Genetic modifiers of sickle cell anemia phenotype in a cohort of Angolan children

This research was funded by FCT/Aga Khan (project nº330842553) and FCT/MCTES (UIDB/05608/2020 and UIDP/05608/2020) – H&TRC.This study aimed to identify genetic markers in the HBB Cluster; HBS1L-MYB intergenic region; and BCL11A, KLF1, FOX3, and ZBTB7A genes associated with the heterogeneous phenotypes of Sickle Cell Anemia (SCA) using the next-generation sequencing, as well as to assess their influence and prevalence in an Angolan population. Hematological, biochemical, and clinical data were considered to determine patients’ severity phenotypes. Samples from 192 patients were sequenced, and 5,019,378 variants of high quality were registered. A catalog of candidate modifier genes that clustered in pathophysiological pathways important for SCA was generated, and candidate genes associated with increasing vaso-occlusive crises (VOC) and with lower fetal hemoglobin (HbF) were identified. These data support the polygenic view of the genetic architecture of SCA phenotypic variability. Two single nucleotide polymorphisms in the intronic region of 2q16.1, harboring the BCL11A gene, are genome-wide and significantly associated with decreasing HbF. A set of variants was identified to nominally be associated with increasing VOC and are potential genetic modifiers harboring phenotypic variation among patients. To the best of our knowledge, this is the first investigation of clinical variation in SCA in Angola using a well-customized and targeted sequencing approach.info:eu-repo/semantics/publishedVersio

Impact of Viral Protease Activity in the Production of LV Pseudotypes

Lentiviral vectors (LVs) are excellent tools for gene transfer into mammalian cells. It is noteworthy that the first gene therapy treatment using LVs was approved for commercialization in 2017. The G glycoprotein from rhabdovirus vesicular stomatitis virus (VSV-G) is the glycoprotein most used to pseudotype LVs, due to its high efficiency in transducing several cell types and its resistance to viral vector purification and storage conditions. However, VSV-G expression induces cytotoxicity, which limits LV production to short periods. As alternative to VSV-G, γ-retrovirus glycoproteins (4070A derived, GaLV derived, and RD114 derived) have been used to pseudotype both γ-retroviral vectors (RVs) and LVs. These glycoproteins do not induce cytotoxicity, allowing the development of stable LV producer cells. Additionally, these LV pseudotypes present higher transduction efficiencies of hematopoietic stem cells when compared to VSV-G. Here, new 4070A-, RD114-TR-, and GaLV-TR-derived glycoproteins were developed with the aim of improving its cytoplasmic tail R-peptide cleavage and thus increase LV infectious titers. The new glycoproteins were tested in transient LV production using the wild-type or the less active T26S HIV-1 protease. The GaLV-TR-derived glycoproteins were able to overcome titer differences observed between LV production using wild-type and T26S protease. Additionally, these glycoproteins were even able to increase LV titers, evidencing its potential as an alternative glycoprotein to pseudotype LVs.publishe

ANÁLISE DE CONSUMO NUMA UNIDADE HOTELEIRA NO ALGARVE – PORTUGAL, COM O RECURSO DE FERRAMENTAS DE BUSINESS INTELLIGENCE

O presente artigo tem como objetivo dotar o setor da hotelaria com dados relevantes para a previsão de vendas, receitas, ocupação e encomendas de stock, com base na análise de uma amostra de clientes de uma unidade hoteleira de quatro estrelas localizada no Algarve - Portugal, constituída pelas quinze nacionalidades com maior taxa de ocupação durante o ano de 2014. Desta forma, pretende-se aferir as preferências dos hóspedes relativamente a consumos nos estabelecimentos de restauração e bebidas, de acordo com a tipologia de quarto, regime de alojamento e agência de viagem/operador turístico, examinando igualmente, utilizando estatística univariada, as despesas com o alojamento e os consumos realizados no ano de 2014. A partir da análise e da interpretação dos resultados obtidos, foi possível verificar que, apesar de Portugal ser a nacionalidade com maior número de hóspedes na unidade em 2014, os portugueses despenderam menos do que os germânicos no que toca aos consumos nos estabelecimentos de restauração e bebidas. Todavia, os hóspedes portugueses foram os clientes mais assíduos do Restaurante X no último quadrimestre do ano e terão, efetivamente, efetuado maiores despesas com o alojamento e os respetivos regimes em todo o ano civil

Discriminative capacity and construct validity of the Clock Drawing Test in Mild Cognitive Impairment and Alzheimer's disease

