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Microbicides are an important strategy for preventing the sexual transmission of HIV but, so far, the most advanced tenofovir-based microbicides have had modest efficacy. This has been related to adherence problems and high prevalence of tenofovir-resistant HIV-1 strains. P3 is a new peptide with potent activity against HIV that may be a good microbicide candidate. In this work P3 was formulated in a gel of hydroxyethyl cellulose and its activity, stability and safety profile in Balb/c mice were evaluated. HIV infection was fully blocked by a 1.5% gel containing P3 at the IC90 (366.4 nM) concentration. The antiviral activity did not change at 4°C during 4 months and at 25, 37 and 65°C for 1 week. P3 was stable and fully functional at acidic pH up to 24h, under different concentrations of hydrogen peroxide and in the presence of genital fluids up to 48h. P3 had no antibacterial activity and did not affect sperm motility and vitality. Finally, P3 didn't cause significant alterations in the vaginal epithelium of Balb/c mice at 0.06 (456.8 μM) and 0.2 mg/day (1522.7 μM) doses. These findings indicate that P3 is an excellent candidate for further development as a microbicide gel for the prevention of HIV transmission in women.

[This corrects the article DOI: 10.1371/journal.pone.0195744.].

Integrase inhibitors (INIs) are an important class of drugs for treating HIV-2 infection, given the limited number of drugs active against this virus. While the clinical efficacy of raltegravir and dolutegravir is well established, the clinical efficacy of bictegravir for treating HIV-2 infected patients has not been determined. Little information is available regarding the activity of bictegravir against HIV-2 isolates from patients failing raltegravir-based therapy. In this study, we examined the phenotypic and matched genotypic susceptibility of HIV-2 primary isolates from raltegravir-naïve and raltegravir-failing patients to raltegravir, dolutegravir, and bictegravir, and to the new spiro-β-lactam BSS-730A. The instantaneous inhibitory potential (IIP) was calculated to help predict the clinical activity of bictegravir and BSS-730A. Isolates from raltegravir-naïve patients were highly sensitive to all INIs and BSS-730A. Combined integrase mutations E92A and Q148K conferred high-level resistance to raltegravir, and E92Q and T97A conferred resistance to raltegravir and dolutegravir. The antiviral activity of bictegravir and BSS-730A was not affected by these mutations. BSS-730A displayed strong antiviral synergism with raltegravir. Mean IIP values at Cmax were similar for all INIs and were not significantly affected by resistance mutations. IIP values were significantly higher for BSS-730A than for INIs. The high IIP values of bictegravir and BSS-730A for raltegravir-naïve and raltegravir-resistant HIV-2 isolates highlight their potential value for treating HIV-2 infection. Overall, the results are consistent with the high clinical efficacy of raltegravir and dolutegravir for HIV-2 infection and suggest a promising clinical profile for bictegravir and BSS-730A.

To successfully control the global spread of HIV, it is crucial to combine effective prevention and treatment strategies. The aims of this thesis are: a) to characterize the antiviral activity of dolutegravir (DTG) against HIV-2 primary isolates; b) to develop dendrimers as topical anti-HIV-2 microbicides; c) to evaluate P3 peptide as a potential microbicide to prevent HIV transmission in women. In Chapter 2, we observed that DTG had potent activity against all raltegravir (RAL)-resistant HIV-2 isolates, indicating its usefulness as second line therapy for patients failing RAL. Mutation Q148K was responsible for high-level of resistance to RAL, however, it did not affect the activity of DTG. Importantly, we described for the first time primary resistance to DTG and we propose a new mechanism of resistance: mutations K221Q and D222K increase the activity of reverse transcriptase, thus increasing viral replication, leading to indirect resistance to DTG. In Chapter 3, we showed that dendrimers G2-S16, G2-NS16 and G3-Sh16 inhibited HIV-2 infection acting in the early steps of the HIV-2 lifecycle. They blocked HIV-2 cell-free and cell-to-cell fusion and had synergistic effects with tenofovir and RAL. Vaginal application of 3% HEC-G2-S16 gel formulation in mice did not affect mucosa integrity, further confirming that these dendrimers are promising candidates for future topical microbicides. In Chapter 4, we proved that the fusion inhibitor peptide P3 was stable and active in the presence of body fluids and at different temperatures. P3 was also active in the acidic environment of the vagina, was not be affected by the H2O2 produced by Lactobacillus and did not have spermicidal activity. Importantly, we showed that a P3-1.5% HEC gel was very effective at blocking HIV-1 infection. These findings suggest that dendrimers and P3 are good microbicide candidates to prevent vaginal HIV transmission in humans.

Os acidentes rodoviários em meio urbano contribuem para o decréscimo da qualidade de vida e para a inequidade social das cidades. Em Portugal, o número e gravidade dos acidentes rodoviários decresceu muito nos últimos vinte anos, mas a situação continua a ser preocupante.Na cidade de Lisboa, apesar da evolução positiva que se tem verificado nos últimos anos, o número de acidentes rodoviários continua elevado, afastando-se inaceitavelmente da média europeia. Deste modo, com base no conjunto de todos os acidentes com vítimas ocorridos na cidade de Lisboa entre 2004 e 2007, foi realizada uma análise exploratória das características dos mesmos, com vista a encontrar os factores mais importantes na explicação da ocorrência e gravidade dos acidentes com vítimas. Recorrendo aos modelos lineares generalizados, concluiu-se que factores humanos, ambientais e circunstanciais têm influência na gravidade dos acidentes e algumas variáveis de exposição foram consideradas importantes na explicação da ocorrência dos mesmos por freguesia.Estes dados foram ainda georreferenciados, com o intuito de uma exploração da natureza espacial dos mesmos, tentando perceber padrões geográficos existentes, identificando factores de risco associados. Considerando a localização da ocorrência de cada acidente como aleatória, enquadra-se este problema na teoria dos processos pontuais espaciais. Uma análise envolvendo testes de hipótese e descrições sumárias da localização dos acidentes permitiu concluir que estes não se encontram uniformemente distribuidos no espaço, rejeitando-se a designada hipótese de aleatoriedade completa.Pretende-se, assim, contribuir para a identificação de medidas eficientes, tendo em conta as condições prevalencentes a nível local, bem como facilitar a realização de comparações com realidades internacionais no que respeita à segurança rodoviária.

