Comparing reverse complementary genomic words based on their distance distributions and frequencies

In this work we study reverse complementary genomic word pairs in the human DNA, by comparing both the distance distribution and the frequency of a word to those of its reverse complement. Several measures of dissimilarity between distance distributions are considered, and it is found that the peak dissimilarity works best in this setting. We report the existence of reverse complementary word pairs with very dissimilar distance distributions, as well as word pairs with very similar distance distributions even when both distributions are irregular and contain strong peaks. The association between distribution dissimilarity and frequency discrepancy is explored also, and it is speculated that symmetric pairs combining low and high values of each measure may uncover features of interest. Taken together, our results suggest that some asymmetries in the human genome go far beyond Chargaff's rules. This study uses both the complete human genome and its repeat-masked version.Comment: Post-print of a paper accepted to publication in "Interdisciplinary Sciences: Computational Life Sciences" (ISSN: 1913-2751, ESSN: 1867-1462

Dissimilar Symmetric Word Pairs in the Human Genome

In this work we explore the dissimilarity between symmetric word pairs, by comparing the inter-word distance distribution of a word to that of its reversed complement. We propose a new measure of dissimilarity between such distributions. Since symmetric pairs with different patterns could point to evolutionary features, we search for the pairs with the most dissimilar behaviour. We focus our study on the complete human genome and its repeat-masked version.Comment: Submitted 13-Feb-2017; accepted, after a minor revision, 17-Mar-2017; 11th International Conference on Practical Applications of Computational Biology & Bioinformatics, PACBB 2017, Porto, Portugal, 21-23 June, 201

The interplay between redox signalling and proteostasis in neurodegeneration: In vivo effects of a mitochondria-targeted antioxidant in Huntington's disease mice.

Abnormal protein homeostasis (proteostasis), dysfunctional mitochondria, and aberrant redox signalling are often associated in neurodegenerative disorders, such as Huntington's (HD), Alzheimer's and Parkinson's diseases. It remains incompletely understood, however, how changes in redox signalling affect proteostasis mechanisms, including protein degradation pathways and unfolded protein responses (UPR). Here we address this open question by investigating the interplay between redox signalling and proteostasis in a mouse model of HD, and by examining the in vivo effects of the mitochondria-targeted antioxidant MitoQ. We performed behavioural tests in wild-type and R6/2 HD mice, examined markers of oxidative stress, UPR activation, and the status of key protein degradation pathways in brain and peripheral tissues. We show that R6/2 mice present widespread markers of oxidative stress, with tissue-specific changes in proteostasis that were more pronounced in the brain and muscle than in the liver. R6/2 mice presented increased levels of cytosolic and mitochondrial chaperones, particularly in muscle, indicating UPR activation. Treatment with MitoQ significantly ameliorated fine motor control of R6/2 mice, and reduced markers of oxidative damage in muscle. Additionally, MitoQ attenuated overactive autophagy induction in the R6/2 muscle, which has been associated with muscle wasting. Treatment with MitoQ did not alter autophagy markers in the brain, in agreement with its low brain bioavailability, which limits the risk of impairing neuronal protein clearance mechanisms. This study supports the hypotheses that abnormal redox signalling in muscle contributes to altered proteostasis and motor impairment in HD, and that redox interventions can improve muscle performance, highlighting the importance of peripheral therapeutics in HD

Co-ingestion of amatoxins and isoxazoles-containing mushrooms and successful treatment: A case report

