Spectroscopic and Computational Study of the Protonation Equilibria of Amino-Substituted benzo[b]thieno[2,3-b]pyrido[1,2-a]benzimidazoles as Novel pH-Sensing Materials

We present the synthesis and analytical, spectroscopic and computational characterization of three amino-substituted benzo[b]thieno[2,3-b]pyrido[1,2-a]benzimidazoles as novel pH probes with a potential application in pH-sensing materials. The designed systems differ in the number and position of the introduced isobutylamine groups on the pentacyclic aromatic core, which affects their photophysical and acid-base properties. The latter were investigated by UV-Vis absorption and fluorescence spectroscopies and interpreted by DFT calculations. An excellent agreement in experimentally measured and computationally determined pKa values and electronic excitations suggests that all systems are unionized at neutral pH, while their transition to monocationic forms occurs at pH values between 3 and 5, accompanied by substantial changes in spectroscopic responses that make them suitable for detecting acidic conditions in solutions. Computations identified imidazole imino nitrogen as the most favorable protonation site, further confirmed by analysis of perturbations in the chemical shifts of 1H and 13C NMR, and showed that the resulting basicity emerges as a compromise between the basicity-reducing effect of a nearby nitrile and a favorable contribution from the attached secondary amines. With this in mind, we designed a system with three amino substituents for which calculations predict pKa = 7.0 that we suggest as an excellent starting point for a potential pH sensor able to capture solution changes during the transition from neutral towards acidic media.

The Role of Transmission Electron Microscopy in the Early Development of Mesoporous Materials for Tissue Regeneration and Drug Delivery Applications

For the last 20 years, silica-based mesoporous materials have provided a sound platform for the development of biomedical technology applied to tissue engineering and drug delivery. Their unique structural and textural characteristics, chiefly, the ordered distribution of homogeneous and tunable pores with high surface areas and large pore volume, and their excellent biocompatibility provide an excellent starting point for bone tissue regeneration on the mesoporous surface, and also to load species of interest inside the pores. Adequate control of the synthesis conditions and functionalization of the mesoporous surface are critical factors in the design of new systems that are suitable for use in specific medical applications. Simultaneously, the use of appropriate characterization techniques in the several stages of design and manufacture of mesoporous particles allows us to ascertain the textural, structural and compositional modifications induced during the synthesis, functionalization and post-in vitro assays processes. In this scenario, the present paper shows, through several examples, the role of transmission electron microscopy and associated spectroscopic techniques in the search for useful information in the early design stages of mesoporous systems, with application in the fields of tissue regeneration and drug delivery systems.

Benzimidazole Derivatives as New and Selective Inhibitors of Arginase from Leishmania mexicana with Biological Activity against Promastigotes and Amastigotes

Leishmaniasis is a disease caused by parasites of the Leishmania genus that affects 98 countries worldwide, 2 million of new cases occur each year and more than 350 million people are at risk. The use of the actual treatments is limited due to toxicity concerns and the apparition of resistance strains. Therefore, there is an urgent necessity to find new drugs for the treatment of this disease. In this context, enzymes from the polyamine biosynthesis pathway, such as arginase, have been considered a good target. In the present work, a chemical library of benzimidazole derivatives was studied performing computational, enzyme kinetics, biological activity, and cytotoxic effect characterization, as well as in silico ADME-Tox predictions, to find new inhibitors for arginase from Leishmania mexicana (LmARG). The results show that the two most potent inhibitors (compounds 1 and 2) have an I50 values of 52 μM and 82 μM, respectively. Moreover, assays with human arginase 1 (HsARG) show that both compounds are selective for LmARG. According to molecular dynamics simulation studies these inhibitors interact with important residues for enzyme catalysis. Biological activity assays demonstrate that both compounds have activity against promastigote and amastigote, and low cytotoxic effect in murine macrophages. Finally, in silico prediction of their ADME-Tox properties suggest that these inhibitors support the characteristics to be considered drug candidates. Altogether, the results reported in our study suggest that the benzimidazole derivatives are an excellent starting point for design new drugs against leishmanisis.

Animal Farm as a Heuristic Tool for Classroom Teaching of Social Movements

Social movements are a part of the curriculum of Anthropology and Sociology in higher education institutions in India. Traditionally, these courses are taught via snippets of social movements accompanied by theoretical texts and there is little scope for individual teachers to change course content. While these texts are valuable, I found students struggled to make initial engagement with many of the prescribed texts and often became tense or anxious about the material. Students viewed social movements with antipathy and as a hindrance to stability, influenced by the political narratives and media representation of social movements as a disruption to solidarity. They often struggled to connect to the themes and issues of the Social Movement course, positioned within their own prisms of religion, caste, class, gender, and political sympathies. In this article, I vindicate the use of Animal Farm by George Orwell as a heuristic tool, taught alongside standard texts, to help students grasp the nature of social movements in theory and praxis. Teaching and learning social movements require a certain amount of empathy and openness to untangle students from their own biases. Turning to fiction can help because students can connect and become invested in the story, after which point parallels to the academic texts or real-life social movements can be drawn. Set in the animal world, Animal Farm is a parable that is equidistant to human orientations and consequently makes an excellent starting point to distance students from their preconceived ideas. This in turn helps students develop a reflexive understanding from which to engage with the core texts.

