A number of terminal and internal alkynoic acids with different substitution patterns have been efficiently cycloisomerized to the corresponding exocyclic enol lactones in the presence of low amounts of a non-symmetric NNC palladium complex and a catalytic amount of triethylamine.

N-substituted 4-quinolones can be obtained in good yields via intramolecular amine exchage reaction from N-substituted (E)-1-(2-aminophenyl)-3-(dimethylamino)prop-2-en-1-ones or, alternatively, from (E)-1-(2-aminophenyl)-3-(dimethylamino)prop-2-en-1-one through intramolecular amine exchange/N-benzylation. Both strategies can lead to N-(2-halobenzyl)-4-quinolones, functionalized substrates which could undergo further transformations to provide interesting polyheterocycles.

The Ubiquitin Proteasome Pathway (UPP) plays a pivotal role in intracellular protein degradation and turnover in eukaryotic cells.¹ Therefore, modulation of the UPP emerged as a rational therapeutic approach in cancer, neurodegenerative diseases (Alzheimer, Parkinson), inflammatory pathologies (arthritis, psoriasis, asthma, colitis), organ transplant, infective diseases (malaria), among others.²

During the last two decades academia and pharmaceutical industry made huge efforts to develop natural and synthetic proteasome inhibitors (PI). In 2003 FDA approved the pioneering dipeptidyl boronic acid derivative PI bortezomib for the treatment of refractory multiple myeloma (MM) and subsequently frontline therapy for MM. However, despite the enormous potential of PI, their use is still limited to certain types of blood cancer and shows severe side effects, dose limiting toxicity, peripheral neuropathy, limited activity in solid tumour and innate or acquired drug resistance.³

In this work, we have used Molecular Dynamics (MD) simulations to perform the first conformational and structural characterization of the human native 20S proteasome structure⁴. We focused our analysis on the three catalytic subunits well known for their proteolytic activity (b1, b2 and b5) and we further extended our study to additional MD simulations of three different point mutations in the b5 catalytic subunit, with recognized importance in PI’s resistance: Ala49Thr, Ala50Val and Cys52Phe. Hopefully, our studies will be able to shed the light on the structural key determinants that regulate the observed PI’s resistance in the different mutations, and ultimately use the acquired knowledge in the development of new alternative and efficient proteasome inhibitors.

Acknowledgements: We thank the Fundação para a Ciência e a Tecnologia for financial support PTDC/QEQ-MED/7042/2014, UID/DTP/04138/2013 and SAICTPAC/0019/2015.

Bioinformatics allows to automatically characterize a large number of proteins from numerous different databases, thus, uncovering new possible interactions between biomolecules in a huge set of individuals in a conscious and cost-efficient way. Membrane proteins are indisputably important for the assurance of major processes in the cell, occupying approximately 25% of the whole cell genome. In this work, some of the major features displayed at Protein Data Bank (original species, chains and ligands, oligomer state, multimeric states, stoichiometry, among others) of membrane proteins listed in the Membrane Proteins with Known 3D Structure database were registered together using manual and automated methods - some of these methods include the usage of python specific tools (like Selenium and BioPython). We aimed to construct a membrane-membrane dimers database that will serve as input for data-mining algorithms to unveiling new functional and evolutionary knowledge.

Medicinal plants continue to attract increasing attention because of their potential benefits in the field of medicine and pharmacology. Recently, the study of antioxidant levels in plants has received a great deal of attention because it is widely believed that increased oxidative stress and free radical levels in the body lead to the progression of any diseases. In the present study, Schinus terebinthifolius (Brazilian Pepper Tree) extracts were evaluated for antioxidant activity using free radical scavenging activity, and ferric reducing power. The plant was collected in the organic garden at St. Thomas University and the extracts were prepared by maceration of three parts of the plants, the leaves, the berries, and the bark. The extracts were made using varying proportions of ethanol and hexane solvents. All the samples were analyzed using thin layer chromatography (TLC). Multiple extract samples were submitted to DPPH (2,2-diphenyl-1- picrylhydrazyl) assay to determine the free radical scavenging (FRS) capacity, and absorbance was read at 517 and 520 nm in a plate reader. A control sample was prepared containing the same volume of solvent and DPPH without any extract and reference ascorbic acid. Percent scavenging activity of the DPPH free radical is expressed as an ascorbic acid (AA) equivalent antioxidant capacity (mg AA/100g). A Ferric reducing anti-oxidant power assay (FRAP) was performed and absorbance was measured at 700 nm to quantify the total antioxidant activity. FRAP and DPPH assays indicated that the bark has significantly higher free radical scavenging ability than any other part of the plant. Ethanol was optimal for extracting and preserving the plant’s active compounds. Cytotoxicity assay on chemical extracts were tested on breast cancer cells, and methylthiazol tetrazolium (MTT) assays were used to quantify cytotoxicity. Preliminary data indicated the extracts were not cytotoxic at the concentrations tested.

