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Synchronous tracings of Korotkov's sounds, electrocardiogram, and pressure in sphygmomanometer cuff make possible to construct a curve whose shape is practically congruent with the ascending limb of the arterial pressure wave; the curve is usable for determining several haemodynamic indicators, namely, the maximal and minimal pulse, and mean pressures, pulse wave propagation velocity, and myocardial contraction capacity. When arterial sounds are objectively recorded with dur regard to the cuff dimensions and adherence to the "ipsilaterality principle", the error of pressure measurement does not exceed 4--5 mmHg.

Článek

Down-regulation of the brain-specific cell-adhesion molecule contactin-3 in tuberous sclerosis complex during the early postnatal period

Journal of neurodevelopmental disorders. 2022 ; 14 (1) : 8. [pub] 20220115

J Neurodev Disord
ISSN 1866-1955
Medvik
Zdroj

BACKGROUND: The genetic disorder tuberous sclerosis complex (TSC) is frequently accompanied by the development of neuropsychiatric disorders, including autism spectrum disorder and intellectual disability, with varying degrees of impairment. These co-morbidities in TSC have been linked to the structural brain abnormalities, such as cortical tubers, and recurrent epileptic seizures (in 70-80% cases). Previous transcriptomic analysis of cortical tubers revealed dysregulation of genes involved in cell adhesion in the brain, which may be associated with the neurodevelopmental deficits in TSC. In this study we aimed to investigate the expression of one of these genes - cell-adhesion molecule contactin-3. METHODS: Reverse transcription quantitative polymerase chain reaction for the contactin-3 gene (CNTN3) was performed in resected cortical tubers from TSC patients with drug-resistant epilepsy (n = 35, age range: 1-48 years) and compared to autopsy-derived cortical control tissue (n = 27, age range: 0-44 years), as well as by western blot analysis of contactin-3 (n = 7 vs n = 7, age range: 0-3 years for both TSC and controls) and immunohistochemistry (n = 5 TSC vs n = 4 controls). The expression of contactin-3 was further analyzed in fetal and postnatal control tissue by western blotting and in-situ hybridization, as well as in the SH-SY5Y neuroblastoma cell line differentiation model in vitro. RESULTS: CNTN3 gene expression was lower in cortical tubers from patients across a wide range of ages (fold change = - 0.5, p < 0.001) as compared to controls. Contactin-3 protein expression was lower in the age range of 0-3 years old (fold change = - 3.8, p < 0.001) as compared to the age-matched controls. In control brain tissue, contactin-3 gene and protein expression could be detected during fetal development, peaked around birth and during infancy and declined in the adult brain. CNTN3 expression was induced in the differentiated SH-SY5Y neuroblastoma cells in vitro (fold change = 6.2, p < 0.01). CONCLUSIONS: Our data show a lower expression of contactin-3 in cortical tubers of TSC patients during early postnatal period as compared to controls, which may affect normal brain development and might contribute to neuropsychiatric co-morbidities observed in patients with TSC.

MeSH
dítě MeSH
dospělí MeSH
down regulace MeSH
kojenec MeSH
kontaktiny * genetika metabolismus MeSH
lidé středního věku MeSH
lidé MeSH
mladiství MeSH
mladý dospělý MeSH
mozek metabolismus MeSH
novorozenec MeSH
poruchy autistického spektra komplikace metabolismus MeSH
předškolní dítě MeSH
tuberózní skleróza * komplikace metabolismus MeSH
Check Tag
dítě MeSH
dospělí MeSH
kojenec MeSH
lidé středního věku MeSH
lidé MeSH
mladiství MeSH
mladý dospělý MeSH
novorozenec MeSH
předškolní dítě MeSH
Publikační typ
časopisecké články MeSH
práce podpořená grantem MeSH

Článek

MicroRNA-34a activation in tuberous sclerosis complex during early brain development may lead to impaired corticogenesis

