Discovery of thiazolo [5,4-c] isoquinoline based compounds as acetylcholinesterase inhibitors through computational target prediction, molecular docking and bioassay

We thank Nathalie Reichmann and Leendert Hamoen (University of Amsterdam) for critical reading of the manuscript, Ana Velic (Proteome Center Tübingen) for help with proteome analysis and Mike VanNieuwenhze (Indiana University) for the generous gift of HADA. This study was funded by the European Research Council through grant ERC‐2017‐CoG‐771709 (to MGP), by national funds through FCT– Fundação para a Ciência e a Tecnologia, PTDC/BIA‐MIC/6982/2020 (to HV); PTDC/BIA‐PLA/3432/2012 (to SRF); FCT through MOSTMICRO‐ITQB R&D Unit (UIDB/04612/2020, UIDP/04612/2020) and LS4FUTURE Associated Laboratory (LA/P/0087/2020) and FCT fellowship SFRH/BD/147052/2019 (to BMS); by the Swiss National National Foundation through P300P3_155346 (to AJ); by the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska‐Curie grant agreement No 839596 (to SS) and by the European Molecular Biology Organization through award ALTF 673‐2018 (to SS). Figure 6D and Appendix Fig S7 were created with Biorender.com .A computer-aided drug design (CADD) approach was developed for a focused chemical library comprising a series of sixteen thiazolo[5,4-c]isoquinoline derivatives. Little is known about this group of heteroaromatic compounds, both from the point of view of their synthesis and their biological properties. First, our CADD approach included target prediction by Mondrian conformal prediction with the ChEMBL database. The acetylcholinesterase (AChE) was identified as having a high probability of thiazolo[5,4-c]isoquinolines being active against it. Secondly, the molecular docking predictions revealed four promising thiazoloisoquinolines (2, 7, 13 and 14) according to their prominent ligand-protein energy scores and relevant binding affinities with the AChE pocket residues. The subsequent in vitro evaluation of promising hits and related ones revealed a set of novel AChE inhibitors. Therefore, the findings reported herein may provide a new strategy for discovering novel AChE inhibitors.publishersversionpublishe

Curcumin-loaded lipid and polymeric nanocapsules stabilized by nonionic surfactants: An In Vitro and In Vivo antitumor activity on B16-F10 melanoma and macrophage uptake comparative study

Curcumin is a polyphenol obtained from the plant Curcuma longa (called turmeric) that displays several pharmacological activities, including anti-inflammatory, antioxidant, antimicrobial and antitumoral activity, but clinical use has been limited by its poor solubility in water and, consequently, minimal systemic bioavailability. We have therefore formulated the drug into nanocarrier systems in an attempt to improve its therapeutic properties. This study evaluates the effect of intraperitoneally administered nanocapsules containing curcumin on subcutaneous melanoma in mice inoculated with B16-F10 cells, and on the cytotoxicity activity against B16-F10 cells in vitro. Phagocytic uptake of formulations was also evaluated upon incubation with macrophage J774 cells by fluorescence microscopy. Lipid and polymeric nanocapsules were prepared by the phase inversion and nanoprecipitation methods, respectively. The uptake of the lipid nanocapsules prepared using Solutol HS15 was significantly reduced in J774 cells. Curcumin, as free drug or as drug-loaded nanocapsules, was administrated at a dose of 6 mg/kg twice a week for 21 days. Free drug and curcuminloaded nanocapsules significantly reduced tumor volume (P < 0.05 vs. control), but no difference was found in the antitumor activity displayed by lipid and polymeric nanocapsules. This assumption was supported by the in vitro study, in which free curcumin as well as loaded into nanocapsules caused significant reduction of cell viability in a concentration- and time-dependent manner.Fil: Mazzarino, Letícia. Universidade Federal de Santa Catarina; BrasilFil: Silva, Luís F. C.. Universidade Federal de Santa Catarina; BrasilFil: Curta, Juliana C.. Universidade Federal de Santa Catarina; BrasilFil: Licínio, Marley A.. Universidade Federal de Santa Catarina; BrasilFil: Costa, Aline. Universidade Federal de Santa Catarina; BrasilFil: Pacheco, Letícia K.. Universidade Federal de Santa Catarina; BrasilFil: Siqueira, Jarbas M.. Universidade Federal de Santa Catarina; BrasilFil: Martinetti Montanari, Jorge Anibal. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Romero, Eder. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; ArgentinaFil: Assreuy, Jamil. Universidade Federal de Santa Catarina; BrasilFil: Santos Silva, Maria C.. Universidade Federal de Santa Catarina; BrasilFil: Lemos Senna, Elenara. Universidade Federal de Santa Catarina; Brasi

