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1.
Am J Med Genet A ; 2019 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-31587467

RESUMO

Pathogenic DNM1L mutations cause a mitochondrial disorder with a highly variable clinical phenotype characterized by developmental delay, hypotonia, seizures, microcephaly, poor feeding, ocular abnormalities, and dysarthria. We report the case of an 8-month-old female with autosomal dominant, de novo DNM1L c. 1228G>A (p. E410K) mutation and mitochondrial disorder, septo-optic dysplasia, hypotonia, developmental delay, elevated blood lactate, and severe mitochondrial cardiomyopathy leading to nonischemic congestive heart failure and cardiogenic shock resulting in death. This case suggests that cardiac involvement, previously undescribed, can be a clinically important feature of this syndrome and should be screened for at diagnosis.

2.
Vet Rec ; 185(14): 448, 2019 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-31604874
3.
J Cell Mol Med ; 23(10): 7000-7009, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31402541

RESUMO

Marfan syndrome (MFS) is a connective tissue disorder that results in aortic root aneurysm formation. Reactive oxygen species (ROS) seem to play a role in aortic wall remodelling in MFS, although the mechanism remains unknown. MFS Fbn1C1039G/+ mouse root/ascending (AS) and descending (DES) aortic samples were examined using DHE staining, lucigenin-enhanced chemiluminescence (LGCL), Verhoeff's elastin-Van Gieson staining (elastin breakdown) and in situ zymography for protease activity. Fbn1C1039G/+ AS- or DES-derived smooth muscle cells (SMC) were treated with anti-TGF-ß antibody, angiotensin II (AngII), anti-TGF-ß antibody + AngII, or isotype control. ROS were detected during early aneurysm formation in the Fbn1C1039G/+ AS aorta, but absent in normal-sized DES aorta. Fbn1C1039G/+ mice treated with the unspecific NADPH oxidase inhibitor, apocynin reduced AS aneurysm formation, with attenuated elastin fragmentation. In situ zymography revealed apocynin treatment decreased protease activity. In vitro SMC studies showed Fbn1C1039G/+ -derived AS SMC had increased NADPH activity compared to DES-derived SMC. AS SMC NADPH activity increased with AngII treatment and appeared TGF-ß dependent. In conclusion, ROS play a role in MFS aneurysm development and correspond anatomically with aneurysmal aortic segments. ROS inhibition via apocynin treatment attenuates MFS aneurysm progression. AngII enhances ROS production in MFS AS SMCs and is likely TGF-ß dependent.

4.
Nat Commun ; 10(1): 2760, 2019 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-31235787

RESUMO

Heart failure is a leading cause of mortality, yet our understanding of the genetic interactions underlying this disease remains incomplete. Here, we harvest 1352 healthy and failing human hearts directly from transplant center operating rooms, and obtain genome-wide genotyping and gene expression measurements for a subset of 313. We build failing and non-failing cardiac regulatory gene networks, revealing important regulators and cardiac expression quantitative trait loci (eQTLs). PPP1R3A emerges as a regulator whose network connectivity changes significantly between health and disease. RNA sequencing after PPP1R3A knockdown validates network-based predictions, and highlights metabolic pathway regulation associated with increased cardiomyocyte size and perturbed respiratory metabolism. Mice lacking PPP1R3A are protected against pressure-overload heart failure. We present a global gene interaction map of the human heart failure transition, identify previously unreported cardiac eQTLs, and demonstrate the discovery potential of disease-specific networks through the description of PPP1R3A as a central regulator in heart failure.


