Investigation of the 3D flow characteristics in a rotating channel setup

Tableau d'honneur de la Faculté des études supérieures et postdoctorales, 2006-200

Functional rescue of REP1 following treatment with PTC124 and novel derivative PTC-414 in human choroideremia fibroblasts and the nonsense-mediated zebrafish model

Choroideremia (CHM) is an X-linked chorioretinal dystrophy that is caused by mutations within a single gene, CHM Currently no effective treatment exists for these patients. Since over 30% of patients harbour nonsense mutations in CHM, nonsense suppression therapy using translational readthrough inducing drugs may provide functional rescue of REP1, thus attenuating progressive sight loss. Here, we employed two CHM model systems to systematically test the efficacy and safety of ataluren (PTC124) and its novel analog PTC-414: (1) the chm(ru848) zebrafish, the only nonsense mutation animal model of CHM harbouring a TAA nonsense mutation, and (2) a primary human fibroblast cell line from a CHM patient harbouring a TAG nonsense mutation. PTC124 or PTC-414 treatment of chm(ru848) embryos led to a ∼2.0-fold increase in survival, prevented the onset of retinal degeneration with reduced oxidative stress and apoptosis, increased rep1 protein by 23.1% (PTC124) and 17.2% (PTC-414) and restored biochemical function as confirmed through in vitro prenylation assays (98 ± 2% [PTC124] and 68 ± 5% [PTC-414]). In CHM(Y42X/y) fibroblasts, there was a recovery of prenylation activity following treatment with either PTC124 (42 ± 5%) or PTC-414 (36 ± 11%), although an increase in REP1 protein was not detected in these cells, in contrast to the zebrafish model. This comprehensive study on the use of PTC124 and PTC-414 as successful nonsense suppression agents for the treatment of CHM highlights the translational potential of these drugs for inherited retinal disease

Identificazione di caratteristiche rilevanti in capi di abbigliamento mediante deep-learning

Il mondo della moda è in continua e costante evoluzione, non solo dal punto di vista sociale, ma anche da quello tecnologico. Nel corso del presente elaborato si è studiata la possibilità di riconoscere e segmentare abiti presenti in una immagine utilizzando reti neurali profonde e approcci moderni. Sono state, quindi, analizzate reti quali FasterRCNN, MaskRCNN, YOLOv5, FashionPedia e Match-RCNN. In seguito si è approfondito l’addestramento delle reti neurali profonde in scenari di alta parallelizzazione e su macchine dotate di molteplici GPU al fine di ridurre i tempi di addestramento. Inoltre si è sperimentata la possibilità di creare una rete per prevedere se un determinato abito possa avere successo in futuro analizzando semplicemente dati passati e una immagine del vestito in questione. Necessaria per tali compiti è stata, inoltre, una approfondita analisi dei dataset esistenti nel mondo della moda e dei metodi per utilizzarli per l’addestramento. Il presente elaborato è stato svolto nell’ambito del progetto FA.RE.TRA. per il quale l'Università di Bologna svolge un compito di consulenza per lo studio di fattibilità su reti neurali in grado di svolgere i compiti menzionati

Nonsense-mediated mRNA decay efficiency varies in choroideremia providing a target to boost small molecule therapeutics

Choroideremia (CHM) is an x-linked recessive chorioretinal dystrophy, with 30% caused by nonsense mutations in the CHM gene resulting in an in-frame premature termination codon (PTC). Nonsense mediated decay (NMD) is the cell's natural surveillance mechanism, that detects and destroys PTC containing transcripts, with UPF1 being the central NMD modulator. NMD efficiency can be variable amongst individuals with some transcripts escaping destruction, leading to the production of a truncated non-functional or partially functional protein. Nonsense suppression drugs, such as ataluren, target these transcripts and read-through the PTC, leading to the production of a full length functional protein. Patients with higher transcript levels are considered to respond better to these drugs, as more substrate is available for read-through. Using RT-qPCR, we show that CHM mRNA expression in blood from nonsense mutation CHM patients is 2.8-fold lower than controls, and varies widely amongst patients, with 40% variation between those carrying the same UGA mutation (c.715 C > T; p.[R239*]). These results indicate that although NMD machinery is at work, efficiency is highly variable and not wholly dependent on mutation position. No significant difference in CHM mRNA levels was seen between two patients' fibroblasts and their iPSC-derived RPE. There was no correlation between CHM mRNA expression and genotype, phenotype or UPF1 transcript levels. NMD inhibition with caffeine was shown to restore CHM mRNA transcripts to near wildtype levels. Baseline mRNA levels may provide a prognostic indicator for response to nonsense suppression therapy, and caffeine may be a useful adjunct to enhance treatment efficacy where indicated

A Comprehensive Analysis of Choroideremia: From Genetic Characterization to Clinical Practice.

