Fator 6 de Transcrição de Octâmero/metabolismo , Fenótipo , Proteínas Repressoras/metabolismo , Células-Tronco/citologia , Fatores de Tempo , Fatores de Transcrição/deficiência , Fatores de Transcrição/genética
14.
Development ; 151(6)2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38411343

RESUMO

In the nascent mesoderm, TBXT expression must be precisely regulated to ensure that cells exit the primitive streak and pattern the anterior-posterior axis, but how varying dosage informs morphogenesis is not well understood. In this study, we define the transcriptional consequences of TBXT dosage reduction during early human gastrulation using human induced pluripotent stem cell models of gastrulation and mesoderm differentiation. Multi-omic single-nucleus RNA and single-nucleus ATAC sequencing of 2D gastruloids comprising wild-type, TBXT heterozygous or TBXT null human induced pluripotent stem cells reveal that varying TBXT dosage does not compromise the ability of a cell to differentiate into nascent mesoderm, but instead directly influences the temporal progression of the epithelial-to-mesenchymal transition with wild type transitioning first, followed by TBXT heterozygous and then TBXT null. By differentiating cells into nascent mesoderm in a monolayer format, we further illustrate that TBXT dosage directly impacts the persistence of junctional proteins and cell-cell adhesions. These results demonstrate that epithelial-to-mesenchymal transition progression can be decoupled from the acquisition of mesodermal identity in the early gastrula and shed light on the mechanisms underlying human embryogenesis.


Assuntos
Células-Tronco Pluripotentes Induzidas , Humanos , Mesoderma/metabolismo , Gástrula/metabolismo , Gastrulação/genética , Diferenciação Celular/genética
15.
Cell ; 151(1): 206-20, 2012 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-22981692

RESUMO

Heart development is exquisitely sensitive to the precise temporal regulation of thousands of genes that govern developmental decisions during differentiation. However, we currently lack a detailed understanding of how chromatin and gene expression patterns are coordinated during developmental transitions in the cardiac lineage. Here, we interrogated the transcriptome and several histone modifications across the genome during defined stages of cardiac differentiation. We find distinct chromatin patterns that are coordinated with stage-specific expression of functionally related genes, including many human disease-associated genes. Moreover, we discover a novel preactivation chromatin pattern at the promoters of genes associated with heart development and cardiac function. We further identify stage-specific distal enhancer elements and find enriched DNA binding motifs within these regions that predict sets of transcription factors that orchestrate cardiac differentiation. Together, these findings form a basis for understanding developmentally regulated chromatin transitions during lineage commitment and the molecular etiology of congenital heart disease.


Assuntos
Epigênese Genética , Redes Reguladoras de Genes , Miocárdio/citologia , Animais , Diferenciação Celular , Cromatina/metabolismo , Células-Tronco Embrionárias/metabolismo , Elementos Facilitadores Genéticos , Coração/embriologia , Humanos , Camundongos , Fatores de Transcrição/metabolismo , Transcriptoma
16.
Mol Cell ; 76(3): 412-422.e5, 2019 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-31522988

RESUMO

The function of the CCCTC-binding factor (CTCF) in the organization of the genome has become an important area of investigation, but the mechanisms by which CTCF dynamically contributes to genome organization are not clear. We previously discovered that CTCF binds to large numbers of endogenous RNAs, promoting its self-association. In this regard, we now report two independent features that disrupt CTCF association with chromatin: inhibition of transcription and disruption of CTCF-RNA interactions through mutations of 2 of its 11 zinc fingers that are not required for CTCF binding to its cognate DNA site: zinc finger 1 (ZF1) or zinc finger 10 (ZF10). These mutations alter gene expression profiles as CTCF mutants lose their ability to form chromatin loops and thus the ability to insulate chromatin domains and to mediate CTCF long-range genomic interactions. Our results point to the importance of CTCF-mediated RNA interactions as a structural component of genome organization.


Assuntos
Fator de Ligação a CCCTC/metabolismo , Cromatina/metabolismo , Células-Tronco Embrionárias Murinas/metabolismo , RNA/metabolismo , Animais , Sítios de Ligação , Fator de Ligação a CCCTC/química , Fator de Ligação a CCCTC/genética , Linhagem Celular , Cromatina/química , Cromatina/genética , Camundongos , Mutação , Conformação de Ácido Nucleico , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , RNA/química , RNA/genética , Relação Estrutura-Atividade , Transcrição Gênica , Dedos de Zinco
17.
Development ; 150(9)2023 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-36994838

RESUMO

Transcriptional networks governing cardiac precursor cell (CPC) specification are incompletely understood owing, in part, to limitations in distinguishing CPCs from non-cardiac mesoderm in early gastrulation. We leveraged detection of early cardiac lineage transgenes within a granular single-cell transcriptomic time course of mouse embryos to identify emerging CPCs and describe their transcriptional profiles. Mesp1, a transiently expressed mesodermal transcription factor, is canonically described as an early regulator of cardiac specification. However, we observed perdurance of CPC transgene-expressing cells in Mesp1 mutants, albeit mislocalized, prompting us to investigate the scope of the role of Mesp1 in CPC emergence and differentiation. Mesp1 mutant CPCs failed to robustly activate markers of cardiomyocyte maturity and crucial cardiac transcription factors, yet they exhibited transcriptional profiles resembling cardiac mesoderm progressing towards cardiomyocyte fates. Single-cell chromatin accessibility analysis defined a Mesp1-dependent developmental breakpoint in cardiac lineage progression at a shift from mesendoderm transcriptional networks to those necessary for cardiac patterning and morphogenesis. These results reveal Mesp1-independent aspects of early CPC specification and underscore a Mesp1-dependent regulatory landscape required for progression through cardiogenesis.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos , Epigenômica , Miócitos Cardíacos , Animais , Camundongos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Diferenciação Celular/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Mesoderma/metabolismo , Miócitos Cardíacos/metabolismo , Fatores de Transcrição/metabolismo
18.
Cell ; 142(3): 375-86, 2010 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-20691899