Medicinal plants have been part of the health-care system since ancient human civilization. Traditional medicine is widely used, and plants are a large source of antioxidant compounds such as phenols, carotenoids, and flavonoids with a potent antioxidant properties that have received much attention recently. The oyster plant (Tradescantia spathacea) is a fleshy or succulent perennial garden herb ornamental plant and. medicinally, it is used for colds, sore throat, whooping cough, nasal bleeding, and also as an anti-inflammatory. The plant was collected in the organic garden at St. Thomas University and the extracts were prepared by maceration of the stems, roots, leaves, and flowers in ethanol/hexane solvent mixtures. In this study, the antioxidant activity was measured by three different assays, using the UV-Visible spectrophotometer. Ferric reducing anti-oxidant power assay (FRAC) is based on the principle of increase in the absorbance of various concentrations of the plant extracts and the formation of colored complex with the antioxidant compounds at 700 nm. DPPH Free Radical Scavenging (FRS) assay in vitro antioxidant activity was determined at 517 and 520 nm of multiples samples in a plate reader. % of scavenging activity of the DPPH free radical is expressed as ascorbic acid (AA) equivalent antioxidant capacity (mg AA/100g). The Total Phenolic Content (TPC) in extracts was determined with the Folin-Ciocalteau reagent. Gallic acid was used as a standard, and the total phenolics were expressed as mg/g gallic acid equivalents (GAE). The plant extracts were evaluated for anticancer properties to quantify cytotoxicity. Preliminary data indicated the extracts were not cytotoxic at the concentrations tested.

Vitis rotundifolia (muscadine grape) is a grapevine species found in humid subtropical climate areas such as south-central and southeastern United States. Previous researches have reported the bioactivity of the muscadine grapes and our purpose is to look for valuable compounds from plants with medicinal properties or health benefits. The plant used in this research was collected in the organic garden at St. Thomas University. Muscadine plant extracts were analyzed by TLC (Thin Layer Chromatography) using polar and non-polar solvents, and the spots were developed and visualized with Iodine and UV light. The antioxidant activity assays were performed with the extracts of oven and freeze-dried leaves, grapes, and roots. Antioxidants are compounds capable of hindering process of oxidation caused by reactive oxygen species and raiding free radicals. The free radical scavenging activity (FRS) was evaluated with the DPPH reagent, and is reported as ascorbic acid equivalent antioxidant capacity, measured spectrophotometrically at 517 and 520 nm. The estimation of the ferric reducing power (FRP) with potassium ferricyanide was obtained, and the absorbances of the colored complex in the extracts were taken at 700 nm. Total Phenolic Content (TPC) assay of the samples using Folin-Ciocalteu reagent for all parts of the plant showed up the grapes exhibiting the highest antioxidant content compare with the leaves and roots. Cytotoxicity assay on chemical extracts were tested on breast cancer cells and methylthiazol tetrazolium (MTT) assays were used to quantify cytotoxicity. Preliminary data indicated the extracts were not cytotoxic at the concentration tested.

The growing concerns about global climate changes and the need to shift to more sustainable models of urban development create technical challenges for civil engineers and architectures altogether. In this project, a model house was designed appealing to AutoCAD, and scaled version was assembled using low cost materials. The design pretends to take advantage of the cooling ability of the circulating air around it. In order to assess how the thermal load is distributed around the house, a system of three spotlights is located at different angles and configurations, such that, the motion of the sun might be approximated. A Thermal Infrared Camera (TIC) was used to map the heat distribution around the house. Simultaneously, a group of temperature probe sensors were introduced inside the house in order to obtain the approximated heat distribution. Finally, the heat equation is solved appealing to the software Mathematica and using the Method of Finite Differences. This way the irregular geometry of the house could be mapped into a mesh of points and sole the problem numerically. Based on the obtained results, some recommendations are advanced which could be of great benefit for civil engineers and architectures.

Protein degradation is a key function developed by organisms to remove damaged and abnormal proteins, preventing their accumulation, and serving at the same time to regulate cellular processes by removing enzymes and regulatory proteins that are no longer needed.¹ This regulatory process can be achieved through two independent pathways: proteolysis in lysosome, or a ubiquitin-dependent process targeting unwanted proteins to proteasome. Due to its shattering function, proteasome has constituted an important therapeutic target to the control of different diseases such as malaria, cancer, multiple sclerosis, psoriasis, among others.² Since this protein can be found both on the cell cytoplasm and nucleus, inhibitors developed to target it, must be able to cross the membrane lipidic barrier. Until now, it is unclear if transport involves simple passive diffusion or occurs via a yet unidentified transport system. In both scenarios, associations with the cell wall and the membrane are to be expected. Modeling the interaction of different inhibitors derivatives with the cell wall is not feasible because of its complicated and variable structure. However, it is possible to model and compare the interactions of different proven proteasome inhibitors with a lipid bilayer.

In this work, by using restrained (Potential of Mean Force - PMF) and unrestrained Molecular Dynamics simulations at the water/membrane interface, we have evaluated the membrane permeability rates of different proteasome inhibitors (available on the market and identified in our lab) and their configurational and positional preference in this mixed medium. Our results will allow us to compare the trafficking of the evaluated compounds through the cell membrane and to relate it with the proteasome inhibition efficiency.

Acknowledgements: We thank the Fundação para a Ciência e a Tecnologia for financial support through PTDC/QEQ-MED/7042/2014, UID/DTP/04138/2013, and SAICTPAC/0019/2015.

References:

1. Sommer, T.; Wolf, D.H.; Biochim. Biophys. Acta – Mol. Cell Res., 2014, f843 (1), 1.
2. Napela, G.; Rolfe, M.; Harper, J. W.; Nat. Rev. Drug Discov., 2006, 5 (7), 596-613

Due to commercial globalization, the market goes through constant changes, which increasingly demands that company servers keep up with these changes, along with organizations. The leadership of a business team is of paramount importance for the progress of a team of employees and, because it is not an easy task, it must be performed by suitably competent professionals. Based on this context, this study proposed to approach the theoretical aspects, through a bibliographical review, of the coaching and mentoring tools, which are extremely relevant for the formation of new leaders and for the management of teams within companies.