Effect of different cleansers on the weight and ion release of removable partial denture: an in vitro study

OBJECTIVE: Removable partial dentures (RPD) require different hygiene care, and association of brushing and chemical cleansing is the most recommended to control biofilm formation. However, the effect of cleansers has not been evaluated in RPD metallic components. The aim of this study was to evaluate in vitro the effect of different denture cleansers on the weight and ion release of RPD. MATERIAL AND METHODS: Five specimens (12x3 mm metallic disc positioned in a 38x18x4 mm mould filled with resin), 7 cleanser agents [Periogard (PE), Cepacol (CE), Corega Tabs (CT), Medical Interporous (MI), Polident (PO), 0.05% sodium hypochlorite (NaOCl), and distilled water (DW) (control)] and 2 cobalt-chromium alloys [DeguDent (DD), and VeraPDI (VPDI)] were used for each experimental situation. One hundred and eighty immersions were performed and the weight was analyzed with a high precision analytic balance. Data were recorded before and after the immersions. The ion release was analyzed using mass spectrometry with inductively coupled plasma. Data were analyzed by two-way ANOVA and Tukey HSD post hoc test at 5% significance level. RESULTS: Statistical analysis showed that CT and MI had higher values of weight loss with higher change in VPDI alloy compared to DD. The solutions that caused more ion release were NaOCl and MI. CONCLUSIONS: It may be concluded that 0.05% NaOCl and Medical Interporous tablets are not suitable as auxiliary chemical solutions for RPD care

Comprehensive molecular landscape of cetuximab resistance in head and neck cancer cell lines

Cetuximab is the sole anti-EGFR monoclonal antibody that is FDA approved to treat head and neck squamous cell carcinoma (HNSCC). However, no predictive biomarkers of cetuximab response are known for HNSCC. Herein, we address the molecular mechanisms underlying cetuximab resistance in an in vitro model. We established a cetuximab resistant model (FaDu), using increased cetuximab concentrations for more than eight months. The resistance and parental cells were evaluated for cell viability and functional assays. Protein expression was analyzed by Western blot and human cell surface panel by lyoplate. The mutational profile and copy number alterations (CNA) were analyzed using whole-exome sequencing (WES) and the NanoString platform. FaDu resistant clones exhibited at least two-fold higher IC50 compared to the parental cell line. WES showed relevant mutations in several cancer-related genes, and the comparative mRNA expression analysis showed 36 differentially expressed genes associated with EGFR tyrosine kinase inhibitors resistance, RAS, MAPK, and mTOR signaling. Importantly, we observed that overexpression of KRAS, RhoA, and CD44 was associated with cetuximab resistance. Protein analysis revealed EGFR phosphorylation inhibition and mTOR increase in resistant cells. Moreover, the resistant cell line demonstrated an aggressive phenotype with a significant increase in adhesion, the number of colonies, and migration rates. Overall, we identified several molecular alterations in the cetuximab resistant cell line that may constitute novel biomarkers of cetuximab response such as mTOR and RhoA overexpression. These findings indicate new strategies to overcome anti-EGFR resistance in HNSCC.This work was supported by Barretos Cancer Hospital and the Public Ministry of Labor Campinas (Research, Prevention, and Education of Occupational Cancer) in Campinas, Brazil, CAPESDFATD (88887.137283/2017-00). INFG is the recipient of a FAPESP Ph.D. fellowship (2017/22305-9)