Assuntos
Redes Reguladoras de Genes/genética , Insuficiência Cardíaca/genética , Miócitos Cardíacos/patologia , Fosfoproteínas Fosfatases/metabolismo , Animais , Benzenoacetamidas , Células Cultivadas , Conjuntos de Dados como Assunto , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Estudo de Associação Genômica Ampla , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Humanos , Masculino , Redes e Vias Metabólicas/genética , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Fosfoproteínas Fosfatases/genética , Cultura Primária de Células , Piridinas , Locos de Características Quantitativas/genética , Ratos , Ratos Sprague-Dawley , Análise de Sequência de RNA/métodos
5.
Nat Commun ; 10(1): 2027, 2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-31048694

RESUMO

Traditional tests of concept knowledge generate scores to assess how well a learner understands a concept. Here, we investigated whether patterns of brain activity collected during a concept knowledge task could be used to compute a neural 'score' to complement traditional scores of an individual's conceptual understanding. Using a novel data-driven multivariate neuroimaging approach-informational network analysis-we successfully derived a neural score from patterns of activity across the brain that predicted individual differences in multiple concept knowledge tasks in the physics and engineering domain. These tasks include an fMRI paradigm, as well as two other previously validated concept inventories. The informational network score outperformed alternative neural scores computed using data-driven neuroimaging methods, including multivariate representational similarity analysis. This technique could be applied to quantify concept knowledge in a wide range of domains, including classroom-based education research, machine learning, and other areas of cognitive science.


Assuntos
Mapeamento Encefálico/métodos , Encéfalo/fisiologia , Educação/métodos , Individualidade , Aprendizagem/fisiologia , Adulto , Encéfalo/diagnóstico por imagem , Currículo , Engenharia/educação , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Matemática/educação , Ciência/educação , Estudantes/psicologia , Tecnologia/educação , Adulto Jovem
6.
J Am Heart Assoc ; 7(21): e008543, 2018 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-30571378

RESUMO

Background Statins reduce aneurysm growth in mouse models of Marfan syndrome, although the mechanism is unknown. In addition to reducing cholesterol, statins block farnesylation and geranylgeranylation, which participate in membrane-bound G-protein signaling, including Ras. We dissected the prenylation pathway to define the effect of statins on aneurysm reduction. Methods and Results Fbn1C1039G/+ mice were treated with (1) pravastatin (HMG-CoA [3-hydroxy-3-methylglutaryl coenzyme A] reductase inhibitor), (2) manumycin A ( MA ; FPT inhibitor), (3) perillyl alcohol ( GGPT 1 and -2 inhibitor), or (4) vehicle control from age 4 to 8 weeks and euthanized at 12 weeks. Histological characterization was performed. Protein analysis was completed on aortic specimens to measure ERK (extracellular signal-regulated kinase) signaling. In vitro Fbn1C1039G/+ aortic smooth muscle cells were utilized to measure Ras-dependent ERK signaling and MMP (matrix metalloproteinase) activity. Pravastatin and MA significantly reduced aneurysm growth compared with vehicle control (n=8 per group). In contrast, PA did not significantly decrease aneurysm size. Histology illustrated reduced elastin breakdown in MA -treated mice compared with vehicle control (n=5 per group). Although elevated in control Marfan mice, both phosphorylated c-Raf and phosphorylated ERK 1/2 were significantly reduced in MA -treated mice (4-5 per group). In vitro smooth muscle cell studies confirmed phosphorylated cR af and phosphorylated ERK 1/2 signaling was elevated in Fbn1C1039G/+ smooth muscle cells (n=5 per group). Fbn1C1039G/+ smooth muscle cell Ras-dependent ERK signaling and MMP activity were reduced following MA treatment (n=5 per group). Corroborating in vitro findings, MMP activity was also decreased in pravastatin-treated mice. Conclusions Aneurysm reduction in Fbn1C1039G/+ mice following pravastatin and MA treatment was associated with a decrease in Ras-dependent ERK signaling. MMP activity can be reduced by diminishing Ras signaling.

