Daring You to Ask, What If?

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Landscape attributes governing local transmission of an endemic zoonosis: rabies virus in domestic dogs

Landscape heterogeneity plays an important role in disease spread and persistence, but quantifying landscape influences and their scale dependence is challenging. Studies have focused on how environmental features or global transport networks influence pathogen invasion and spread, but their influence on local transmission dynamics that underpin the persistence of endemic diseases remains unexplored. Bayesian phylogeographic frameworks that incorporate spatial heterogeneities are promising tools for analysing linked epidemiological, environmental and genetic data. Here, we extend these methodological approaches to decipher the relative contribu- tion and scale-dependent effects of landscape influences on the transmission of endemic rabies virus in Serengeti district, Tanzania (area ~4,900 km2). Utilizing detailed epidemiological data and 152 complete viral genomes collected between 2004 and 2013, we show that the localized presence of dogs but not their density is the most important determinant of diffusion, implying that culling will be ineffec- tive for rabies control. Rivers and roads acted as barriers and facilitators to viral spread, respectively, and vaccination impeded diffusion despite variable annual cov- erage. Notably, we found that landscape effects were scale-dependent: rivers were barriers and roads facilitators on larger scales, whereas the distribution of dogs was important for rabies dispersal across multiple scales. This nuanced understanding of the spatial processes that underpin rabies transmission can be exploited for targeted control at the scale where it will have the greatest impact. Moreover, this research demonstrates how current phylogeographic frameworks can be adapted to improve our understanding of endemic disease dynamics at different spatial scales

Cytotoxic effects of curcumin on osteosarcoma cell lines

Summary: Curcumin (diferuloylmethane), one of the main components of the Indian spice turmeric, is known to possess potent anti-inflammatory and anti-oxidant properties. In addition, curcumin has also been shown to have in vitro and in vivo efficacy against a variety of malignancies. In the current study we examined the cytotoxic effect of curcumin on seven osteosarcoma (OS) cell lines with varying degrees of in vivo metastatic potential. Curcumin inhibited the growth of all OS cell lines tested with half-maximal inhibitory concentration values ranging from 14.4 to 24.6μM. Growth inhibition was associated with a dose dependent increase in the number of apoptotic cells and accumulation of cells in the G2/M phase of the cell cycle. Curcumin treatment also resulted in cleavage of caspase-3 and poly adenosine diphosphate-ribose polymerase. Moreover, curcumin treatment was associated with an increase in cellular levels of the apoptotic B-cell leukemia/lymphoma 2 (Bcl-2)-associated X protein and a decrease in cellular content of the anti-apoptotic protein Bcl-2. In addition, curcumin treatment also inhibited the migration of OS cell lines. These data indicate that the potent cytotoxic activity of curcumin on OS cell lines is mediated by induction of apoptotic processes. Thus, curcumin has potential to be a novel OS chemotherapeutic agen

Cytotoxic effects of curcumin on osteosarcoma cell lines

Summary: Curcumin (diferuloylmethane), one of the main components of the Indian spice turmeric, is known to possess potent anti-inflammatory and anti-oxidant properties. In addition, curcumin has also been shown to have in vitro and in vivo efficacy against a variety of malignancies. In the current study we examined the cytotoxic effect of curcumin on seven osteosarcoma (OS) cell lines with varying degrees of in vivo metastatic potential. Curcumin inhibited the growth of all OS cell lines tested with half-maximal inhibitory concentration values ranging from 14.4 to 24.6μM. Growth inhibition was associated with a dose dependent increase in the number of apoptotic cells and accumulation of cells in the G2/M phase of the cell cycle. Curcumin treatment also resulted in cleavage of caspase-3 and poly adenosine diphosphate-ribose polymerase. Moreover, curcumin treatment was associated with an increase in cellular levels of the apoptotic B-cell leukemia/lymphoma 2 (Bcl-2)-associated X protein and a decrease in cellular content of the anti-apoptotic protein Bcl-2. In addition, curcumin treatment also inhibited the migration of OS cell lines. These data indicate that the potent cytotoxic activity of curcumin on OS cell lines is mediated by induction of apoptotic processes. Thus, curcumin has potential to be a novel OS chemotherapeutic agen

Taurolidine: a novel anti-neoplastic agent induces apoptosis of osteosarcoma cell lines