Molecular systematics of the genus Artibeus (Chiroptera

a b s t r a c t A molecular phylogeny of the genus Artibeus using 19 of the 20 recognized species, many with samples from a broad geographic range, is presented. The analysis shows a clear distinction between the two subgenera (or genera), the &apos;large&apos; Artibeus and the &apos;small&apos; Dermanura, in both mitochondrial and nuclear genes. The placement and status of A. concolor remains inconclusive and is presented as the third subgenus Koopmania. The phylogenies and divergence time estimates show a marked influence of the Andes in the formation of the subgenera and the main lineages inside each subgenus. Nuclear genes showed a highly incomplete lineage sorting among species inside subgenera Artibeus and Dermanura. Indeed, shared alleles were also found between Artibeus and Koopmania, which are presumed to have split apart during the Miocene, showing that great care should be taken in using these markers. Cytochrome-b gene divergences and monophyly analyses suggest that A. lituratus and A. intermedius are indeed conspecifics. These analyses also suggested the existence of at least four &apos;new&apos; species revealing a significant cryptic diversity inside the genus

Phenology and Seasonal Ecosystem Productivity in an Amazonian Floodplain Forest

everal studies have explored the linkages between phenology and ecosystem productivity across the Amazon basin. However, few studies have focused on flooded forests, which correspond to c.a. 14% of the basin. In this study, we assessed the seasonality of ecosystem productivity (gross primary productivity, GPP) from eddy covariance measurements, environmental drivers and phenological patterns obtained from the field (leaf litter mass) and satellite measurements (enhanced vegetation index (EVI) from the Moderate Resolution Imaging Spectroradiometer/multi-angle implementation correction (MODIS/MAIAC)) in an Amazonian floodplain forest. We found that ecosystem productivity is limited by soil moisture in two different ways. During the flooded period, the excess of water limits GPP (Spearman’s correlation; rho = −0.22), while during non-flooded months, GPP is positively associated with soil moisture (rho = 0.34). However, GPP is maximized when cumulative water deficit (CWD) increases (rho = 0.81), indicating that GPP is dependent on the amount of water available. EVI was positively associated with leaf litter mass (Pearson’s correlation; r = 0.55) and with GPP (r = 0.50), suggesting a coupling between new leaf production and the phenology of photosynthetic capacity, decreasing both at the peak of the flooded period and at the end of the dry season. EVI was able to describe the inter-annual variations on forest responses to environmental drivers, which have changed during an observed El Niño-Southern Oscillation (ENSO) year (2015/2016)

A MEDIAÇÃO EM MUSEUS: desafios observados em duas modalidades de visitas ao MZFS

O Museu de Zoologia da Universidade Estadual de Feira de Santana/MZFS realiza diversas atividades públicas como visitas guiadas a exposição Linha do Tempo e o Museu Itinerante. De abril de 2018 a junho de 2019, realizamos 273 atendimentos no espaço do MZFSe em saídas extracampos

ALTERNATIVAS LÚDICAS PARA A RECEPÇÃO DO PÚBLICO INFANTIL NO MZFS

A DEADD tem como meta auxiliar no processo de alfabetização científica a partir do seu acervo didático zoológico. Tal processo é feito através das visitas guiadas à exposição Linha do Tempo

Well-being at work, productivity, and coping with stress during the COVID-19 pandemic

This study aims to analyze the mechanisms through which the coronavirus disease (COVID-19) pandemic impacts on well-being at work and on productivity. The secondary objective is to identify stress management strategies for the work environment during the pandemic. This is an integrative review. Phase 1 consisted of searches of open access electronic databases (MEDLINE, SciELO, Bireme, and LILACS) for papers published in 2020 addressing mental health, work, and pandemics. Phase 2 consisted of selecting literature recommended by specialists in occupational psychiatry and positive psychology. These materials were read and critically analyzed. Forty references were included in the literature review. The articles reviewed were classified into the following categories: articles concerning work relationships in Brazil; articles describing the impact of pandemics on mental health and work; articles focusing on the work of health professionals during pandemics; articles about well-being at work; and papers proposing strategies to improve well-being and productivity and to promote mental health. The COVID-19 pandemic can have a significant impact on workers’ mental health and productivity. Most professionals face a need to adapt to changes, which can decrease their feeling of well-being. Consequently, strategies to promote well-being and mental health in the work environment should be a priority. Work routines were modified after the COVID-19 pandemic set in and assessing these changes is essential to maintain workers’ mental health. By so doing, it is possible to promote general well-being and post-traumatic recovery and reduce stress levels