7.
Am J Med Genet A ; 2018 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-30380203

RESUMO

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) describes a group of developmental disorders affecting the lungs with its pulmonary vasculature. Mutations in the FOXF1 gene have been reported in most cases, and extrapulmonary findings were described. We present two patients with ACDMPV and FOXF1 mutations that illustrate the variability in presentation and outcome of their disease. Patient 1 was a full-term infant with imperforate anus and pulmonary hypertension. He required Extracorporeal Membrane Oxygenation on day of life (DOL) 3, and passed away on DOL 13 after no clinical improvement. Postmortem findings were consistent with ACDMPV. FOXF1 testing revealed a heterozygous pathogenic frameshift de novo mutation, c.1057_1078dup, p.(Gly360Valfs*58). Patient 2 is a 6-month-old female, with a small omphalocele. She had intermittent retractions at 1 week of age. She was admitted with pulmonary hypertension at 7 weeks of age. Lung biopsy confirmed ACDMPV. FOXF1 testing revealed a de novo, heterozygous likely pathogenic missense mutation c.253T>C, p.(Phe85Leu]). Our two patients had different presentations, ages of onset, and progression of their disease. Our second patient had patchy lung involvement on biopsy, which may explain the relatively delayed onset and longer survival. ACDMPV is an important consideration for full-term infants with worsening pulmonary hypertension early in life.

8.
Neuroimage ; 183: 99-111, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30081195

RESUMO

How does the brain represent a newly-learned mental model? Representational similarity analysis (RSA) has revealed the neural basis of common representational spaces learned early in development, such as categories of natural kinds. This study uses RSA to examine the neural implementation of a newly-learned mental model-i.e., a representational space created through deductive reasoning-and study the structure of previously found parietal activity in reasoning tasks. Specifically, all the information in this mental model could only be obtained through abstract transitive reasoning, as there were no predictive differences between observable features in the stimuli, and stimuli were counterbalanced across participants. Participants were shown unfamiliar face portraits paired with names and asked to learn about the height of each person pictured in the portraits through comparison to other individuals in the set. Participants learned the relative heights only of adjacent pairs in the set and then used transitive reasoning to generate a linear ranking of heights (e.g., "Matthew is taller than Thomas; Thomas is taller than Andrew; therefore Matthew is taller than Andrew"). During fMRI, participants recalled the approximate height of each individual based on these inferences. Using a predictive model based on the relative heights of the set of individuals, RSA revealed three brain regions in the right hemisphere that encoded this newly-learned representational space, located within the intraparietal sulcus, precuneus, and inferior frontal gyrus. These findings demonstrate the value of RSA for analyzing structure within patterns of activity and support theories asserting that logical reasoning recruits spatial processing mechanisms.

9.
Front Neurosci ; 12: 437, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30042652

RESUMO

Encoding models for mapping voxelwise semantic tuning are typically estimated separately for each individual, limiting their generalizability. In the current report, we develop a method for estimating semantic encoding models that generalize across individuals. Functional MRI was used to measure brain responses while participants freely viewed a naturalistic audiovisual movie. Word embeddings capturing agent-, action-, object-, and scene-related semantic content were assigned to each imaging volume based on an annotation of the film. We constructed both conventional within-subject semantic encoding models and between-subject models where the model was trained on a subset of participants and validated on a left-out participant. Between-subject models were trained using cortical surface-based anatomical normalization or surface-based whole-cortex hyperalignment. We used hyperalignment to project group data into an individual's unique anatomical space via a common representational space, thus leveraging a larger volume of data for out-of-sample prediction while preserving the individual's fine-grained functional-anatomical idiosyncrasies. Our findings demonstrate that anatomical normalization degrades the spatial specificity of between-subject encoding models relative to within-subject models. Hyperalignment, on the other hand, recovers the spatial specificity of semantic tuning lost during anatomical normalization, and yields model performance exceeding that of within-subject models.