Neuropathology and applied neurobiology. 2021 ; 47 (6) : 796-811. [pub] 20210614

Neuropathol Appl Neurobiol
ISSN 1365-2990
Medvik
Zdroj

AIMS: Tuberous sclerosis complex (TSC) is a genetic disorder associated with dysregulation of the mechanistic target of rapamycin complex 1 (mTORC1) signalling pathway. Neurodevelopmental disorders, frequently present in TSC, are linked to cortical tubers in the brain. We previously reported microRNA-34a (miR-34a) among the most upregulated miRs in tubers. Here, we characterised miR-34a expression in tubers with the focus on the early brain development and assessed the regulation of mTORC1 pathway and corticogenesis by miR-34a. METHODS: We analysed the expression of miR-34a in resected cortical tubers (n = 37) compared with autopsy-derived control tissue (n = 27). The effect of miR-34a overexpression on corticogenesis was assessed in mice at E18. The regulation of the mTORC1 pathway and the expression of the bioinformatically predicted target genes were assessed in primary astrocyte cultures from three patients with TSC and in SH-SY5Y cells following miR-34a transfection. RESULTS: The peak of miR-34a overexpression in tubers was observed during infancy, concomitant with the presence of pathological markers, particularly in giant cells and dysmorphic neurons. miR-34a was also strongly expressed in foetal TSC cortex. Overexpression of miR-34a in mouse embryos decreased the percentage of cells migrated to the cortical plate. The transfection of miR-34a mimic in TSC astrocytes negatively regulated mTORC1 and decreased the expression of the target genes RAS related (RRAS) and NOTCH1. CONCLUSIONS: MicroRNA-34a is most highly overexpressed in tubers during foetal and early postnatal brain development. miR-34a can negatively regulate mTORC1; however, it may also contribute to abnormal corticogenesis in TSC.

MeSH
astrocyty metabolismus MeSH
dítě MeSH
dospělí MeSH
kojenec MeSH
lidé MeSH
mikro RNA genetika metabolismus MeSH
mladiství MeSH
mladý dospělý MeSH
mozek růst a vývoj patologie MeSH
mozková kůra patologie MeSH
myši inbrední C57BL MeSH
neurony patologie MeSH
předškolní dítě MeSH
signální transdukce genetika MeSH
tuberózní skleróza komplikace genetika patologie MeSH
zvířata MeSH
Check Tag
dítě MeSH
dospělí MeSH
kojenec MeSH
lidé MeSH
mladiství MeSH
mladý dospělý MeSH
mužské pohlaví MeSH
předškolní dítě MeSH
ženské pohlaví MeSH
zvířata MeSH
Publikační typ
časopisecké články MeSH
práce podpořená grantem MeSH

Článek

The coding and non-coding transcriptional landscape of subependymal giant cell astrocytomas

Brain. 2020 ; 143 (1) : 131-149. [pub] 20200101

ISSN 1460-2156
Medvik
Zdroj

Tuberous sclerosis complex (TSC) is an autosomal dominantly inherited neurocutaneous disorder caused by inactivating mutations in TSC1 or TSC2, key regulators of the mechanistic target of rapamycin complex 1 (mTORC1) pathway. In the CNS, TSC is characterized by cortical tubers, subependymal nodules and subependymal giant cell astrocytomas (SEGAs). SEGAs may lead to impaired circulation of CSF resulting in hydrocephalus and raised intracranial pressure in patients with TSC. Currently, surgical resection and mTORC1 inhibitors are the recommended treatment options for patients with SEGA. In the present study, high-throughput RNA-sequencing (SEGAs n = 19, periventricular control n = 8) was used in combination with computational approaches to unravel the complexity of SEGA development. We identified 9400 mRNAs and 94 microRNAs differentially expressed in SEGAs compared to control tissue. The SEGA transcriptome profile was enriched for the mitogen-activated protein kinase (MAPK) pathway, a major regulator of cell proliferation and survival. Analysis at the protein level confirmed that extracellular signal-regulated kinase (ERK) is activated in SEGAs. Subsequently, the inhibition of ERK independently of mTORC1 blockade decreased efficiently the proliferation of primary patient-derived SEGA cultures. Furthermore, we found that LAMTOR1, LAMTOR2, LAMTOR3, LAMTOR4 and LAMTOR5 were overexpressed at both gene and protein levels in SEGA compared to control tissue. Taken together LAMTOR1-5 can form a complex, known as the 'Ragulator' complex, which is known to activate both mTORC1 and MAPK/ERK pathways. Overall, this study shows that the MAPK/ERK pathway could be used as a target for treatment independent of, or in combination with mTORC1 inhibitors for TSC patients. Moreover, our study provides initial evidence of a possible link between the constitutive activated mTORC1 pathway and a secondary driver pathway of tumour growth.

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Korotkov, V A* Dotaz Zobrazit nápovědu

Korotkov, V A* Dotaz Zobrazit nápovědu

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