Chronic hemolytic anemia is associated with a new glucose-6-phosphate dehydrogenase in-frame deletion in an older woman

Glucose-6-phosphate dehydrogenase (G6PD) deficiency, an X-linked disorder, is usually observed in hemizygote males and very rarely in females. The G6PD class 1 variants, very uncommon, are associated with chronic hemolytic anemia. Here we report a Portuguese woman who suffered in her sixties from a chronic hemolytic anemia due to G6PD deficiency. Molecular studies revealed heterozygosity for an in-frame 18-bp deletion, mapping to exon 10 leading to a deletion of 6 residues, 362-367 (LNERKA), which is a novel G6PD class 1 variant, G6PD Tondela. Two of her three daughters, asymptomatic, with G6PD activity within the normal range, are heterozygous for the same deletion. The patient's leukocyte and reticulocyte mRNA studies revealed an almost exclusive expression of the mutant allele, explaining the chronic hemolytic anemia. Patient whole blood genomic DNA HUMARA assay showed a balanced pattern of X chromosome inactivation (XCI), but granulocyte DNA showed extensive skewing, harboring the mutated allele, implying that in whole blood, lymphocyte DNA, with a very long lifetime, may cover up the current high XCI skewing. This observation indicates that HUMARA assay in women should be assessed in granulocytes and not in total leukocytes

Ensaios de integridade estrutural de placas angulares de fixação de fracturas ósseas do fémur

Neste trabalho descreve-se o projecto de um dispositivo mecânico desenvolvido para a realização de ensaios segundo a norma ASTM F384-00 (2000) de placas de osteossíntese anguladas. O dispositivo foi objecto de uma análise estrutural usando o método dos elementos finitos. Algumas placas foram ensaiadas estaticamente e suas características mecânicas, de acordo com a norma, determinadas

Study of inflammation mediated by fatty acids in a microglia cell model - the obesity perspective

info:eu-repo/semantics/publishedVersio

The role of saturated and polyunsaturated fatty acids in microglia modulation

info:eu-repo/semantics/publishedVersio

Study of inflammation mediated by lipids in a Microglia Cell Model to deepen into brain dysregulation by obesity

info:eu-repo/semantics/publishedVersio

Potential of omega-3 and conjugated fatty acids to control microglia inflammatory imbalance elicited by obesogenic nutrients

High-fat diet-induced obesity detrimentally affects brain function by inducing chronic low-grade inflammation. This neuroinflammation is, at least in part, likely to be mediated by microglia, which are the main immune cell population in the brain. Microglia express a wide range of lipid-sensitive receptors and their activity can be modulated by fatty acids that cross the blood-brain barrier. Here, by combining live cell imaging and FRET technology we assessed how different fatty acids modulate microglia activity. We demonstrate that the combined action of fructose and palmitic acid induce Ikβα degradation and nuclear translocation of the p65 subunit nuclear factor kB (NF-κB) in HCM3 human microglia. Such obesogenic nutrients also lead to reactive oxygen species production and LynSrc activation (critical regulators of microglia inflammation). Importantly, short-time exposure to omega-3 (EPA and DHA), CLA and CLNA are sufficient to abolish NF-κB pathway activation, suggesting a potential neuroprotective role. Omega-3 and CLA also show an antioxidant potential by inhibiting reactive oxygen species production, and the activation of LynSrc in microglia. Furthermore, using chemical agonists (TUG-891) and antagonists (AH7614) of GPR120/FFA4, we demonstrated that omega-3, CLA and CLNA inhibition of the NF-κB pathway is mediated by this receptor, while omega-3 and CLA antioxidant potential occurs through different signaling mechanisms.info:eu-repo/semantics/publishedVersio

Target score—a proteomics data selection tool applied to esophageal cancer identifies glut1-sialyl tn glycoforms as biomarkers of cancer aggressiveness