10.
Brain Lang ; 183: 54-63, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29940339

RESUMO

In an fMRI investigation of the neural representation of word frequency and animacy, participants read high- and low-frequency words within living and nonliving semantic categories. Both temporal (left fusiform gyrus) and parietal (left supramarginal gyrus) activation patterns differentiated between animal and tool words after controlling for frequency. Activation patterns in a smaller ventral temporal region, a subset of the voxels identified in the animacy contrast, differentiated between high- and low-frequency words after controlling for animacy. Activation patterns in the larger temporal region distinguished between high- and low-frequency words just as well as patterns within the smaller region. However, in analyses by animacy category, frequency effects in these temporal regions were significant only for tool, not for animal, words. Thus, lexical word frequency information and semantic animacy category information are conjointly represented in left fusiform gyrus activation patterns for some, but not all, concrete nouns.

12.
Nat Commun ; 8(1): 2053, 2017 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-29233960

RESUMO

Large-scale genomic analyses of human cancers have cataloged somatic point mutations thought to initiate tumor development and sustain cancer growth. However, determining the functional significance of specific alterations remains a major bottleneck in our understanding of the genetic determinants of cancer. Here, we present a platform that integrates multiplexed AAV/Cas9-mediated homology-directed repair (HDR) with DNA barcoding and high-throughput sequencing to simultaneously investigate multiple genomic alterations in de novo cancers in mice. Using this approach, we introduce a barcoded library of non-synonymous mutations into hotspot codons 12 and 13 of Kras in adult somatic cells to initiate tumors in the lung, pancreas, and muscle. High-throughput sequencing of barcoded Kras HDR alleles from bulk lung and pancreas reveals surprising diversity in Kras variant oncogenicity. Rapid, cost-effective, and quantitative approaches to simultaneously investigate the function of precise genomic alterations in vivo will help uncover novel biological and clinically actionable insights into carcinogenesis.


Assuntos
Carcinogênese/genética , Análise Mutacional de DNA/métodos , Neoplasias/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Reparo de DNA por Recombinação/genética , Animais , Sistemas CRISPR-Cas/genética , Análise Custo-Benefício , Análise Mutacional de DNA/economia , Estudos de Viabilidade , Feminino , Genômica/economia , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Masculino , Camundongos , Mutação , Neoplasias/patologia , Reprodutibilidade dos Testes
13.
Nature ; 550(7674): 80-83, 2017 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-28980637

RESUMO

Type Ia supernovae arise from the thermonuclear explosion of white-dwarf stars that have cores of carbon and oxygen. The uniformity of their light curves makes these supernovae powerful cosmological distance indicators, but there have long been debates about exactly how their explosion is triggered and what kind of companion stars are involved. For example, the recent detection of the early ultraviolet pulse of a peculiar, subluminous type Ia supernova has been claimed as evidence for an interaction between a red-giant or a main-sequence companion and ejecta from a white-dwarf explosion. Here we report observations of a prominent but red optical flash that appears about half a day after the explosion of a type Ia supernova. This supernova shows hybrid features of different supernova subclasses, namely a light curve that is typical of normal-brightness supernovae, but with strong titanium absorption, which is commonly seen in the spectra of subluminous ones. We argue that this early flash does not occur through previously suggested mechanisms such as the companion-ejecta interaction. Instead, our simulations show that it could occur through detonation of a thin helium shell either on a near-Chandrasekhar-mass white dwarf, or on a sub-Chandrasekhar-mass white dwarf merging with a less-massive white dwarf. Our finding provides evidence that one branch of previously proposed explosion models-the helium-ignition branch-does exist in nature, and that such a model may account for the explosions of white dwarfs in a mass range wider than previously supposed.

14.
Cell Rep ; 20(8): 1978-1990, 2017 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-28834758

RESUMO

There is growing interest in using embryonic stem cell (ESC) and induced pluripotent stem cell (iPSC) derivatives for tissue regeneration. However, an increased understanding of human immune responses to stem cell-derived allografts is necessary for maintaining long-term graft persistence. To model this alloimmunity, humanized mice engrafted with human hematopoietic and immune cells could prove to be useful. In this study, an in-depth analysis of graft-infiltrating human lymphocytes and splenocytes revealed that humanized mice incompletely model human immune responses toward allogeneic stem cells and their derivatives. Furthermore, using an "allogenized" mouse model, we show the feasibility of reconstituting immunodeficient mice with a functional mouse immune system and describe a key role of innate immune cells in the rejection of mouse stem cell allografts.


Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Imunidade Inata/imunologia , Células-Tronco Pluripotentes/metabolismo , Condicionamento Pré-Transplante/métodos , Animais , Modelos Animais de Doenças , Rejeição de Enxerto , Humanos , Camundongos
15.
J Card Fail ; 23(12): 876-886, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28801076

RESUMO

BACKGROUND: Our aim was to develop a model of acute right heart failure (ARHF) in the setting of pulmonary hypertension and to characterize acute right ventricular lesions that develop early after hemodynamic restoration. METHODS AND RESULTS: We used a described piglet model of chronic pulmonary hypertension (cPH) induced by pulmonary artery occlusions. We induced ARHF in animals with cPH (ARHF-cPH group, n = 9) by volume loading and iterative acute pulmonary embolism until hemodynamic compromise followed by dobutamine infusion for hemodynamic restoration before sacrifice for right ventricular tissue evaluation. The median duration of ARHF before sacrifice was 162 (135-189) minutes. Although ventriculoarterial coupling (measured with multibeat pressure-volume loops) and stroke volume decreased after iterative pulmonary embolism and improved with dobutamine, relative pulmonary to systemic pressure increased by 2-fold and remained similarly increased with dobutamine. Circulating high-sensitivity troponin I increased after hemodynamic restoration. We found an increase in right ventricular subendocardial and subepicardial focal ischemic lesions and in expression of autophagy-related protein LC3-II (Western blot) in the ARHF-cPH group compared with the cPH (n = 5) and control (n = 5) groups. CONCLUSIONS: We developed and phenotyped a novel large animal model of ARHF on cPH in which right ventricular ischemic lesions were observed early after hemodynamic restoration.


Assuntos
Modelos Animais de Doenças , Insuficiência Cardíaca/diagnóstico por imagem , Hipertensão Pulmonar/diagnóstico por imagem , Embolia Pulmonar/diagnóstico por imagem , Disfunção Ventricular Direita/diagnóstico por imagem , Animais , Animais Recém-Nascidos , Biomarcadores/sangue , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/fisiopatologia , Hipertensão Pulmonar/sangue , Hipertensão Pulmonar/fisiopatologia , Embolia Pulmonar/sangue , Embolia Pulmonar/fisiopatologia , Suínos , Disfunção Ventricular Direita/sangue , Disfunção Ventricular Direita/fisiopatologia
16.
Cereb Cortex ; 27(8): 4277-4291, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28591837

RESUMO

Humans prioritize different semantic qualities of a complex stimulus depending on their behavioral goals. These semantic features are encoded in distributed neural populations, yet it is unclear how attention might operate across these distributed representations. To address this, we presented participants with naturalistic video clips of animals behaving in their natural environments while the participants attended to either behavior or taxonomy. We used models of representational geometry to investigate how attentional allocation affects the distributed neural representation of animal behavior and taxonomy. Attending to animal behavior transiently increased the discriminability of distributed population codes for observed actions in anterior intraparietal, pericentral, and ventral temporal cortices. Attending to animal taxonomy while viewing the same stimuli increased the discriminability of distributed animal category representations in ventral temporal cortex. For both tasks, attention selectively enhanced the discriminability of response patterns along behaviorally relevant dimensions. These findings suggest that behavioral goals alter how the brain extracts semantic features from the visual world. Attention effectively disentangles population responses for downstream read-out by sculpting representational geometry in late-stage perceptual areas.