Mushroom poisonings occur when ingestion of wild mushrooms containing toxins takes place, placing the consumers at life-threatening risk. In the present case report, an unusual multiple poisoning with isoxazoles- and amatoxins-containing mushrooms in a context of altered mental state and poorly controlled hypertension is presented. A 68-year-old female was presented to São João hospital (Portugal) with complaints of extreme dizziness, hallucinations, vertigo and imbalance, 3 h after consuming a stew of wild mushrooms. The first observations revealed altered mental state and elevated blood pressure. The examination of cooked mushroom fragments allowed a preliminary identification of Amanita pantherina. Gas chromatography-mass spectrometry (GC-MS) showed the presence of muscimol in urine. Moreover, through high-performance liquid chromatography-ultraviolet detection (HPLC-UV) analysis of the gastric juice, the presence of α-amanitin was found, showing that amatoxins-containing mushrooms were also included in the stew. After 4 days of supportive treatment, activated charcoal, silybin and N-acetylcysteine, the patient recovered being discharged 10 days post-ingestion with no organ complications. The prompt and appropriate therapy protocol for life-threatening amatoxins toxicity probably saved the patient's life as oral absorption was decreased and also supportive care was immediately started.This work received financial support from the European Union (FEDER funds through COMPETE) and National Funds (FCT, Fundação para a Ciência e Tecnologia) through project Pest-C/EQB/LA0006/2013. Juliana Garcia and Vera Marisa Costa thank FCT e Foundation for Science and Technology e for their PhD grant (SFRH/BD/74979/2010) and Post-doc grant (SFRH/BPD/63746/2009), respectively.info:eu-repo/semantics/publishedVersio

CD20+ T cells in monoclonal B cell lymphocytosis and chronic lymphocytic leukemia: frequency, phenotype and association with disease progression

IntroductionIn monoclonal B cell lymphocytosis (MBL) and chronic lymphocytic leukemia (CLL), the expansion of malignant B cells disrupts the normal homeostasis and interactions between B cells and T cells, leading to immune dysregulation. CD20+ T cells are a subpopulation of T cells that appear to be involved in autoimmune diseases and cancer.MethodsHere, we quantified and phenotypically characterized CD20+ T cells from MBL subjects and CLL patients using flow cytometry and correlated our findings with the B-cell receptor mutational status and other features of the disease. Results and discussionCD20+ T cells were more represented within the CD8+ T cell compartment and they showed a predominant memory Tc1 phenotype. CD20+ T cells were less represented in MBL and CLL patients vs healthy controls, particularly among those with unmutated IGVH gene. The expansion of malignant B cells was accompanied by phenotypic and functional changes in CD20+ T cells, including an increase in follicular helper CD4+ CD20+ T cells and CD20+ Tc1 cells, in addition to the expansion of the TCR Vβ 5.1 in CD4+ CD20+ T cells in CLL

Preclinical validation of a new hybrid molecule loaded in liposomes for melanoma management

The aggressiveness of melanoma and lack of effective therapies incite the discovery of novel strategies. Recently, a new dual acting hybrid molecule (HM), combining a triazene and a ʟ-tyrosine analogue, was synthesized. HM was designed to specifically be activated by tyrosinase, the enzyme involved in melanin biosynthesis and overexpressed in melanoma. HM displayed remarkable superior antiproliferative activity towards various cancer cell lines compared with temozolomide (TMZ), a triazene drug in clinical use, that acts through DNA alkylation. In B16-F10 cells, HM induced a cell cycle arrest at phase G0/G1 with a 2.8-fold decrease in cell proliferation index. Also, compared to control cells, HM led to a concentration-dependent reduction in tyrosinase activity and increase in caspase 3/7 activity. To maximize the therapeutic performance of HM in vivo, its incorporation in long blood circulating liposomes, containing poly(ethylene glycol) (PEG) at their surface, was performed for passively targeting tumour sites. HM liposomes (LIP HM) exhibited high stability in biological fluids. Preclinical studies demonstrated its safety for systemic administration and in a subcutaneous murine melanoma model, significantly reduced tumour progression. In a metastatic murine melanoma model, a superior antitumour effect was also observed for mice receiving LIP HM, with markedly reduction of lung metastases compared to positive control group (TMZ). Biodistribution studies using 111In-labelled LIP HM demonstrated its ability for passively targeting tumour sites, thus correlating with the high therapeutic effect observed in the two experimental murine melanoma models. Overall, our proposed nanotherapeutic strategy was validated as an effective and safe alternative against melanoma.</p

