85 research outputs found
New lysosomal acid lipase gene mutants explain the phenotype of Wolman disease and cholesteryl ester storage disease.
Deficiency of lysosomal acid lipase (LAL) leads to either Wolman disease(WD) or the more benign cholesteryl ester storage disease (CESD). To identifythe molecular basis of the different phenotypes we have characterised the LALgene mutations in three new patients with LAL deficiency. A patient with WD washomozygote for a null allele Y303X. The other two patients, with CESD, presentedeither homozygosity for T267I or compound heterozygosity consisting of Q64R andan exon 8 donor splice site substitution (GâA in positionâ1). The mutants T267I and Q64R and the previously reported L273S, G66V,and H274Y CESD substitutions, overexpressed in stable clones, were found to befully glycosylated and show an enzymatic activity of 3â8% of that ofnormal LAL. On the other hand, the Î254â277 mutant proteinderived from exon 8 skipping and the Y303X protein were totally inactive. Bytransient transfection of hybrid minigene constructs, the CESD GâA(â1) substitution resulted in partial exon inclusion, thus allowing theproduction of a small amount of normal LAL mRNA and hence of a functionalenzyme. In contrast, a GâAsubstitution observed in WD at position +1 of the same exon 8 donor siteresulted in complete exon skipping and the sole production of an inactiveÎ254â277 protein.In conclusion,LAL genotypes determine the level of residual enzymatic activity, thusexplaining the severity of the phenotype.âPagani, F., R. Pariyarath, R.Garcia, C. Stuani, A. B. Burlina, G. Ruotolo, M. Rabusin, and F. E. Baralle. Newlysosomal acid lipase gene mutants explain the phenotype of Wolman disease andcholesteryl ester storage disease. J. Lipid Res. 1998. 39:1382â1388
Mutation within TARDBP leads to Frontotemporal Dementia without motor neuron disease.
2009 AUG 4. [EPUB AHEAD OF PRINT
Evolutionarily conserved heterogeneous nuclear ribonucleoprotein (hnRNP) A/B proteins functionally interact with human and drosophila tar DNA-binding protein 43 (TDP-43)
Background: TDP-43 and hnRNPA1/A2 factors are implicated in neurodegeneration. Results: The human and fruit fly TDP-43 and hnRNPA1/A2 orthologs show physical, genetic, and functional interplays. Conclusion: The functional cooperation between TBPH/Hrp38 and TDP-43/hnRNP A/B is conserved throughout evolution. Significance: TBPH/Hrp38 interplay can be critical for neurodegeneration, and Drosophila is a model suitable to study the impact of this interaction. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc
Projeto tecnologias sociais para a gestão da ågua ? TSGA: contribuição para a gestão participativa da ågua.
Projeto: 06.09.06.001
Quantification of Myocardial Contraction Fraction with Three-Dimensional Automated, Machine-Learning-Based Left-Heart-Chamber Metrics: Diagnostic Utility in Hypertrophic Phenotypes and Normal Ejection Fraction
Aims: The differentiation of left ventricular (LV) hypertrophic phenotypes is challenging in patients with normal ejection fraction (EF). The myocardial contraction fraction (MCF) is a simple dimensionless index useful for specifically identifying cardiac amyloidosis (CA) and hypertrophic cardiomyopathy (HCM) when calculated by cardiac magnetic resonance. The purpose of this study was to evaluate the value of MCF measured by three-dimensional automated, machine-learning-based LV chamber metrics (dynamic heart model [DHM]) for the discrimination of different forms of hypertrophic phenotypes. Methods and Results: We analyzed the DHM LV metrics of patients with CA (n = 10), hypertrophic cardiomyopathy (HCM, n = 36), isolated hypertension (IH, n = 87), and 54 healthy controls. MCF was calculated by dividing LV stroke volume by LV myocardial volume. Compared with controls (median 61.95%, interquartile range 55.43â67.79%), mean values for MCF were significantly reduced in HCMâ48.55% (43.46â54.86% p < 0.001)âand CAâ40.92% (36.68â46.84% p < 0.002)âbut not in IHâ59.35% (53.22â64.93% p < 0.7). MCF showed a weak correlation with EF in the overall cohort (R2 = 0.136) and the four study subgroups (healthy adults, R2 = 0.039 IH, R2 = 0.089; HCM, R2 = 0.225; CA, R2 = 0.102). ROC analyses showed that MCF could differentiate between healthy adults and HCM (sensitivity 75.9%, specificity 77.8%, AUC 0.814) and between healthy adults and CA (sensitivity 87.0%, specificity 100%, AUC 0.959). The best cut-off values were 55.3% and 52.8%. Conclusions: The easily derived quantification of MCF by DHM can refine our echocardiographic discrimination capacity in patients with hypertrophic phenotype and normal EF. It should be added to the diagnostic workup of these patients
Anti-AMPA GluA3 antibodies in Frontotemporal dementia: A new molecular target
Frontotemporal Dementia (FTD) is a neurodegenerative disorder mainly characterised by Tau or TDP43 inclusions. A co-autoimmune aetiology has been hypothesised. In this study, we aimed at defining the pathogenetic role of anti-AMPA GluA3 antibodies in FTD. Serum and cerebrospinal fluid (CSF) anti-GluA3 antibody dosage was carried out and the effect of CSF with and without anti-GluA3 antibodies was tested in rat hippocampal neuronal primary cultures and in differentiated neurons from human induced pluripotent stem cells (hiPSCs). TDP43 and Tau expression in hiPSCs exposed to CSF was assayed. Forty-one out of 175 screened FTD sera were positive for the presence of anti-GluA3 antibodies (23.4%). FTD patients with anti-GluA3 antibodies more often presented presenile onset, behavioural variant FTD with bitemporal atrophy. Incubation of rat hippocampal neuronal primary cultures with CSF with anti-GluA3 antibodies led to a decrease of GluA3 subunit synaptic localization of the AMPA receptor (AMPAR) and loss of dendritic spines. These results were confirmed in differentiated neurons from hiPSCs, with a significant reduction of the GluA3 subunit in the postsynaptic fraction along with increased levels of neuronal Tau. In conclusion, autoimmune mechanism might represent a new potentially treatable target in FTD and might open new lights in the disease underpinnings