Neste trabalho é apresentada e discutida uma metodologia para avaliar o risco de exploração bem como o potencial de exploração para acumulações de hidrocarbonetos com base na quantidade e controle da qualidade dos dados adquiridos da área de estudo. Este método, fortemente suportado em tecnologias SIG, foi aplicado a um sector localizado na zona Noroeste da Bacia Potiguar (Brasil), e permitiu elaborar um conjunto de mapas geológicos, informativos e culturais, e ainda um mapa de Probabilidade de Sucesso Geológico que traduz o inverso do Risco de Exploração aquele sector da bacia, com o intuito de optimizar a taxa de sucesso geológico e auxiliar na selecção da área a explorar.

Iron (Fe) is an essential mineral for metabolism and plays a central role in a range of biochemical processes. Therefore, this study aimed to identify differentially expressed (DE) genes and metabolic pathways in Longissimus dorsi (LD) muscle from cattle with divergent iron content, as well as to investigate the likely role of these DE genes in biological processes underlying beef quality parameters. Samples for RNA extraction for sequencing and iron, copper, manganese, and zinc determination were collected from LD muscles at slaughter. Eight Nelore steers, with extreme genomic estimated breeding values for iron content (Fe-GEBV), were selected from a reference population of 373 animals. From the 49 annotated DE genes (FDR<0.05) found between the two groups, 18 were up-regulated and 31 down-regulated for the animals in the low Fe-GEBV group. The functional enrichment analyses identified several biological processes, such as lipid transport and metabolism, and cell growth. Lipid metabolism was the main pathway observed in the analysis of metabolic and canonical signaling pathways for the genes identified as DE, including the genes FASN, FABP4, and THRSP, which are functional candidates for beef quality, suggesting reduced lipogenic activities with lower iron content. Our results indicate metabolic pathways that are partially influenced by iron, contributing to a better understanding of its participation in skeletal muscle physiology.

Leishmaniasis is a zoonotic disease of major public health and veterinary importance, affecting 88 countries with up to 2 million cases per year. This review emphasizes the animal reservoirs and spreading of visceral leishmaniasis (VL) in urban areas, particularly in two Brazilian metropolitan areas, namely São Luis and Belo Horizonte, where the disease has become endemic in the past few years. Urbanization of visceral leishmaniasis in Brazil during the last decades has created favorable epidemiological conditions for maintenance of the disease, with dense human populations sharing a tropical environment with abundant populations of the mammalian reservoir and the invertebrate vector, facilitating transmission of the disease.

Deep eutectic systems (DES) have shown increasing popularity in last decade; however, the number of studies on the potential toxicity towards living organisms remains scarce. These studies are of the utmost importance to infer on the claimed non-toxicity and biocompatibility of DES. Most articles published, at this moment, only evaluate the toxicity towards a cell model or in different strains of bacteria. For this purpose, in this work, the effect of two DES (betaine:sorbitol:water 1:1:3 and betaine:glycerol 1:2) and their individual components were evaluated at different concentrations after administered via intraperitoneal injection in zebrafish ( Danio rerio ). The total antioxidant capacity, lipoperoxidation, and the activity of various enzymes that work in different antioxidant pathways (superoxide dismutase, glutathione peroxidase, catalase, and glutathione S-transferase) were assessed. The results show no significant toxicity within the tested concentrations: up to 5000 µM and 3000 µM, for the assays using the system betaine:sorbitol:water 1:1:3 and for betaine:glycerol 1:2, respectively. The toxicity of individual components was studied up to 1000 µM. Based on the encouraging results that have been obtained, it is safe to conclude that these two deep eutectic systems can be used as the new class of environmentally friendly solvents. Graphical Abstract

Sharks have maintained a key role in marine food webs for 400 million years and across varying physicochemical contexts, suggesting plasticity to environmental change. In this study, we investigated the biochemical effects of ocean acidification (OA) levels predicted for 2100 (pCO2 ~ 900 μatm) on newly hatched tropical whitespotted bamboo sharks (Chiloscyllium plagiosum). Specifically, we measured lipid, protein, and DNA damage levels, as well as changes in the activity of antioxidant enzymes and non-enzymatic ROS scavengers in juvenile sharks exposed to elevated CO2 for 50 days following hatching. Moreover, we also assessed the secondary oxidative stress response, i.e., heat shock response and ubiquitin levels. Newly hatched sharks appear to cope with OA-related stress through a range of tissue-specific biochemical strategies, specifically through the action of antioxidant enzymatic compounds. Our findings suggest that ROS-scavenging molecules, rather than complex enzymatic proteins, provide an effective defense mechanism in dealing with OA-elicited ROS formation. We argue that sharks' ancient antioxidant system, strongly based on non-enzymatic antioxidants (e.g., urea), may provide them with resilience towards OA, potentially beyond the tolerance of more recently evolved species, i.e., teleosts. Nevertheless, previous research has provided evidence of detrimental effects of OA (interacting with other climate-related stressors) on some aspects of shark biology. Moreover, given that long-term acclimation and adaptive potential to rapid environmental changes are yet experimentally unaccounted for, future research is warranted to accurately predict shark physiological performance under future ocean conditions.