Choroideremia (CHM) is a rare X-linked disease leading to progressive retinal degeneration resulting in blindness. The disorder is caused by mutations in the CHM gene encoding REP-1 protein, an essential component of the Rab geranylgeranyltransferase (GGTase) complex. In the present study, we evaluated a multi-technique analysis algorithm to describe the mutational spectrum identified in a large cohort of cases and further correlate CHM variants with phenotypic characteristics and biochemical defects of choroideremia patients. Molecular genetic testing led to the characterization of 36 out of 45 unrelated CHM families (80%), allowing the clinical reclassification of four CHM families. Haplotype reconstruction showed independent origins for the recurrent p.Arg293* and p.Lys178Argfs*5 mutations, suggesting the presence of hotspots in CHM, as well as the identification of two different unrelated events involving exon 9 deletion. No certain genotype-phenotype correlation could be established. Furthermore, all the patients´ fibroblasts analyzed presented significantly increased levels of unprenylated Rabs proteins compared to control cells; however, this was not related to the genotype. This research demonstrates the major potential of the algorithm proposed for diagnosis. Our data enhance the importance of establish a differential diagnosis with other retinal dystrophies, supporting the idea of an underestimated prevalence of choroideremia. Moreover, they suggested that the severity of the disorder cannot be exclusively explained by the genotype

Thermal degradation assessment of Kraft paper in power transformers insulated with natural esters

Kraft paper in combination with dielectric oil is the most common as insulation system used in power transformers. The most used oil in power transformers is mineral oil. However, dielectric oils based on natural esters possess some advantages in comparison with mineral oil such as higher biodegradability, fire safety and availability. Therefore, they might be the most ideal substitute for mineral oil. The introduction of a new material requires the evaluation of its degradation rate because this determines transformers’ life span. In order to assess the performance of new insulating systems based on vegetable oils, simulations to obtain the hot-spot temperatures in power transformers using vegetable oils and controlled laboratory experiments of ageing were carried out. The reason is that hot spot temperature inside windings of the oil-immersed power transformers is one of the main manifestations of the thermal stress which leads to aging of insulation systems.The research leading to these results has received funding from multiple sources during years but we would specifically like to acknowledge the support received in the later stages from the Spanish Plan Estatal de I+D under the grant agreement DPI2013- 43897-P

Flow and temperature distributions in a disc type winding-part I: Forced and directed cooling modes

© 2019 The Authors The thermal design of a power transformer determines its lifetime and loading capability, so correct modelling of liquid flow and temperature distributions in the winding is of vital importance. Existing standards and widely used simple calculation models can seriously under/overestimate winding hotspot temperatures under certain circumstances. In this paper, liquid flow and temperature distributions in a physical model representing a disc-type winding in a liquid forced and directed cooling mode are investigated experimentally using Particle Image Velocimetry (PIV) and a temperature measurement system and numerically using Computational Fluid Dynamics (CFD). Dimensional analysis is used to generalise the results into a form useful for design review. The operating conditions investigated include different liquid inlet velocities, inlet temperatures, power losses in individual disc segments, and the effect of alternative liquids. It is shown that hotspot temperature and position within the winding are a non-linear function of liquid inlet velocity, with stagnation and reverse flow demonstrated in both experiments and CFD models. Comparisons of liquid flow and temperature distributions between measurements and CFD simulation results show that 2D CFD results are representative when there are no reverse flows and 3D CFD simulations are needed when reverse flows occur. The results are presented first in dimensional forms to show the effect of each parameter, and then in non-dimensional forms to provide a generalised insight into transformer thermal design

Post-mortem estimation of temperature distribution on a power transformer: Physicochemical and mechanical approaches

Power transformers are electrical machines that allow us to transport electric energy, with reduced losses, from generation stations to consumption points. This definition gives us an idea of the number of transformers that are used in power distribution systems worldwide. The main problem that may affect power transformers is the operation at high temperature. This paper summarizes the results of a postmortem temperature estimation carried out on an 800 kVA distribution transformer. Two methodologies are considered for estimating the temperature distribution in the windings of the machine. The first is based on the calculation of the degree of polymerization and the second is obtained from the tensile strength index. By knowing the value of these two magnitudes for a new and for an aged paper, and the period of operation of a transformer, the temperature distribution along the height of the windings can be estimated. None other previous works have used the tensile strength of winding paper for temperature distribution estimation. With these results and the loading regime records, similar transformers still in operation can be operated in an alternative manner and future designs can be improved

Productive infection of the retinal pigment epithelium by SARS-CoV-2: Initial effects and consideration of long-term consequences

As the SARS-CoV-2 coronavirus continues to evolve and infect the global population, many individuals are likely to suffer from post-acute sequelae of SARS-CoV-2 infection (PASC). Manifestations of PASC include vision symptoms, but little is known about the ability of SARS-CoV-2 to infect and impact the retinal cells. Here, we demonstrate that SARS-CoV-2 can infect and perturb the retinal pigment epithelium (RPE) in vivo, after intranasal inoculation of a transgenic mouse model of SARS-CoV-2 infection, and in cell culture. Separate lentiviral studies showed that SARS-CoV-2 Spike protein mediates viral entry and replication in RPE cells, while the Envelope and ORF3a proteins induce morphological changes. Infection with major variants of SARS-CoV-2 compromised the RPE barrier function and phagocytic capacity. It also caused complement activation and production of cytokines and chemokines, resulting in an inflammatory response that spread across the RPE layer. This inflammatory signature has similarities to that associated with the onset of age-related macular degeneration (AMD), a major cause of human blindness, resulting from RPE pathology that eventually leads to photoreceptor cell loss. Thus, our findings suggest that post-acute sequelae of SARS-CoV-2 infection of the RPE may have long-term implications for vision, perhaps comparable to the increased occurrence of AMD found among individuals infected by HIV, but with greater public health consequences due to the much larger number of SARS-CoV-2 infections