In vivo imaging of the dynamic interactions of acute leukaemias with the bone marrow microenvironment

Adult haematopoietic stem cells (HSC) reside in the bone marrow (BM) microenvironment, or niche, where they are regulated by several cell types including osteoblasts, endothelial cells and Nestin-expressing perivascular cells, and by niche-derived signals, such as CXCL12. In parallel, leukaemia growth and chemoresistance have been proposed to be dependent on an analogous malignant microenvironment. Using a murine model of MLL-AF9 driven acute myeloid leukaemia (AML), I show that AML outcompetes non-malignant haematopoiesis by gradual elimination of stroma cells, endosteal endothelium and osteoblastic cells. I further demonstrate that blood vessels in AML-burdened mice are more cell-permeable and likely contribute to loss of haematopoietic cells. The rescue of the endosteal vascular microenvironment in AML rescues HSC loss and improves chemotherapy efficacy (Chapter 3). To address the reverse question, i.e. whether the microenvironment influences disease progression, I studied a mouse model of T-cell acute lymphoblastic leukaemia (T-ALL) driven by constitutively active Notch1. Our group had previously shown that T-ALL progression is independent from particular niches. Here, I show that chemoresistant T-ALL cells are also niche-independent and highly motile, maintaining very transient interactions with surrounding microenvironments (Chapter 4). Studying the in vivo behaviour of Notch-1 T-ALL and MLL-AF9 cells in parallel, I observed that chemoresistant AML cells, in contrast with T-ALL, are less migratory than naïve ones. I also show that AMD3100, an antagonist of CXCR4 (the receptor of CXCL12), inhibits the migration of treatment-naïve and chemoresistant T-ALL cell migration. In contrast, AML cell behaviour remains unaltered after CXCR4 inhibition, likely because of disease-specific, more complex interactions with the BM microenvironment (Chapter 5). These results support the importance of cell-intrinsic and overall tissue influence rather than stroma-specific signals supporting chemoresistant T-ALL. Additionally I show that therapies targeting the endosteal vasculature could potentially improve existing AML therapeutic regimes. The different nature of leukaemia-microenvirnment interactions for the two diseases is further demonstrated by the observation that CXCR4 inhibition affects T-ALL but not AML cell migration within the BM space.Open Acces

Percepções de envelhecimento : percursos imaginados de velhice

As expectativas que os indivíduos criam em relação ao seu futuro parecem ter repercussões ao nível das atitudes e comportamentos que estes desenvolvem no presente. Nesta investigação, assumindo-se um modelo de investigação interpretativo e utilizando-se uma metodologia de cariz qualitativo, procurou-se explorar as expectativas que indivíduos portugueses do sexo masculino, não viúvos, que pela sua idade cronológica (60-65 anos) se encontram em vias de serem rotulados como “idosos” pela sociedade, possuem em relação ao seu envelhecimento. Como objectivo secundário, procurou-se perceber se existem diferenças ao nível de tais expectativas em função do nível de escolaridade dos participantes. Recorreu-se a uma amostra de 16 participantes com as características já mencionadas e a residir nas suas casas, com diferentes níveis de escolaridade. A recolha de dados foi feita mediante a utilização do método focus groups e a análise qualitativa dos dados foi realizada com o auxílio do NVivo8, um programa de computador facilitador desta fase do processo. Este estudo permitiu aceder a pontos de vista que sujeitos do sexo masculino na faixa etária em questão apresentam relativamente ao processo de envelhecimento em geral e a considerações, preocupações e esperanças que produzem relativamente à sua trajectória de envelhecimento individual. Os resultados apontam, entre outros aspectos, para o facto de os indivíduos com estas idades não se sentirem idosos nem costumarem pensar muito sobre a sua trajectória futura de envelhecimento, embora considerem que o avanço da idade possa trazer consigo aspectos negativos para o seu bem-estar. As percepções e expectativas que apresentam tendem a ser mais favoráveis para si do que para as outras pessoas e têm repercussões afectivas e comportamentais. Os resultados vão também ao encontro da hipótese de que um nível de escolaridade mais elevado está associado a um maior optimismo na forma como se perspectiva o envelhecimento.The expectations that people create in respect to their future seem to have repercussions on the attitudes and behaviors that they develop at the present. In this research, assuming an interpretative model of research and using qualitative methodology, an attempt was made to explore the expectations that male Portuguese indivduals, not widows, who by their chronological age (60-65 years) are in imminence to be labeled as “elders” by the society, have in regard to their process of aging. As a secondary objective, there was made an attempt to understand if there are differences in this matter between participants with different educational levels. A sample of 16 participants with the already mentioned characteristics, living in their homes, with different levels of education, was recruited. Data collection was performed using focus groups method and qualitative data analysis was done with the help of NVivo8, a computer program which facilitates this phase of the process. This study enabled the access to points of view that male subjects in the considered age group have in respect to the general aging process and to considerations, concerns and hopes that they produce relatively to their individual trajectory of aging. The results point, among other things, to the fact that individuals with these ages do not feel elderly and do not think much about their future trajectory of aging, despite they consider that the aging process may bring some bad changes that that might challenge their well-being. The perceptions and expectations tended to be more favorable to the self than to the other people and have emotional and behavioral consequences. The results also seem to corroborate the hypothesis that a higher education level is associated with greater optimism in the way aging process is seen

