2,163 research outputs found
Transthyretin interacts with actin regulators in a Drosophila model of familial amyloid polyneuropathy
Familial amyloid polyneuropathy (FAP) is a neurodegenerative disorder whose major hallmark is the deposition of mutated transthyretin (TTR) in the form of amyloid fibrils in the peripheral nervous system (PNS). The exposure of PNS axons to extracellular TTR deposits leads to an axonopathy that culminates in neuronal death. However, the molecular mechanisms underlying TTR-induced neurodegeneration are still unclear, despite the extensive studies in vertebrate models. In this work we used a Drosophila FAP model, based on the expression of the amyloidogenic TTR (V30M) in the fly retina, to uncover genetic interactions with cytoskeleton regulators. We show that TTR interacts with actin regulators and induces cytoskeleton alterations, leading to axonal defects. Moreover, our study pinpoints an interaction between TTRV30M and members of Rho GTPase signaling pathways, the major actin regulators. Based on these findings we propose that actin cytoskeleton alterations may mediate the axonopathy observed in FAP patients, and highlight a molecular pathway, mediated by Rho GTPases, underlying TTR-induced neurodegeneration. We expect this work to prompt novel studies and approaches towards FAP therapy.This work was supported by: FEDER—Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020—Operacional Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, and by Portuguese funds through FCT—Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Ensino Superior in the framework of the project POCI-01-0145-FEDER-028336 (PTDC/MED-NEU/28336/2017), to MAL; and Norte-01-0145-FEDER-000008—Porto Neurosciences and Neurologic Disease Research Initiative at I3S, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through FEDER, to CSL and MAL. MIOS is a FCT fellow (SFRH/ BD/118728/2016). CSL is funded by DL 57/2016/CP1355/CT0022. MAL is an FCT Investigator. Flies expressing wild-type and mutant alleles of TTR were kindly provided by Malgorzata Pokrzywa and Per Hammarström. The DCAD2, PDF and Rho1 monoclonal antibodies were obtained from the Developmental Studies Hybridoma Bank, created by the NICHD of the NIH and maintained at The University of Iowa, Department of Biology, Iowa City, IA 52242. We would like to thank the SEM facility at CEMUP (University of Porto) for technical help and Mónica M Sousa and Fernando Casares for comments on the manuscript
A thousand total colonoscopies: what is the relationship between distal and proximal findings?
BACKGROUND: Flexible sigmoidoscopy is indicated for colorectal cancer screening. The decision about who needs total colonoscopy based on distal findings is still controversial because of the uncertainty of the associations between distal and proximal findings. AIM: The purpose of the study was to characterize distal findings in patients with total colonoscopy, to investigate its importance as markers of advanced proximal lesions and to evaluate the usefulness of a clinical Predictive Index, already published in the literature, in the identification of these lesions. METHODS: Retrospective analysis of the patients submitted to total colonoscopy between January 2006 and February 2007, with selection of 1000 consecutive cases with reference to polyps. We analysed demographic data, indication for the exam and morphological and histological characteristics of the polyps. Advanced lesion was defined as any adenoma larger than 10 mm or any polyp with villous characteristics, high grade dysplasia or cancer. The Predictive Index was obtained through the assignment of points to 3 categories: sex, age and distal findings, which result in 3 groups: low, intermediate and high risk. RESULTS: The mean age of patients was 64,69 years and 65,1% were male. Distal and proximal polyps were identified in 829 (82,9%) and 369 (36,9%) patients, respectively. Advanced distal lesion was found in 342 patients (34,2%) and advanced proximal lesion in 98 (9,8%). 587 patients (58,7%) were in the high risk group. In the group of patients with advanced proximal lesion, a third presented low and intermediate risk, 52% had no distal polyps, 88,7% had less than three distal polyps and 71,4% had no advanced distal lesion. Sensitivity values for these four categories ranged between 11,2% and 66,6%. CONCLUSION: If the decision to perform total colonoscopy is based on distal colonic findings or on the Predictive Index, the ability to identify advanced proximal lesion is markedly reduced, endangering the aim of a screening program
New combined CFH/MCP mutations and a rare clinical course in atypical haemolytic uraemic syndrome
Atypical haemolytic uraemic syndrome (aHUS) is a rare, life-threatening, chronic, genetic disease due to uncontrolled alternative pathway complement activation. In this report, we discuss the case of a heterozygous carrier of a mutation on both factor H and membrane cofactor protein, who persistently presents haemolytic anaemia without need for blood transfusions, normal platelet count, normal renal function and no signs or symptoms of organ injury due to thrombotic microangiopathy 4 years after the diagnosis of aHUS.info:eu-repo/semantics/publishedVersio