Application of PEG400 in the one-pot synthesis of 7-[4-alkyl- or (hetero) aryl-1H-1,2,3-triazol-1-yl]thieno[3,2-b]pyridines via SNAr and Cu(I)- Catalyzed Azide-Alkyne Cycloaddition and preliminary evaluation of their anti-tumour activity

Several novel 7-[4-alkyl- or (hetero)aryl-1H-1,2,3-triazol-1-yl]thieno[3,2-b]pyridines were prepared in good to high yields, using the environmentally friendly solvent PEG400 in a one-pot procedure from 7- chlorothieno[3,2-b]pyridine to form the corresponding azide via SNAr with NaN3, followed by Cu(I)-catalyzed Azide-Alkyne Cycloaddition (CuAAC) using different types of alkynes. This one-pot reaction in PEG400 starting from a halogenated heteroaromatic system is reported for the first time and demonstrated a wide scope of application for alkynes. Preliminary anti-tumour activity on human tumour cell lines using the prepared 1,4-di(hetero)aryl-1,2,3-triazoles was evaluated, together with their toxicity in non-tumour cells. Among the tested compounds the most promising one was a 2-ethynylpyridine derivative.Fundação para a Ciência e Tecnologia (FCT)–Portugal financially supports CQUM (UID/QUI/686/2019), CIMO-IPBragança (UID/ AGR/690/2019), the research project PTDC/QUI-QFI/28020/2017 (POCI-01-0145-FEDER-028020) also financed by European Regional Development Fund (ERDF), COMPETE2020 and Portugal2020, the PTNMR network also supported by Portugal2020 and the PhD grant of J.M.R. (SFRH/BD/115844/2016) also financed by ESF (European Social Fund) and HCOP (Human Capital Operational Programme).info:eu-repo/semantics/publishedVersio

Global Women’s Breakfast (GWB): #UnidaspelaQuímica

Global Women’s Breakfast (GWB): #BoundbyChemistry. Global Women’s Breakfast is an initiative of the International Union of Pure and Applied Chemistry, aiming to give women scientists, from all over the world, the opportunity to know each other, communicating virtually and sharing their experiences. Many countries joined this initiative and Portugal was not an exception, with its participation already at the first Networking Breakfast in 2011, celebrating the year of the centenaries of Marie Curie Nobel Prize in Chemistry, the Portuguese Chemical Society and the Faculdade de Ciências da Universidade de Lisboa as well. The success of these networking breakfasts, involving students, young researchers, and scientists, encouraged its further organization in Portugal, annually since 2019. This article describes the interventions of Portuguese women scientists, coming from Institutions throughout Portugal, in the Global Women’s Breakfast as partners in their mission as scientists, creative and open to international collaborations. Global Women's Breakfast é uma iniciativa criada pela International Union of Pure and Applied Chemistry para dar oportunidade às mulheres cientistas de todo o mundo de se conhecerem, comunicando virtualmente e compartilhando as suas experiências. A adesão dos países foi muito elevada e Portugal não foi exceção, participando já no primeiro Networking Breakfast em 2011, Ano Internacional da Química, no qual se celebraram os centenários do Prémio Nobel da Química a Marie Curie, da Sociedade Portuguesa de Química e da Faculdade de Ciências da Universidade de Lisboa. O sucesso destes pequenos-almoços em rede, que envolvem estudantes, jovens investigadoras e cientistas, encorajou a continuação da participação de Portugal anualmente, desde 2019. Este artigo descreve a intervenção de mulheres cientistas portuguesas, pertencentes a instituições de Norte a Sul do país, no Global Women’s Breakfast, cúmplices na sua missão de cientistas, criativas e abertas à colaboração internacional