Extending Eventually Consistent Cloud Databases for Enforcing Numeric Invariants

Geo-replicated databases often operate under the principle of eventual consistency to offer high-availability with low latency on a simple key/value store abstraction. Recently, some have adopted commutative data types to provide seamless reconciliation for special purpose data types, such as counters. Despite this, the inability to enforce numeric invariants across all replicas still remains a key shortcoming of relying on the limited guarantees of eventual consistency storage. We present a new replicated data type, called bounded counter, which adds support for numeric invariants to eventually consistent geo-replicated databases. We describe how this can be implemented on top of existing cloud stores without modifying them, using Riak as an example. Our approach adapts ideas from escrow transactions to devise a solution that is decentralized, fault-tolerant and fast. Our evaluation shows much lower latency and better scalability than the traditional approach of using strong consistency to enforce numeric invariants, thus alleviating the tension between consistency and availability

Smart auditorium: development and analysis of a power and environment monitoring platform

First Online: 09 April 2020The Internet of Things (IoT) is applied to many cases on the topic of smart cities. In the scope of this paper, we apply a flexible IoT-Developed platform, using LoRa communication, applied to university auditoriums in order to try and find patterns and/or anomalies in energy consumption and in the interior temperature. This platform enables the interested parties to monitor the energy consumption of lighting, of HVAC (Heating, Ventilation, and Air Conditioning) and if electrical plugs alongside the monitoring of temperatures, aiming to create a report about the efficient, the thermal insulation and the HVAC behavior. Based on the acquired information, a management strategy is applied to find that the lack of certain systems leads to an extreme waste of energy and the lack of proper cleaning procedures can lead to decreasing the efficiency of the HVAC.This work has been supported by FCT – Fundação para a Ciência e Tecnologia within the Project Scope: UID/CEC/00319/2019. This work is financed by the ERDF – European Regional Development Fund through the Operational Programme for Competitiveness and Internationalisation – COMPETE 2020 Programme, and by National Funds through the Portuguese funding agency, FCT – Fundação para a Ciência e a Tecnologia, within project SAICTPAC/0004/2015 – POCI – 01–0145–FEDER–016434

A network Data Envelopment Analysis to estimate nations’ efficiency in the fight against SARS-CoV-2

The ongoing outbreak of SARS-CoV-2 has been deeply impacting health systems worldwide. In this context, it is pivotal to measure the efficiency of different nations’ response to the pandemic, whose insights can be used by governments and health authorities worldwide to improve their national COVID-19 strategies. Hence, we propose a network Data Envelopment Analysis (DEA) to estimate the efficiencies of fifty-five countries in the current crisis, including the thirty-seven Organisation for Economic Co-operation and Development (OECD) member countries, six OECD prospective members, four OECD key partners, and eight other countries. The network DEA model is designed as a general series structure with five single-division stages – population, contagion, triage, hospitalisation, and intensive care unit admission –, and considers an output maximisation orientation, denoting a social perspective, and an input minimisation orientation, denoting a financial perspective. It includes inputs related to health costs, desirable and undesirable intermediate products related to the use of personal protective equipment and infected population, respectively, and desirable and undesirable outputs regarding COVID-19 recoveries and deaths, respectively. To the best of the authors’ knowledge, this is the first study proposing a cross-country efficiency measurement using a network DEA within the context of the COVID-19 crisis. The study concludes that Estonia, Iceland, Latvia, Luxembourg, the Netherlands, and New Zealand are the countries exhibiting higher mean system efficiencies. Their national COVID-19 strategies should be studied, adapted, and used by countries exhibiting worse performances. In addition, the observation of countries with large populations presenting worse mean efficiency scores is statistically significant.info:eu-repo/semantics/publishedVersio