A toggle-switch and a feed-forward loop engage in the control of the Drosophila retinal determination gene network
Dipterans show a striking range of eye sizes, shapes, and functional specializations. Their eye is of the compound type, the most frequent eye architecture in nature. The development of this compound eye has been most studied in Drosophila melanogaster. The early development of the Drosophila eye is under the control of a gene regulatory network of transcription factors and signaling molecules called the retinal determination gene network (RDGN). Nodes in this network have been found to be involved not only in the development of different eye types in invertebrates and vertebrates, but also of other organs. Here we have analyzed the network properties in detail. First, we have generated quantitative expression profiles for a number of the key RDGN transcription factors, at a single-cell resolution. With these profiles, and applying a correlation analysis, we revisited several of the links in the RDGN. Our study uncovers a new link, that we confirm experimentally, between the transcription factors Hth/Meis1 and Optix/Six3 and indicates that, at least during the period of eye differentiation, positive feedback regulation from Eya and Dac on the Pax6 gene Ey is not operating. From this revised RDGN we derive a simplified gene network that we model mathematically. This network integrates three basic motifs: a coherent feedforward loop, a toggle-switch and a positive autoregulation which, together with the input from the Dpp/BMP2 signaling molecule, recapitulate the gene expression profiles obtained experimentally, while ensuring a robust transition from progenitor cells into retinal precursors.This work was funded by MINECO and the Agencia Estatal de Investigacion (AEI) of Spain, co-financed by FEDER funds (EU) through grants BFU2012-34324 and BFU2015-66040-P to FC, MDM-2016-0687 in which FC is participant researcher, and TIN2017-89842 P in which MCL is participant researcher
Stroke-based splatting: an efficient multi-resolution point cloud visualization technique
Current state-of-the-art point cloud visualization techniques have shortcomings when dealing with sparse and less accurate data or close-up interactions. In this paper, we present a visualization technique called stroke-based splatting, which applies concepts of stroke-based rendering to surface-aligned splatting, allowing for better shape perception at lower resolutions and close-ups. We create a painterly depiction of the data with an impressionistic aesthetic, which is a metaphor the user is culturally trained to recognize, thus attributing higher quality to the visualization. This is achieved by shaping each object-aligned splat as a brush stroke, and orienting it according to globally coherent tangent vectors from the Householder formula, creating a painterly depiction of the scanned cloud. Each splat is sized according to a color-based clustering analysis of the data, ensuring the consistency of brush strokes within neighborhood areas. By controlling brush shape generation parameters and blending factors between neighboring splats, the user is able to simulate different painting styles in real time. We have tested our method with data sets captured by commodity laser scanners as well as publicly available high-resolution point clouds, both having highly interactive frame rates in all cases. In addition, a user study was conducted comparing our approach to state-of-the-art point cloud visualization techniques. Users considered stroke-based splatting a valuable technique as it provides a higher or similar visual quality to current approaches
Uso do Doppler vascular para detectar o efeito agudo do estradiol em mulheres na pós-menopausa
OBJECTIVES: To report on a simple practical test for assessing acute estradiol vascular effects on healthy and unhealthy postmenopausal women. INTRODUCTION: Estradiol acts in the endothelium to promote vasodilatation through genomic and non-genomic mechanisms, but its vascular action may be impaired in diabetes mellitus, hypertension, smoking and obesity. METHODS: Nineteen postmenopausal women (nine healthy and 10 with two or more of the above factors) of similar age and time since menopause were examined with vascular Doppler ultrasound. Resistance indexes and systolic and diastolic flow velocities were determined for the brachial and internal carotid arteries at baseline and 20 minutes after administration of a nasal estradiol formulation, available on the market, which reaches 1,200-1,500 pg/ml in the serum in 10-30 minutes. Estradiol blood levels were measured at 30 minutes. RESULTS: The carotid resistance index increased 14.2% (vasoconstriction) in the unhealthy group after estradiol, from a mean ± S.E. of 0.56 ± 0.016 at baseline to 0.64 ± 0.05 (p=0.033), and remained unchanged in healthy women. Brachial diastolic flow velocity increased 19.7% (vasodilatation) in healthy women, from 16.2 ± 1.93 to 19.4 ± 0.64 cm/s (p=0.046), and did not change in the unhealthy subjects. Estradiol levels were similar in both groups. DISCUSSION: Healthy postmenopausal women showed brachial vasodilatation while unhealthy postmenopausal women displayed vasoconstriction at the carotid artery. Vascular responses to estradiol were divergent between the groups. CONCLUSIONS: The acute estradiol test, coupled with Doppler ultrasound, seemed to be able to differentiate women with normal and abnormal endothelial function in a simple, non-invasive manner.OBJETIVO: Descrever um teste simples e prático para avaliar o efeito vascular agudo do estradiol em mulheres saudáveis e não-saudáveis na menopausa. INTRODUÇÃO: O estradiol atua no endotélio promovendo vasodilatação através de mecanismos genômicos e não-genômicos e esta ação pode estar prejudicada em morbidades como diabetes mellitus, hipertensão, tabagismo e obesidade. MÉTODOS: Dezenove mulheres na pós-menopausa (9 saudáveis e 10 com dois ou mais dos fatores acima), com idade e tempo de menopausa semelhantes foram examinadas por Doppler vascular. O Ãndice de resistência e as velocidades de fluxo sistólico e diastólico foram medidos nas artérias braquial e carótida, em condições basais e 20 min após a administração de uma preparação nasal de estradiol, disponÃvel comercialmente, que atinge 1200 a 1500 pg/ml no soro, entre 10 e 30 min após a aplicação. Os nÃveis séricos de estradiol foram determinados 30 min após a aplicação nasal. RESULTADOS: O Ãndice de resistência da artéria carótida aumentou em 14,2% (vasoconstricção) após o estradiol no grupo não-saudável, partindo da média ± SE de 0,56 ± 0,016 para 0,64 ± 0,05 (p=0,033) e não se modificou nas mulheres saudáveis. A velocidade de fluxo diastólico da artéria braquial aumentou 19,7% (vasodilatação) nas mulheres saudáveis, partindo de 16,2 ± 1,93 para 19,4 ± 0,64 cm/s (p=0,046) e não apresentou alteração nas não saudáveis. Os nÃveis de estradiol foram semelhantes nos dois grupos. DISCUSSÃO: Nas mulheres saudáveis na menopausa houve vasodilatação da artéria braquial e nas não-saudáveis vasoconstricção na artéria carótida. A resposta vascular ao estradiol foi divergente entre os grupos estudados. CONCLUSÃO: O teste com estradiol agudo, associado ao Doppler vascular, parecem diferenciar, de forma simples e não-invasiva, mulheres com função endotelial normal e anormal
Cholesteryl hemiazelate causes lysosome dysfunction impacting vascular smooth muscle cell homeostasis
In atherosclerotic lesions, vascular smooth muscle cells (VSMCs) represent half of the foam cell population, which is characterized by an aberrant accumulation of undigested lipids within lysosomes. Loss of lysosome function impacts VSMC homeostasis and disease progression. Understanding the molecular mechanisms underlying lysosome dysfunction in these cells is, therefore, crucial. We identify cholesteryl hemiazelate (ChA), a stable oxidation end-product of cholesteryl-polyunsaturated fatty acid esters, as an inducer of lysosome malfunction in VSMCs. ChA-treated VSMCs acquire a foam-cell-like phenotype, characterized by enlarged lysosomes full of ChA and neutral lipids. The lysosomes are perinuclear and exhibit degradative capacity and cargo exit defects. Lysosome luminal pH is also altered. Even though the transcriptional response machinery and autophagy are not activated by ChA, the addition of recombinant lysosomal acid lipase (LAL) is able to rescue lysosome dysfunction. ChA significantly affects VSMC proliferation and migration, impacting atherosclerosis. In summary, this work shows that ChA is sufficient to induce lysosomal dysfunction in VSMCs, that, in ChA-treated VSMCs, neither lysosome biogenesis nor autophagy are triggered, and, finally, that recombinant LAL can be a therapeutic approach for lysosomal dysfunction
THERMODYNAMIC SIMULATION OF BIOMASS GAS STEAM REFORMING FOR A SOLID OXIDE FUEL CELL (SOFC) SYSTEM
This paper presents a methodology to simulate a small-scale fuel cell system for power generation using biomass gas as fuel. The methodology encompasses the thermodynamic and electrochemical aspects of a solid oxide fuel cell (SOFC), as well as solves the problem of chemical equilibrium in complex systems. In this case the complex system is the internal reforming of biomass gas to produce hydrogen. The fuel cell input variables are: operational voltage, cell power output, composition of the biomass gas reforming, thermodynamic efficiency, electrochemical efficiency, practical efficiency, the First and Second law efficiencies for the whole system. The chemical compositions, molar flows and temperatures are presented to each point of the system as well as the exergetic efficiency. For a molar water/carbon ratio of 2, the thermodynamic simulation of the biomass gas reforming indicates the maximum hydrogen production at a temperature of 1070 K, which can vary as a function of the biomass gas composition. The comparison with the efficiency of simple gas turbine cycle and regenerative gas turbine cycle shows the superiority of SOFC for the considered electrical power range.26474575
Diffusion tensor magnetic resonance imaging may show abnormalities in the normal-appearing cervical spinal cord from patients with multiple sclerosis
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