OBJECTIVES: The aim of this study was to analyze the psychometric and diagnostic properties of the Clock Drawing Test (CDT), scored according to the Babins, Rouleau, and Cahn scoring systems, for Mild Cognitive Impairment (MCI) and Alzheimer's disease (AD) screening, and develop corresponding cutoff scores. Additionally, we assessed the construct validity of the CDT through exploratory and confirmatory factor analysis. METHODS: We developed a cross-sectional study of ambulatory MCI and AD patients, divided in two clinical groups (450 MCI and 250 mild AD patients) and a normal control group (N = 400). All participants were assessed with the CDT, Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) for convergent validity. RESULTS: The selected scoring systems presented adequate validity and reliability values. The proposed cutoff scores showed 60 to 65% sensitivity and 58 to 62% specificity to identify MCI patients. The corresponding values for AD were 84 to 90% sensitivity and 76 to 78% specificity. Exploratory and confirmatory factor analysis revealed that the Babins scoring system had good construct validity and allowed us to propose a three-factor model for this system. CONCLUSIONS: Our results confirmed the complexity of the CDT and support it as a cognitive screening instrument particularly sensitive to AD. The use of the CDT with MCI patients should be interpreted with more caution due to the lower sensitivity and specificity for milder forms of cognitive impairment.info:eu-repo/semantics/publishedVersio

Habitat and trophic ecology of Southern Ocean cephalopods from stable isotope analyses

Although cephalopods play a critical role in marine food webs both as predators and prey, there is a limited knowledge of several basic aspects of their ecology, including their habitat and trophic level, in the Southern Ocean. We examined the ecological role of several Southern Ocean cephalopod species by analyzing δ13C and δ15N values in lower cephalopod beaks obtained from diet samples of wandering albatross Diomedea exulans from South Georgia (Atlantic Ocean), and from Crozet and Kerguelen Islands (Indian Ocean). Beak δ13C values ranged from -25.7 to -17.9‰, and were used to assign different cephalopod species to the subtropical, sub-Antarctic or Antarctic Zones. Beak δ15N values were more variable among species, ranging from 2.4 to 13.3‰, a difference of ~11‰ that represents approx. 3 trophic levels. Differences among islands in isotope ratios in the same cephalopod species (higher δ15N and lower δ13C values in South Georgia) were attributed to regional oceanographic processes. Antarctic cephalopods occupy niches similar to those found in some pelagic fish, seabirds and marine mammals. As cephalopods are key components in Southern Ocean food webs, these results greatly advance our understanding of the structure, energy and carbon flows in this polar ecosystem

Show your beaks and we tell you what you eat: Different ecology in sympatric Antarctic benthic octopods under a climate change context

Sympatry can lead to higher competition under climate change and other environmental pressures, including in South Georgia, Antarctica, where the two most common octopod species, Adelieledone polymorpha and Pareledone turqueti, occur side by side. Since cephalopods are typically elusive animals, the ecology of both species is poorly known. As beaks of cephalopods are recurrently found in top predator's stomachs, we studied the feeding ecology of both octopods through the evaluation of niche overlapping and specific beak adaptations that both species present. A multidisciplinary approach combining carbon (δ13C) and nitrogen (δ15N) stable isotope signatures, mercury (Hg) analysis and biomaterials' engineering techniques was applied to investigate the beaks. An isotopic niche overlap of 95.6% was recorded for the juvenile stages of both octopod species, dropping to 19.2% for the adult stages. Both A. polymorpha and P. turqueti inhabit benthic ecosystems around South Georgia throughout their lifecycles (δ13C: −19.21 ± 1.87‰, mean ± SD for both species) but explore trophic niches partially different during adult life stages (δ15N: 7.01 ± 0.40‰, in A. polymorpha, and 7.84 ± 0.65‰, in P. turqueti). The beaks of A. polymorpha are less dense and significantly less stiff than in P. turqueti. Beaks showed lower mercury concentration relative to muscle (A. polymorpha - beaks: 0.052 ± 0.009  μg g−1, muscle: 0.322 ± 0.088  μg g−1; P. turqueti - beaks: 0.038 ± 0.009  μg g−1; muscle: 0.434 ± 0.128  μg g−1). Overall, both octopods exhibit similar habitats but different trophic niches, related to morphology/function of beaks. The high Hg concentrations in both octopods can have negative consequences on their top predators and may increase under the present climate change context.British Antarctic Survey for assisting in the collection of the specimens for this work. Many thanks to 3B's Research Group (University of Minho) and MAREFOZ who were responsible for analysing the physical properties of beaks and stable isotope signatures. A special thank you to our colleague José Queirós from MARE-UC (Coimbra, Portugal) for his suggestions and guidance. A debt of gratitude is also owed to Dr. A. Louise Allcock (NUI Galway) for her useful guidelines. This work is an international effort under the Scientific Committee on Antarctic Research (SCAR) associated programs, expert and action groups, namely SCAR AnT-ERA, SCAR EGBAMM and ICED. J.C. Xavier was supported by the Investigator Programme (IF/00616/2013) of the Foundation for Science and Technology (FCT-Portugal) and PROPOLAR, and F.R. Ceia was supported by a postdoctoral fellowship (SFRH/BPD/95372/2013) attributed by FCT-Portugal and the European Social Fund (POPH, EU). This study benefited from the strategic program of MARE, financed by FCT-Portugal (MARE- UID/MAR/04292/2019). We also acknowledge FCT-Portugal through a PhD grant to J. Seco (SRFH/PD/BD/113487