Production of dicarboxylic acid platform chemicals using yeasts: focus on succinic acid

The biotechnological production of biobased dicarboxylic acids has recently become a hot topic in industrial biotechnology, with many investments involved in the development, piloting, and validation at demonstration scale of diverse processes using renewable raw materials. This chapter will review the main markets and applications of commercially relevant dicarboxylic acids and will briefly present their current chemical and biotechnological production processes. The chapter will mainly focus on the particular case of succinic acid. The microbial platforms that have been proposed will be reviewed with emphasis on yeast strains. The basic requirements for setting up and scaling the bioprocess and the required purification strategy to obtain an economically feasible process yielding a product meeting the required specifications will be presented. Throughout the chapter, the specific challenges of using very low-cost raw materials such as agro-industrial residues will be highlighted.(undefined)info:eu-repo/semantics/publishedVersio

Combinatorial delivery of doxorubicin and acridine orange by gold core silica shell nanospheres functionalized with poly(ethylene glycol) and 4- methoxybenzamide for cancer targeted therapy

Combinatorial therapies based on the simultaneous administration of multiple drugs can lead to synergistic effects, increasing the efficacy of the cancer therapy. However, it is crucial to develop new delivery systems that can increase the drugs' therapeutic selectivity and efficacy. Gold core silica shell (AuMSS) nanoparticles present physicochemical properties that allow their simultaneous application as drug delivery and imaging agents. Herein, poly(ethylene glycol) was modified with 4-methoxybenzamide and 3- (triethoxysilyl)propyl isocyanate (TPANIS) to create a novel surface functionalization capable of improving the colloidal stability and specificity of AuMSS nanospheres towards cancer cells. Moreover, a dual drug combination based on Doxorubicin (DOX) and Acridine orange (AO) was characterized and administered using the AuMSS-TPANIS nanospheres. The obtained results show that the DOX:AO drug combination can mediate a synergistic therapeutic effect in both HeLa and MCF-7 cells, particularly at the 2:1, 1:1, and 1:2 ratios. Otherwise, the TPANIS functionalization increased the AuMSS nanospheres colloidal stability and selectivity towards MCF-7 cancer cells (overexpressing sigma receptors). Such also resulted in an enhanced cytotoxic effect against MCF-7 cells when administering the DOX:AO drug combination with the AuMSSTPANIS nanospheres. Overall, the obtained results confirm the therapeutic potential of the DOX:AO drug combination as well as the targeting capacity of AuMSS-TPANIS, supporting its application in the cancer targeted combinatorial chemotherapy.info:eu-repo/semantics/acceptedVersio

Environmentally-friendly reduced graphene oxide functionalized with hyaluronic acid for targeted cancer photothermal therapy

Reduced Graphene Oxide (rGO) is one of the most promising nanomaterials for cancer photothermal therapy (PTT) due to its high near infrared (NIR) absorption. However, the rGO producing methods uses dangerous reducing agents, resulting in poor biocompatibility. Additionally, rGO also displays poor colloidal stability and is unable to target cancer cells. These limitations can be improved by using environmentally-friendly reduction methods and by functionalizing this nanomaterial with amphiphilic polymers. In this work, the production of reduced Graphene Oxide (rGO) rGO was performed by using an environmentally-friendly method (reduction with L-ascorbic Acid (LAA)). Then, the obtained rGO was functionalized with an amphiphilic polymer based on hyaluronic acid (HA-g-PMAO) for application in CD44-targeted breast cancer PTTGrants UBI/Santander-Tottainfo:eu-repo/semantics/publishedVersio