Esophageal cancer (EC) is a life-threatening disease, demanding the discovery of new biomarkers and molecular targets for precision oncology. Aberrantly glycosylated proteins hold tremendous potential towards this objective. In the current study, a series of esophageal squamous cell carcinomas (ESCC) and EC-derived circulating tumor cells (CTCs) were screened by immunoassays for the sialyl-Tn (STn) antigen, a glycan rarely expressed in healthy tissues and widely observed in aggressive gastrointestinal cancers. An ESCC cell model was glycoengineered to express STn and characterized in relation to cell proliferation and invasion in vitro. STn was found to be widely present in ESCC (70% of tumors) and in CTCs in 20% of patients, being associated with general recurrence and reduced survival. Furthermore, STn expression in ESCC cells increased invasion in vitro, while reducing cancer cells proliferation. In parallel, an ESCC mass spectrometry-based proteomics dataset, obtained from the PRIDE database, was comprehensively interrogated for abnormally glycosylated proteins. Data integration with the Target Score, an algorithm developed in-house, pinpointed the glucose transporter type 1 (GLUT1) as a biomarker of poor prognosis. GLUT1-STn glycoproteoforms were latter identified in tumor tissues in patients facing worst prognosis. Furthermore, healthy human tissues analysis suggested that STn glycosylation provided cancer specificity to GLUT1. In conclusion, STn is a biomarker of worst prognosis in EC and GLUT1-STn glycoforms may be used to increase its specificity on the stratification and targeting of aggressive ESCC forms.The authors wish to acknowledge the Portuguese Foundation for Science and Technology (FCT) for the human resources grants: PhD grant SFRH/BD/111242/2015 (AP), SFRH/BD/146500/2019 (MRS), SFRH/BD/142479/2018 (JS), SFRH/BD/105355/2014 (RA) and FCT assistant researcher grant CEECIND/03186/2017 (JAF). FCT is co-financed by European Social Fund (ESF) under Human Potential Operation Programme (POPH) from National Strategic Reference Framework (NSRF). The authors also acknowledge FCT the funding for CI-IPOP research unit (PEst-OE/SAU/UI0776/201) and LAQV-REQUIMTE research unit (UIDB/50006/2020), the Portuguese Oncology Institute of Porto Research Centre (CI-IPOP-29-2016-2020; CI-IPOP-58-2016-2020; CI-IPOP-Proj.70-bolsa2019-GPTE) and PhD Program in Biomedical Sciences of ICBAS-University of Porto. The author also thanks “Early stage cancer treatment, driven by context of molecular imaging (ESTIMA)” framework (NORTE-01-0145-FEDER-000027) and IPO-Score (DSAIPA/DS/0042/2018) for financial support. This work was financed 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/MCTES—Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Ensino Superior. The authors also acknowledge support from the Portuguese League against Cancer grant LPCC-NRN-2020 (DF)

Turbulence, dynamic similarity and scale effects in high-velocity free-surface flows above a stepped chute

In high-velocity free-surface flows, air entrainment is common through the interface, and intense interactions take place between turbulent structures and entrained bubbles. Two-phase flow properties were measured herein in high-velocity open channel flows above a stepped chute. Detailed turbulence measurements were conducted in a large-size facility, and a comparative analysis was applied to test the validity of the Froude and Reynolds similarities. The results showed consistently that the Froude similitude was not satisfied using a 2:1 geometric scaling ratio. Lesser number of entrained bubbles and comparatively greater bubble sizes were observed at the smaller Reynolds numbers, as well as lower turbulence levels and larger turbulent length and time scales. The results implied that small-size models did underestimate the rate of energy dissipation and the aeration efficiency of prototype stepped spillways for similar flow conditions. Similarly a Reynolds similitude was tested. The results showed also some significant scale effects. However a number of self-similar relationships remained invariant under changes of scale and confirmed the analysis of Chanson and Carosi (Exp Fluids 42:385-401, 2007). The finding is significant because self-similarity may provide a picture general enough to be used to characterise the air– water flow field in large prototype channels

Dominant negative effect of polyglutamine expansion perturbs normal function of ataxin-3 in neuronal cells

The physiological function of Ataxin-3 (ATXN3), a deubiquitylase (DUB) involved in Machado–Joseph Disease (MJD), remains elusive. In this study, we demonstrate that ATXN3 is required for neuronal differentiation and for normal cell morphology, cytoskeletal organization, proliferation and survival of SH-SY5Y and PC12 cells. This cellular phenotype is associated with increased proteasomal degradation of a5 integrin subunit (ITGA5) and reduced activation of integrin signalling and is rescued by ITGA5 overexpression. Interestingly, silencing of ATXN3, overexpression of mutant versions of ATXN3 lacking catalytic activity or bearing an expanded polyglutamine (polyQ) tract led to partially overlapping phenotypes. In vivo analysis showed that both Atxn3 knockout and MJD transgenic mice had decreased levels of ITGA5 in the brain. Furthermore, abnormal morphology and reduced branching were observed both in cultured neurons expressing shRNA for ATXN3 and in those obtained from MJD mice. Our results show that ATXN3 rescues ITGA5 from proteasomal degradation in neurons and that polyQ expansion causes a partial loss of this cellular function, resulting in reduced integrin signalling and neuronal cytoskeleton modifications, which may be contributing to neurodegeneration.National Institutes of Health (NIH) ‘(R01NS038712)Fundação para a Ciência e a Tecnologia (FCT) and COMPETE through the project ‘(PTDC/SAU-GMG/ 101572/2008)Fundação para a Ciência e a Tecnologia (FCT) - fellowships SFRH/BD/51059/2010, SFRH/BD/ 78388/2011 and SFRH/BPD/91562/201

The importance of a correct alignment in contactless inspection of Additive Manufactured parts

Nowadays products having complex freeform custom-made shapes can be fabricated without any tool by means of additive manufacturing processes. Additive manufactured parts must be inspected for quality to verify that they meet dimensional and geometrical specifications among other requirements just as any other product. Contactless inspection carried out with optical 3D scanners is preferred to traditional pointwise measurements because of the higher amount of data retrieved in short times. A key step of the contactless inspection process is the definition of the part reference frame for the alignment of scan data. This paper considers different 3-2-1 alignments and analyze their influence on the inspection results, putting in evidence that an inattentive or inaccurate definition of the part reference frame can lead to incorrect evaluations of real part deviation