Assuntos
Atenção/fisiologia , Encéfalo/fisiologia , Percepção de Movimento/fisiologia , Semântica , Adulto , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico/métodos , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Modelos Estatísticos , Vias Neurais/diagnóstico por imagem , Vias Neurais/fisiologia , Testes Neuropsicológicos , Reconhecimento Visual de Modelos/fisiologia
17.
Stem Cells ; 35(8): 1994-2000, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28600830

RESUMO

Human pluripotent stem cells, including human embryonic stem cells (hESCs) and human induced PSCs (hiPSCs), have great potential as an unlimited donor source for cell-based therapeutics. The risk of teratoma formation from residual undifferentiated cells, however, remains a critical barrier to the clinical application of these cells. Herein, we describe external beam radiation therapy (EBRT) as an attractive option for the treatment of this iatrogenic growth. We present evidence that EBRT is effective in arresting growth of hESC-derived teratomas in vivo at day 28 post-implantation by using a microCT irradiator capable of targeted treatment in small animals. Within several days of irradiation, teratomas derived from injection of undifferentiated hESCs and hiPSCs demonstrated complete growth arrest lasting several months. In addition, EBRT reduced reseeding potential of teratoma cells during serial transplantation experiments, requiring irradiated teratomas to be seeded at 1 × 103 higher doses to form new teratomas. We demonstrate that irradiation induces teratoma cell apoptosis, senescence, and growth arrest, similar to established radiobiology mechanisms. Taken together, these results provide proof of concept for the use of EBRT in the treatment of existing teratomas and highlight a strategy to increase the safety of stem cell-based therapies. Stem Cells 2017;35:1994-2000.


Assuntos
Células-Tronco Pluripotentes/patologia , Radiação Ionizante , Teratoma/radioterapia , Apoptose/efeitos da radiação , Diferenciação Celular/efeitos da radiação , Proliferação de Células/efeitos da radiação , Humanos , Células-Tronco Pluripotentes/efeitos da radiação , Teratoma/patologia
18.
Nature ; 545(7655): 495-499, 2017 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-28514441

RESUMO

Programmed cell death protein 1 (PD-1) is an immune checkpoint receptor that is upregulated on activated T cells for the induction of immune tolerance. Tumour cells frequently overexpress the ligand for PD-1, programmed cell death ligand 1 (PD-L1), facilitating their escape from the immune system. Monoclonal antibodies that block the interaction between PD-1 and PD-L1, by binding to either the ligand or receptor, have shown notable clinical efficacy in patients with a variety of cancers, including melanoma, colorectal cancer, non-small-cell lung cancer and Hodgkin's lymphoma. Although it is well established that PD-1-PD-L1 blockade activates T cells, little is known about the role that this pathway may have in tumour-associated macrophages (TAMs). Here we show that both mouse and human TAMs express PD-1. TAM PD-1 expression increases over time in mouse models of cancer and with increasing disease stage in primary human cancers. TAM PD-1 expression correlates negatively with phagocytic potency against tumour cells, and blockade of PD-1-PD-L1 in vivo increases macrophage phagocytosis, reduces tumour growth and lengthens the survival of mice in mouse models of cancer in a macrophage-dependent fashion. This suggests that PD-1-PD-L1 therapies may also function through a direct effect on macrophages, with substantial implications for the treatment of cancer with these agents.


Assuntos
Neoplasias do Colo/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Fagocitose , Receptor de Morte Celular Programada 1/metabolismo , Animais , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Modelos Animais de Doenças , Feminino , Humanos , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Estadiamento de Neoplasias , Fagocitose/efeitos dos fármacos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Physiol Rep ; 5(8)2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28455451

