| 1. |
- Figueiredo, Joana, et al.
(författare)
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ADP-Ribosylation Factor 6 Mediates E-Cadherin Recovery by Chemical Chaperones
- 2011
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:8, s. e23188-
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Tidskriftsartikel (refereegranskat)abstract
- E-cadherin plays a powerful tumor suppressor role. Germline E-cadherin mutations justify 30% of Hereditary Diffuse Gastric Cancer (HDGC) and missense mutations are found in 30% of these families. We found possible to restore in vitro mutant E-cadherin associated to HDGC syndrome by using Chemical Chaperones (CCs). Herein, our aim was to disclose the molecular mechanisms underlying the CCs effects in E-cadherin regulation. Using cells stably expressing WT E-cadherin or two HDGC-associated missense mutations, we show that upon DMSO treatment, not only mutant E-cadherin is restored and stabilized at the plasma membrane (PM), but also Arf6 and PIPKI gamma expressions are altered. We show that modulation of Arf6 expression partially mimics the effect of CCs, suggesting that the cellular effects observed upon CCs treatment are mediated by Arf6. Further, we show that E-cadherin expression recovery is specifically linked to Arf6 due to its role on endocytosis and recycling pathways. Finally, we demonstrated that, as DMSO, several others CCs are able to modulate the trafficking machinery through an Arf6 dependent mechanism. Interestingly, the more effective compounds in E-cadherin recovery to PM are those that simultaneously inhibit Arf6 and stimulate PIPKI gamma expression and binding to E-cadherin. Here, we present the first evidence of a direct influence of CCs in cellular trafficking machinery and we show that this effect is of crucial importance in the context of juxtamembrane E-cadherin missense mutations associated to HDGC. We propose that this influence should be taken into account when exploring the therapeutic potential of this type of chemicals in genetic diseases associated to protein-misfolding.
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| 2. |
- Figueiredo, Joana, et al.
(författare)
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The importance of E-cadherin binding partners to evaluate the pathogenicity of E-cadherin missense mutations associated to HDGC
- 2013
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 21:3, s. 301-309
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Tidskriftsartikel (refereegranskat)abstract
- In hereditary diffuse gastric cancer (HDGC), CDH1 germline gene alterations are causative events in 30% of the cases. In 20% of HDGC families, CDH1 germline mutations are of the missense type and the mutation carriers constitute a problem in terms of genetic counseling and surveillance. To access the pathogenic relevance of missense mutations, we have previously developed an in vitro method to functionally characterize them. Pathogenic E-cadherin missense mutants fail to aggregate and become more invasive, in comparison with cells expressing the wild-type (WT) protein. Herein, our aim was to develop a complementary method to unravel the pathogenic significance of E-cadherin missense mutations. We used cells stably expressing WT E-cadherin and seven HDGC-associated mutations (five intracellular and two extracellular) and studied by proximity ligation assays (PLA) how these mutants bind to fundamental regulators of E-cadherin function and trafficking. We focused our attention on the interaction with: p120, beta-catenin, PIPKI gamma and Hakai. We showed that cytoplasmic E-cadherin mutations affect the interaction of one or more binding partners, compromising the E-cadherin stability at the plasma membrane and likely affecting the adhesion complex competence. In the present work, we demonstrated that the study of the interplay between E-cadherin and its binding partners, using PLA, is an easy, rapid, quantitative and highly reproducible technique that can be applied in routine labs to verify the pathogenicity of E-cadherin missense mutants for HDGC diagnosis, especially those located in the intracellular domain of the protein.
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| 3. |
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| 5. |
- Kehoe, Laura, et al.
(författare)
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Make EU trade with Brazil sustainable
- 2019
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 364:6438, s. 341-
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 6. |
- Leadley, Paul, et al.
(författare)
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Interacting Regional-Scale Regime Shifts for Biodiversity and Ecosystem Services
- 2014
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Ingår i: BioScience. - : Oxford University Press (OUP). - 0006-3568 .- 1525-3244. ; 64:8, s. 665-679
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Tidskriftsartikel (refereegranskat)abstract
- Current trajectories of global change may lead to regime shifts at regional scales, driving coupled human-environment systems to highly degraded states in terms of biodiversity, ecosystem services, and human well-being. For business-as-usual socioeconomic development pathways, regime shifts are projected to occur within the next several decades, to be difficult to reverse, and to have regional- to global-scale impacts on human society. We provide an overview of ecosystem, socioeconomic, and biophysical mechanisms mediating regime shifts and illustrate how these interact at regional scales by aggregation, synergy, and spreading processes. We give detailed examples of interactions for terrestrial ecosystems of central South America and for marine and coastal ecosystems of Southeast Asia. This analysis suggests that degradation of biodiversity and, ecosystem services over the twenty-first century could be far greater than was previously predicted. We identify key policy and management opportunities at regional to global scales to avoid these shifts.
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| 7. |
- Magalhaes, Ana, et al.
