Subcellular localization and therapeutic efficacy of polymeric micellar nanoparticles encapsulating bedaquiline for tuberculosis treatment in zebrafish

The combination drug regimens that have long been used to treat tuberculosis (TB), caused by Mycobacterium tuberculosis, are fraught with problems such as frequent administration, long duration of treatment, and harsh adverse effects, leading to the emergence of multidrug resistance. Moreover, there is no effective preventive vaccine against TB infection. In this context, nanoparticles (NPs) have emerged as a potential alternative method for drug delivery. Encapsulating antibiotics in biodegradable NPs has been shown to provide effective therapy and reduced toxicity against M. tuberculosis in different mammalian models, when compared to conventional free drug administration. Here, we evaluate the localization, therapeutic efficacy and toxic effects of polymeric micellar NPs encapsulating a promising but highly hydrophobic and toxic antitubercular drug bedaquiline (BQ) in zebrafish embryos infected with Mycobacterium marinum. Our study shows that the NP formulation of BQ improves survival and reduces bacterial burden in the infected embryos after treatment when compared to its free form. The intravenously injected BQ NPs have short circulation times due to their rapid and efficient uptake into the endothelial cells, as observed by correlative light and electron microscopy (CLEM)

Bedaquiline nanoparticle-mediated drug therapy against tuberculosis in the zebrafish embryo model

Tuberculosis (TB), one of the oldest recorded diseases of mankind, remains a major health threat to the global population to date. Its causative agent, Mycobacterium tuberculosis (M.tb), has survived numerous public health strategies and eradication interventions as one of the most pernicious and enduring human pathogens of all time. Even today, TB is responsible for the largest mortality due to a single infectious agent. About one-fourth of the human population harbors the latent bacteria, and its eradication from the countries where it is truly endemic remains a hard-to-reach goal. There is no effective vaccine against TB infection and the current drug regimens are fraught with problems such as lengthy and difficult treatment, inappropriate dosing or administration of drugs, and harsh adverse effects. As a consequence, non-compliance of patients to the treatment have led to the emergence of drug resistant TB. Since these highly resistant strains of M.tb continue to evolve, their further expansion would put at risk the effectiveness of our current antibiotics, therefore, we are in dire need of new regimens. It took over forty years for new drugs to enter the market since the last effective drug against TB was developed. A silver lining, in this otherwise regressive development is that more attention has been drawn to the field, leading to increased funding and research of potential drug candidates and alternative methods of drug delivery against TB. One of the new drugs, bedaquiline is currently in phase III clinical trials and has been approved for use in adult pulmonary multi-drug resistant tuberculosis (MDR-TB), in combination with other standard anti-TB drugs. Bedaquiline (BQ) has the capacity to kill both actively growing and dormant or persistent forms of M.tb. The latter is responsible for latent infection during which there is no apparent clinical manifestations of TB and can last for decades making it difficult to eradicate the disease. The thesis investigates therapeutic effects of BQ, more specifically with respect to its encapsulation within nanoparticles (NP). This approach may be especially beneficial in the case of BQ, which is associated with serious dose-dependent hepatic and cardiac toxicities, and poor oral bioavailability due to its hydrophobic nature. Upon characterization of BQ NP in vivo, these were found to be short circulating, which was a consequence of rapid and efficient uptake of NP, mostly into endothelial cells. Further, we assessed therapy by monitoring survival and quantifying bacterial burden post-treatment in zebrafish embryos infected with Mycobacterium marinum. From our analyses, we found that the NP formulation of BQ improved therapy compared to its free form

Neurocognitive Mechanisms of Anti-Lingual & Accent Bias Stereotyping in Virtual Reality and the Sustainable Development of Linguistic Response

Raising awareness through Virtual Experiencing (RAVE) and a Cross-Cultural Perspective on Raising Awareness through Virtual Experiencing (C-RAVE) approaches are used in this article to promote awareness of concerns relating to linguistic stereotyping. Virtual Reality (VR) technology has completely changed several facets of modern life, including instruction, training and entertainment. We give a summary of the techniques employed to increase awareness of how stereotypes might distort our vision. The patterns of the answers provided by the participants demonstrate that the reported gender of the speaker in addition to the accent (native vs. non-native), has an impact on the respondents' assessments of performance. Additionally, we were able to show that the discussions and ideas produced by these response patterns led to a rise in self-awareness of language and stereotyping-related problems. The paper gives a general description of RAVE and examines how it may improve education, create empathy and foster good social change. Focus on a critique of our methodologies and place our work within a larger debate of strategies and efforts for how educational institutions might actively contribute to combating (language) discrimination and bias in many ways. The relevance of Raising Awareness by Virtual Reality and Cross-Cultural Raising of Awareness by Virtual Reality in fostering inclusion and understanding in a society that is becoming more sustainable globally connected is highlighted in the article’s conclusion