First description of migratory behavior of humpback whales from an Antarctic feeding ground to a tropical calving ground

Background Despite exhibiting one of the longest migrations in the world, half of the humpback whale migratory cycle has remained unexamined. Until now, no study has provided a continuous description of humpback whale migratory behavior from a feeding ground to a calving ground. We present new information on satellite-derived offshore migratory movements of 16 Breeding Stock G humpback whales from Antarctic feeding grounds to South American calving grounds. Satellite locations were used to demonstrate migratory corridors, while the impact of departure date on migration speed was assessed using a linear regression. A Bayesian hierarchical state–space animal movement model (HSSM) was utilized to investigate the presence of Area Restricted Search (ARS) en route. Results 35,642 Argos locations from 16 tagged whales from 2012 to 2017 were collected. The 16 whales were tracked for a mean of 38.5 days of migration (range 10–151 days). The length of individually derived tracks ranged from 645 to 6381 km. Humpbacks were widely dispersed geographically during the initial and middle stages of their migration, but convened in two convergence regions near the southernmost point of Chile as well as Peru’s Illescas Peninsula. The state–space model showed almost no instances of ARS along the migratory route. The linear regression assessing whether departure date affected migration speed showed suggestive but inconclusive support for a positive trend between the two variables. Results suggestive of stratification by sex and reproductive status were found for departure date and route choice. Conclusions This multi-year study sets a baseline against which the effects of climate change on humpback whales can be studied across years and conditions and provides an excellent starting point for the investigation into humpback whale migration.

FluCell-SELEX Aptamers as Specific Binding Molecules for Diagnostics of the Health Relevant Gut Bacterium Akkermansia muciniphila

Based on their unique properties, oligonucleotide aptamers have been named a gift of biological chemistry to life science. We report the development of DNA aptamers as the first high-affinity binding molecules available for fast and rapid labeling of the human gut bacterium Akkermansia muciniphila with a certain impact on Alzheimer´s disease. Fast and reliable analyses of the composition of microbiomes is an emerging field in microbiology. We describe the molecular evolution and biochemical characterization of a specific aptamer library by a FluCell-SELEX and the characterization of specific molecules from the library by bioinformatics. The aptamer AKK13.1 exerted universal applicability in different analysis techniques in modern microbiology, including fluorimetry, confocal laser scanning microscopy and flow cytometry. It was also functional as a specific binding entity hybridized to anchor primers chemically coupled via acrydite-modification to the surface of a polyacrylamide-hydrogel, which can be prototypically used for the construction of affinity surfaces in sensor chips. Together, the performance and methodological flexibility of the aptamers presented here may open new routes not only to develop novel Akkermansia-specific assays for clinical microbiology and the analyses of human stool samples but may also be an excellent starting point for the construction of novel electronic biosensors.

Analysis of saponins detoxification genes in Ilyonectria mors-panacis G3B inducing root rot of Panax notoginseng by RNA-Seq

Saponins are kinds of antifungal compounds produced by Panax notoginseng to resist invasion by pathogens. Ilyonectria mors-panacis G3B was the dominant pathogen inducing root rot of P. notoginseng, and the abilities to detoxify saponins were the key to infect P. notoginseng successfully. To research the molecular mechanisms of detoxifying saponins in I. mors-panacis G3B, we used high-throughput RNA-Seq to identify 557 and 1519 differential expression genes (DEGs) in I. mors-panacis G3B with saponins treatments for 4H (Hours) and 12H (Hours) compared with no saponins treatments, respectively. Among these DEGs, we found 93 genes which were simultaneously highly expressed in I. mors-panacis G3B with saponins treatments for 4H and 12H, they mainly belong to genes encoding transporters, glycoside hydrolases, oxidation–reduction enzymes, transcription factors and so on. In addition, there were 21 putative PHI (Pathogen–Host Interaction) genes out of those 93 up-regulated genes. In this report, we analyzed virulence-associated genes in I. mors-panacis G3B which may be related to detoxifying saponins to infect P. notoginseng successfully. They provided an excellent starting point for in-depth study on pathogenicity of I. mors-panacis G3B and developed appropriate root rot disease management strategies in the future.