RESUMO

The reprogramming of fibroblasts to induced pluripotent stem cells (iPSCs) raises the possibility that a somatic cell could be reprogrammed to an alternative differentiated fate without first becoming a stem/progenitor cell. A large pool of fibroblasts exists in the postnatal heart, yet no single "master regulator" of direct cardiac reprogramming has been identified. Here, we report that a combination of three developmental transcription factors (i.e., Gata4, Mef2c, and Tbx5) rapidly and efficiently reprogrammed postnatal cardiac or dermal fibroblasts directly into differentiated cardiomyocyte-like cells. Induced cardiomyocytes expressed cardiac-specific markers, had a global gene expression profile similar to cardiomyocytes, and contracted spontaneously. Fibroblasts transplanted into mouse hearts one day after transduction of the three factors also differentiated into cardiomyocyte-like cells. We believe these findings demonstrate that functional cardiomyocytes can be directly reprogrammed from differentiated somatic cells by defined factors. Reprogramming of endogenous or explanted fibroblasts might provide a source of cardiomyocytes for regenerative approaches.


Assuntos
Diferenciação Celular , Fibroblastos/citologia , Miocárdio/citologia , Miócitos Cardíacos/citologia , Animais , Separação Celular , Fibroblastos/metabolismo , Fator de Transcrição GATA4/metabolismo , Perfilação da Expressão Gênica , Fatores de Transcrição MEF2 , Camundongos , Contração Muscular , Miócitos Cardíacos/metabolismo , Fatores de Regulação Miogênica/metabolismo , Proteínas com Domínio T/metabolismo
19.
J Acoust Soc Am ; 155(2): 1021-1035, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38341738

RESUMO

Acoustic events exceeding a certain threshold of intensity cannot benefit from a linearization of the governing wave equation, posing an additional burden on the numerical modelling. Weak shock theory associates nonlinearity with the generation of high frequency harmonics that compensate for atmospheric attenuation. Overlooking the persistence of this phenomenon at large distances can lead to mispredictions in gun detection procedures, noise abatement protocols, and auditory risk assessment. The state-of-the-art mostly addresses aircraft jet noise, a stationary and largely random type of signal. The extension of such conclusions to muzzle blasts requires caution in considering their peculiar impulsive and broadband nature. A methodology based on the time and frequency analysis of an experimental dataset of eight calibres intends to find quantitative metrics linked to acoustic nonlinearity in outdoor muzzle blast propagation. Propagating three waveforms (SCAR-L 7.62 mm, Browning 9 mm, and Howitzer 105 mm) up to 300 [m] with the in-house numerical solver based on the nonlinear progressive wave equation, demonstrates that the propagation does not downgrade to truly linear.

20.
J Clin Monit Comput ; 38(3): 679-690, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38557919

RESUMO

This study aims to resolve the unmet need for ventilator surge capacity by developing a prototype device that can alter patient-specific flow in a shared ventilator setup. The device is designed to deliver a predictable tidal volume (VT), requiring minimal additional monitoring and workload. The prototyped device was tested in an in vitro bench setup for its performance against the intended use and design criteria. The ventilation parameters: VT and airway pressures, and ventilation profiles: pressure, flow and volume were measured for different ventilator and device settings for a healthy and ARDS simulated lung pathology. We obtained VTs with a linear correlation with valve openings from 10 to 100% across set inspiratory pressures (IPs) of 20 to 30 cmH2O. Airway pressure varied with valve opening and lung elastance but did not exceed set IPs. Performance was consistent in both healthy and ARDS-simulated lung conditions. The ventilation profile diverged from traditional pressure-controlled profiles. We present the design a flow modulator to titrate VTs in a shared ventilator setup. Application of the flow modulator resulted in a characteristic flow profile that differs from pressure- or volume controlled ventilation. The development of the flow modulator enables further validation of the Individualized Shared Ventilation (ISV) technology with individualization of delivered VTs and the development of a clinical protocol facilitating its clinical use during a ventilator surge capacity problem.


Assuntos
Desenho de Equipamento , Pulmão , Respiração Artificial , Síndrome do Desconforto Respiratório , Volume de Ventilação Pulmonar , Ventiladores Mecânicos , Humanos , Respiração Artificial/instrumentação , Respiração Artificial/métodos , Síndrome do Desconforto Respiratório/terapia , Síndrome do Desconforto Respiratório/fisiopatologia , Pulmão/fisiopatologia , Pressão
SELEÇÃO DE REFERÊNCIAS
Detalhe da pesquisa