(författare)
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The glycan receptors of Helicobacter pylori : decoding the pathways underlying gastric glycophenotype modulation
- 2016
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Ingår i: Glycobiology. - : Oxford University Press (OUP). - 0959-6658 .- 1460-2423. ; 26:12, s. 1401-1402
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Tidskriftsartikel (refereegranskat)abstract
- The gastrointestinal tract is covered by a complex extracellular mucus layer that protects the gastric epithelium fromexternal aggressions such as chemical agents, microorganismsand shear stress. Although this mucus barrier confers protec-tion against certain pathogens, it may also provide a niche formicrobial binding.Helicobacter pyloriexploits the host glycoconjugates present in the gastric mucus layer and lining thesurface epithelium of the gastric mucosa to colonize the stomach. Infection can persist for decades promoting chronicinflammation, and in a subset of individuals lesions cansilently progress to cancer. The secreted MUC5AC mucin isthe main component of the gastric mucus layer, andH. pyloriBabA-mediated binding to MUC5AC confers increased riskfor overt disease. We have shown that FUT2 determines theO-glycosylation pattern of Muc5ac, with Fut2 knock-outleading to a marked decrease inα1,2-fucosylated structuresand increased expression of the terminal type 1 glycan structure Lewisa. Importantly, for thefirst time, we structurallyvalidated the expression of Lewisain murine gastric mucosa(1). We further demonstrated that loss of mucin FUT2-mediated fucosylation impairs gastric mucosal binding ofH.pyloriBabA adhesin, which is a recognized feature of patho-genicity. UponH. pyloriinfection,concomitantly with tissueinflammation, there is a remodeling of the gastric glycopheno-type. We showed that increased expression of sialyl-Lewisa/xantigens is due to transcriptional up-regulation of theB3GNT5,B3GALT5,andFUT3genes. In addition, weobserved thatH. pyloriinfected individuals present a markedgastric local pro-inflammatory signature with significantlyhigher TNF-αlevels and demonstrated that TNF-induced activation of the NF-kappaB pathway results in B3GNT5 up-regulation (2). Furthermore, we showed that this gastric glycosylation shift, characterized by increased sialylation pat-terns, favors SabA-mediatedH. pyloriattachment to humaninflamed gastric mucosa. Our data provides clinically relevantinsights into the regulatory mechanisms underlyingH. pylorimodulation of host glycosylation machinery, and phenotypicalterations crucial for life-long infection and gastric disease.
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| 8. |
- Rainford, Louise, et al.
(författare)
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Education and training in radiation protection in Europe : an analysis from the EURAMED rocc-n-roll project
- 2022
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Ingår i: Insights into Imaging. - : Springer. - 1869-4101. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: A Strengths, weaknesses, opportunities and threats analysis was performed to understand the status quo of education and training in radiation protection (RP) and to develop a coordinated European approach to RP training needs based on stakeholder consensus and existing activities in the field. Fourteen team members represented six European professional societies, one European voluntary organisation, two international healthcare organisations and five professions, namely: Medical Physicists; Nuclear Medicine Physicians; Radiologists; Radiation Oncologists and Radiographers. Four subgroups analysed the "Strengths", "Weaknesses", "Opportunities" and "Threats" related to E&T in RP developed under previous European Union (EU) programmes and on the Guidelines on Radiation Protection Education and Training of Medical Professionals in the EU.Results: Consensus agreement identified four themes for strengths and opportunities, namely: (1) existing structures and training recommendations; (2) RP training needs assessment and education & training (E&T) model(s) development; (3) E&T dissemination, harmonisation, and accreditation; (4) financial supports. Weaknesses and Threats analysis identified two themes: (1) awareness and prioritisation at a national/global level and (2) awareness and prioritisation by healthcare professional groups and researchers.Conclusions: A lack of effective implementation of RP principles in daily practice was identified. EuRnR strategic planning needs to consider processes at European, national and local levels. Success is dependent upon efficient governance structures and expert leadership. Financial support is required to allow the stakeholder professional agencies to have sufficient resources to achieve a pan European radiation protection training network which is sustainable and accredited across multiple national domains.
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| 9. |
- Santos, Joana, et al.
(författare)
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Education and training in radiation protection in Europe : results from the EURAMED Rocc-n-Roll project survey
- 2023
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Ingår i: Insights into Imaging. - : Springer. - 1869-4101. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To analyse the existing radiation protection (RP) education and training (E&T) capabilities in the European Union and identify associated needs, problems and challenges.Method: An online survey was disseminated via the EURAMED Rocc-n-Roll consortium network and prominent medical societies in the field of radiological research. The survey sections analyse the RP E&T during undergraduate, residency/internship and continuous professional development; RP E&T problems and legal implementation. Differences were analysed by European geographic regions, profession, years of professional experience and main area of practice/research.Results: The majority of the 550 respondents indicated that RP topics are part of undergraduate curricula in all courses for their profession and country (55%); however, hands-on practical training is not included according to 30% of the respondents. The lack of E&T, practical aspects in current E&T, and mandatory continuing E&T were considered the major problems. The legal requirement that obtained higher implementation score was the inclusion of the practical aspects of medical radiological procedures on education (86%), and lower score was obtained for the inclusion of RP E&T on medical and dental school curriculums (61%).Conclusions: A heterogeneity in RP E&T during undergraduate, residency/internship and continuous professional development is evident across Europe. Differences were noted per area of practice/research, profession, and European geographic region. A large variation in RP E&T problem rating was also obtained.
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