PROGRAMA CIENTĂFICO PARA O MONITORAMENTO EM TEMPO REAL OU PĂS-PROCESSADO DAS IRREGULARIDADES IONOSFĂRICAS E CINTILAĂĂO DOS SINAIS GNSS
O Brasil Ă© um dos paĂses que mais sofrem os efeitos provocados pela ionosfera, principalmente os oriundos da Anomalia de Ionização Equatorial, irregularidades ionosfĂ©ricas e cintilação dos sinais GNSS (Global Navigation Satellite System). VĂĄrias estratĂ©gias podem ser utilizadas para minimizar os efeitos, tais como: modelos ionosfĂ©ricos, arquivos IONEX ou a combinação linear ion-free. Em se tratando do monitoramento da ionosfera a situação Ă© diferente. A quantidade de instrumentos dedicados ao estudo da camada ionosfĂ©rica Ă© reduzida no Ăąmbito brasileiro. Neste contexto foi desenvolvido o programa cientĂfico denominado Ion_Index, com objetivo de estimar indicadores dos nĂveis de irregularidades da ionosfera e de cintilação dos sinais GNSS em tempo real ou pĂłs-processado, utilizando a infraestrutura jĂĄ existente de dados GNSS de redes ativas pĂșblicas, como a RBMC, a GNSS-SP e a CALIBRA, transformando assim estaçÔes GNSS em estaçÔes monitoras da camada ionosfĂ©rica. Dessa forma Ă© proporcionado um aumento na resolução espacial das informaçÔes sobre o comportamento da ionosfera na regiĂŁo brasileira, permitindo um melhor entendimento e contribuindo para o desenvolvimento ou aprimoramento de modelos de mitigação. Experimentos utilizando dados de ionossondas digitais e de receptores PolaRxS-PRO da Septentrio (fontes externas) comprovam a eficiĂȘncia do program
Sensitivity of the Cherenkov Telescope Array to spectral signatures of hadronic PeVatrons with application to Galactic Supernova Remnants
The local Cosmic Ray (CR) energy spectrum exhibits a spectral softening at
energies around 3~PeV. Sources which are capable of accelerating hadrons to
such energies are called hadronic PeVatrons. However, hadronic PeVatrons have
not yet been firmly identified within the Galaxy. Several source classes,
including Galactic Supernova Remnants (SNRs), have been proposed as PeVatron
candidates. The potential to search for hadronic PeVatrons with the Cherenkov
Telescope Array (CTA) is assessed. The focus is on the usage of very high
energy -ray spectral signatures for the identification of PeVatrons.
Assuming that SNRs can accelerate CRs up to knee energies, the number of
Galactic SNRs which can be identified as PeVatrons with CTA is estimated within
a model for the evolution of SNRs. Additionally, the potential of a follow-up
observation strategy under moonlight conditions for PeVatron searches is
investigated. Statistical methods for the identification of PeVatrons are
introduced, and realistic Monte--Carlo simulations of the response of the CTA
observatory to the emission spectra from hadronic PeVatrons are performed.
Based on simulations of a simplified model for the evolution for SNRs, the
detection of a -ray signal from in average 9 Galactic PeVatron SNRs is
expected to result from the scan of the Galactic plane with CTA after 10 hours
of exposure. CTA is also shown to have excellent potential to confirm these
sources as PeVatrons in deep observations with hours of
exposure per source.Comment: 34 pages, 16 figures, Accepted for publication in Astroparticle
Physic
Deferoxamine mesylate improves splicing and GAA activity of the common c.-32-13T>G allele in late-onset PD patient fibroblasts
Pompe disease (PD) is an autosomal recessive lysosomal storage disorder due to deficient activity of the acid alpha glucosidase enzyme (GAA). As a consequence of the enzymatic defect, undigested glycogen accumulates within lysosomes. Most patients affected by the late-onset (LO) phenotype carry in at least one allele the c.-32-13T>G variant, which leads to exon 2 exclusion from the pre-mRNA. These patients display a variable and suboptimal response to enzyme replacement therapy. To identify novel therapeutic approaches, we developed a fluorescent GAA exon 2 splicing assay and screened a library of US Food and Drug Administration (FDA)-approved compounds. This led to the identification of several drugs able to restore normal splicing. Among these, we further validated the effects of the iron chelator deferoxamine (Defe) in c.-32-13T>G fibroblasts. Defe treatment resulted in a 2-fold increase of GAA exon 2 inclusion and a 40% increase in enzymatic activity. Preliminary results suggest that this effect is mediated by the regulation of iron availability, at least partially. RNA-seq experiments also showed that Defe might shift the balance of splicing factor levels toward a profile promoting GAA exon 2 inclusion. This work provides the basis for drug repurposing and development of new chemically modified molecules aimed at improving the clinical outcome in LO-PD patients
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