Alterations in ALK/ROS1/NTRK/MET drive a group of infantile hemispheric gliomas

© The Author(s) 2019. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome. However, we have little understanding of their biology and therefore cannot explain this behavior nor what constitutes optimal clinical management. Here we report a comprehensive genetic analysis of an international cohort of clinically annotated infant gliomas, revealing 3 clinical subgroups. Group 1 tumors arise in the cerebral hemispheres and harbor alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET. These are typically single-events and confer an intermediate outcome. Groups 2 and 3 gliomas harbor RAS/MAPK pathway mutations and arise in the hemispheres and midline, respectively. Group 2 tumors have excellent long-term survival, while group 3 tumors progress rapidly and do not respond well to chemoradiation. We conclude that infant gliomas comprise 3 subgroups, justifying the need for specialized therapeutic strategies.info:eu-repo/semantics/publishedVersio

Murid Herpesvirus-4 Exploits Dendritic Cells to Infect B Cells

Dendritic cells (DCs) play a central role in initiating immune responses. Some persistent viruses infect DCs and can disrupt their functions in vitro. However, these viruses remain strongly immunogenic in vivo. Thus what role DC infection plays in the pathogenesis of persistent infections is unclear. Here we show that a persistent, B cell-tropic gamma-herpesvirus, Murid Herpesvirus-4 (MuHV-4), infects DCs early after host entry, before it establishes a substantial infection of B cells. DC-specific virus marking by cre-lox recombination revealed that a significant fraction of the virus latent in B cells had passed through a DC, and a virus attenuated for replication in DCs was impaired in B cell colonization. In vitro MuHV-4 dramatically altered the DC cytoskeleton, suggesting that it manipulates DC migration and shape in order to spread. MuHV-4 therefore uses DCs to colonize B cells

Altered plasma protein profiles in genetic FTD – a GENFI study

© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background: Plasma biomarkers reflecting the pathology of frontotemporal dementia would add significant value to clinical practice, to the design and implementation of treatment trials as well as our understanding of disease mechanisms. The aim of this study was to explore the levels of multiple plasma proteins in individuals from families with genetic frontotemporal dementia. Methods: Blood samples from 693 participants in the GENetic Frontotemporal Dementia Initiative study were analysed using a multiplexed antibody array targeting 158 proteins. Results: We found 13 elevated proteins in symptomatic mutation carriers, when comparing plasma levels from people diagnosed with genetic FTD to healthy non-mutation controls and 10 proteins that were elevated compared to presymptomatic mutation carriers. Conclusion: We identified plasma proteins with altered levels in symptomatic mutation carriers compared to non-carrier controls as well as to presymptomatic mutation carriers. Further investigations are needed to elucidate their potential as fluid biomarkers of the disease process.Open access funding provided by Karolinska Institute. C.G. received funding from EU Joint Programme—Neurodegenerative Disease Research -Prefrontals Vetenskapsrådet Dnr 529–2014-7504, Vetenskapsrådet 2015–02926, Vetenskapsrådet 2018–02754, the Swedish FTD Inititative-Schörling Foundation, Alzheimer Foundation, Brain Foundation, Dementia Foundation and Region Stockholm ALF-project. PN received funding from KTH Center for Applied Precision Medicine (KCAP) funded by the Erling-Persson Family Foundation, the Swedish FTD Inititative-Schörling Foundation and Åhlén foundation. D.G. received support from the EU Joint Programme—Neurodegenerative Disease Research and the Italian Ministry of Health (PreFrontALS) grant 733051042. E.F. has received funding from a Canadian Institute of Health Research grant #327387. F.M. received funding from the Tau Consortium and the Center for Networked Biomedical Research on Neurodegenerative Disease. J.B.R. has received funding from the Welcome Trust (103838) and is supported by the Cambridge University Centre for Frontotemporal Dementia, the Medical Research Council (SUAG/051 G101400) and the National Institute for Health Research Cambridge Biomedical Research Centre (BRC-1215–20014). J.C.V.S. was supported by the Dioraphte Foundation grant 09–02-03–00, Association for Frontotemporal Dementias Research Grant 2009, Netherlands Organization for Scientific Research grant HCMI 056–13-018, ZonMw Memorabel (Deltaplan Dementie, project number 733 051 042), Alzheimer Nederland and the Bluefield Project. J.D.R. is supported by the Bluefield Project and the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre, and has received funding from an MRC Clinician Scientist Fellowship (MR/M008525/1) and a Miriam Marks Brain Research UK Senior Fellowship. M.M. has received funding from a Canadian Institute of Health Research operating grant and the Weston Brain Institute and Ontario Brain Institute. M.O. has received funding from Germany’s Federal Ministry of Education and Research (BMBF). R.S-V. is supported by Alzheimer’s Research UK Clinical Research Training Fellowship (ARUK-CRF2017B-2) and has received funding from Fundació Marató de TV3, Spain (grant no. 20143810). R.V. has received funding from the Mady Browaeys Fund for Research into Frontotemporal Dementia. This work was also supported by the EU Joint Programme—Neurodegenerative Disease Research GENFI-PROX grant [2019–02248; to J.D.R., M.O., B.B., C.G., J.C.V.S. and M.S.info:eu-repo/semantics/publishedVersio