Bioprospecting Antiproliferative Marine Microbiota From Submarine Volcano Tagoro

Marine ecosystems are unique and rich reservoirs of biodiversity with high potential toward improving the quality of human life. The extreme physical–chemical conditions of the oceans have favored marine organisms to produce a great variety of new molecules as a mechanism to ensure their survival, and such compounds possess great biopharmaceutical interest. In particular, marine microbiota represent a promising and inexhaustible source for the development of new drugs. This work presents the taxonomic study of the samples obtained from the underwater volcano Tagoro, which has allowed us to develop a collection of 182 marine bacterial strains. On October 10th, 2011, at La Restinga–El Mar de Las Calmas Marine Reserve, an underwater eruption gave rise to a novel shallow submarine volcano at 1.8 km south of the island of El Hierro, Canary Islands, Spain. During the first 6 months, extreme physical–chemical perturbations, comprising thermal changes, water acidification, deoxygenation, and metal enrichment, resulted in significant alterations of the marine ecosystem. After March 2012, the submarine volcano Tagoro entered an active hydrothermal phase that involved a release of heat, gases, metals, and micronutrients that continues till our present. During 2016, our research team had the opportunity to participate in one of the monitoring oceanographic cruises carried out in the area in order to isolate microorganisms associated with both rock samples and deep-sea invertebrates over Tagoro submarine volcano. In this study, Proteobacteria revealed as the most abundant Phylum with 70.2% among all isolated strains, followed by Firmicutes 19%, Actinobacteria 9.5%, and Bacteroidetes 1.2%. Furthermore, we present the results of the antiproliferative assays of the extracts obtained from small-scale cultures of selected bacterial strains. An analysis of the effects of culture conditions in the antiproliferative activity showed that strains grown in Marine Broth (MB) presented lower GI50 values than those cultured in a modified medium (MM1). This effect is improved when the strains are incubated under agitation conditions. The antiproliferative potential of genera such as Halobacillus, Kangiella, Photobacterium, and Halomonas is revealed. Their biotechnological development provides an excellent starting point to access novel secondary metabolites and enzymes with potential for pharmaceutical and industrial applications.

4-Phenethyl-1-Propargylpiperidine-Derived Dual Inhibitors of Butyrylcholinesterase and Monoamine Oxidase B

The multi-target-directed ligands (MTDLs) strategy is encouraged for the development of novel modulators targeting multiple pathways in the neurodegenerative cascade typical for Alzheimer’s disease (AD). Based on the structure of an in-house irreversible monoamine oxidase B (MAO-B) inhibitor, we aimed to introduce a carbamate moiety on the aromatic ring to impart cholinesterase (ChE) inhibition, and to furnish multifunctional ligands targeting two enzymes that are intricately involved in AD pathobiology. In this study, we synthesized three dual hMAO-B/hBChE inhibitors 13–15, with compound 15 exhibiting balanced, low micromolar inhibition of hMAO-B (IC50 of 4.3 µM) and hBChE (IC50 of 8.5 µM). The docking studies and time-dependent inhibition of hBChE confirmed the initial expectation that the introduced carbamate moiety is responsible for covalent inhibition. Therefore, dual-acting compound 15 represents an excellent starting point for further optimization of balanced MTDLs.

RANDOM REWARD MECHANISM IN VIDEO GAMES, IN THE SCOPE OF EUROPEAN GAMBLING REGULATIONS AND CONSUMER PROTECTION LAW, WITH PARTICULAR EMPHASIS ON LOOT BOX MECHANISM

This article focuses on the issue of Random Rewards Mechanisms, in particular loot box mechanism, being implemented in modern video games. Nowadays, in the era of progressive technological progress, the borders between gambling and gaming have blurred as never before. More and more countries came to the conclusion, that different features of video games are problematically similar to classically-understood gambling. The report titled „Loot boxes in online games and their effect on consumers, in particular young consumers” provided by the Policy Department for Economic, Scientific and Quality of Life Policies at the request of the committee on Internal Market and Consumer Protection has accurately defined the problem, as simultaneously concerning both gambling regulations, as well as consumer protection laws. The report constitutes excellent starting point for a further discussion about loot boxes in UE and in Poland. The article provides detailed analysis of the issue, beginning with defining the term “loot box”, followed by scrutiny of both domestic and Union regulations. Relying on the distinction of loot-boxes provided by R. K. L. Nielsen and P. Grabarczyk author have analysed the regulations in order to present different approaches to the issue and their consequences. In the final part of the article author comments on Polish regulations and triers to predict the future development of law concerning loot boxes. The paper refers to multiple reports, laws and rulings regarding discussed matter.