RESUMO

Aortic root aneurysm formation and subsequent dissection and/or rupture remain the leading cause of death in patients with Marfan syndrome. Our laboratory has reported that miR-29b participates in aortic root/ascending aorta extracellular matrix remodeling during early aneurysm formation in Fbn1C1039G/+ Marfan mice. Herein, we sought to determine whether miR-29b suppression can reduce aneurysm formation long-term. Fbn1C1039G/+ Marfan mice were treated with retro-orbital LNA-anti-miR-29b inhibitor or scrambled-control-miR before aneurysms develop either (1) a single dose prenatally (pregnant Fbn1C1039G/+ mice at 14.5 days post-coitum) (n = 8-10, each group) or (2) postnatally every other week, from 2 to 22 weeks of age, and sacrificed at 24 weeks (n = 8-10, each group). To determine if miR-29b blockade was beneficial even after aneurysms develop, a third group of animals were treated every other week, starting at 8 weeks of age, until sacrificed (n = 4-6, each group). miR-29b inhibition resulted in aneurysm reduction, increased elastogenesis, decreased matrix metalloproteinase activity and decreased elastin breakdown. Prenatal LNA-anti-miR-29b inhibitor treatment decreased aneurysm formation up to age 32 weeks, whereas postnatal treatment was effective up to 16 weeks. miR-29b blockade did not slow aortic growth once aneurysms already developed. Systemic miR-29b inhibition significantly reduces aneurysm development long-term in a Marfan mouse model. Drug administration during aortic wall embryologic development appears fundamental. miR-29b suppression could be a potential therapeutic target for reducing aneurysm formation in Marfan syndrome patients.


Assuntos
Aneurisma Aórtico/prevenção & controle , Terapia Genética/métodos , Síndrome de Marfan/terapia , MicroRNAs/antagonistas & inibidores , Animais , Aneurisma Aórtico/diagnóstico por imagem , Aneurisma Aórtico/etiologia , Aneurisma Aórtico/patologia , Modelos Animais de Doenças , Progressão da Doença , Ecocardiografia , Elastina/metabolismo , Matriz Extracelular/fisiologia , Feminino , Terapias Fetais/métodos , Masculino , Síndrome de Marfan/complicações , Síndrome de Marfan/genética , Metaloproteinases da Matriz/fisiologia , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Terapia de Alvo Molecular/métodos , Cuidado Pré-Natal/métodos
20.
Epilepsia ; 58(3): 373-380, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27935031

RESUMO

OBJECTIVES: Interictal epileptiform discharges (IEDs) have been linked to memory impairment, but the spatial and temporal dynamics of this relationship remain elusive. In the present study, we aim to systematically characterize the brain areas and times at which IEDs affect memory. METHODS: Eighty epilepsy patients participated in a delayed free recall task while undergoing intracranial electroencephalography (EEG) monitoring. We analyzed the locations and timing of IEDs relative to the behavioral data in order to measure their effects on memory. RESULTS: Overall IED rates did not correlate with task performance across subjects (r = 0.03, p = 0.8). However, at a finer temporal scale, within-subject memory was negatively affected by IEDs during the encoding and recall periods of the task but not during the rest and distractor periods (p < 0.01, p < 0.001, p = 0.3, and p = 0.8, respectively). The effects of IEDs during encoding and recall were stronger in the left hemisphere than in the right (p < 0.05). Of six brain areas analyzed, IEDs in the inferior-temporal, medial-temporal, and parietal areas significantly affected memory (false discovery rate < 0.05). SIGNIFICANCE: These findings reveal a network of brain areas sensitive to IEDs with key nodes in temporal as well as parietal lobes. They also demonstrate the time-dependent effects of IEDs in this network on memory.


Assuntos
Encéfalo/patologia , Encéfalo/fisiopatologia , Epilepsia/complicações , Epilepsia/patologia , Transtornos da Memória/etiologia , Rememoração Mental/fisiologia , Adulto , Mapeamento Encefálico , Feminino , Humanos , Masculino , Transtornos da Memória/diagnóstico , Pessoa de Meia-Idade , Testes Neuropsicológicos , Curva ROC , Aprendizagem Verbal/fisiologia , Adulto Jovem
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