Summary: Taurolidine, the active agent of Taurolin®, is a broad spectrum anti-biotic that has been used for over 15years for the treatment of severe surgical infections. Recently, taurolidine has been shown to possess anti-neoplastic properties in vitro and in vivo against a variety of cancers including ovarian, colon and prostate. In this study we assessed the cytotoxic activity of taurolidine against human osteosarcoma (OS) cell lines and normal human bone cells. Treatment with taurolidine inhibited the growth of all ten osteosarcoma cell lines tested and taurolidine was equally potent against cell lines with and without distinct genetic defects (i.e. p53, Rb). Moreover, taurolidine-induced growth inhibition was found to be associated with a dose dependent increase in the number of apoptotic cells and apoptosis was shown to be caspase-dependent. Taurolidine treatment was also found to inhibit adhesion of OS cell lines. Compared to OS cell lines, normal bone cells in primary culture were found to be less sensitive to the cytotoxic and anti-adhesive effects of taurolidine. These data indicate that taurolidine possesses potent anti-neoplastic activity against osteosarcoma cell lines and may have potential as a novel OS chemotherapeutic agen

Abandoned, lost and discarded fishing gear ‘ghost nets’ are increasing through time in Northern Australia

The remote Gulf of Carpentaria (GoC) represents 10% of Australia’s coastline. This large, shallow sea supports high value fishing activities and habitat for threatened species, and is a sink for abandoned, lost and discarded fishing gear (ALDFG) ‘ghost nets’, most originating from fishing activities outside of Australia’s Exclusive Economic Zone. With growing concerns about the plastic waste along the world’s coastlines, we retrospectively analyzed ghost net sighting information from four aerial surveys across 15 years, to investigate whether densities of ghost nets are changing through time or in space. We found an increase in ghost nets, despite more than a decade of illegal fishing countermeasure and clean-up efforts in the broader region. This demonstrates that the input of ALDFG into the system currently overwhelms the substantial net removal activities. We make recommendations for improving monitoring and consider the underlying drivers of nets being lost to improve ghost gear management on land and at sea

Elucidating the phylodynamics of endemic rabies virus in eastern Africa using whole-genome sequencing

Many of the pathogens perceived to pose the greatest risk to humans are viral zoonoses, responsible for a range of emerging and endemic infectious diseases. Phylogeography is a useful tool to understand the processes that give rise to spatial patterns and drive dynamics in virus populations. Increasingly, whole-genome information is being used to uncover these patterns, but the limits of phylogenetic resolution that can be achieved with this are unclear. Here, whole-genome variation was used to uncover fine-scale population structure in endemic canine rabies virus circulating in Tanzania. This is the first whole-genome population study of rabies virus and the first comprehensive phylogenetic analysis of rabies virus in East Africa, providing important insights into rabies transmission in an endemic system. In addition, sub-continental scale patterns of population structure were identified using partial gene data and used to determine population structure at larger spatial scales in Africa. While rabies virus has a defined spatial structure at large scales, increasingly frequent levels of admixture were observed at regional and local levels. Discrete phylogeographic analysis revealed long-distance dispersal within Tanzania, which could be attributed to human-mediated movement, and we found evidence of multiple persistent, co-circulating lineages at a very local scale in a single district, despite on-going mass dog vaccination campaigns. This may reflect the wider endemic circulation of these lineages over several decades alongside increased admixture due to human-mediated introductions. These data indicate that successful rabies control in Tanzania could be established at a national level, since most dispersal appears to be restricted within the confines of country borders but some coordination with neighbouring countries may be required to limit transboundary movements. Evidence of complex patterns of rabies circulation within Tanzania necessitates the use of whole-genome sequencing to delineate finer scale population structure that can that can guide interventions, such as the spatial scale and design of dog vaccination campaigns and dog movement controls to achieve and maintain freedom from disease

Experimental model of spinal cord injury in rats with a device for local therapeutic agents access

An experimental model of spinal cord injury at a precise and reproducible site is an extremely important tool for studying new therapies in spinal cord injuries. OBJECTIVES: To develop an experimental model of spinal cord injury in rats that is able to produce a complete injury (paraplegia) and placing a system enabling agents access close to injury site in order to test local therapeutic agents. METHODS: Fifteen Wistar rats were submitted to surgical transection of the spine, performed by using scissors at the level of T-13 to L-3 vertebral bodies, and, at the end of the procedure, to the insertion of a subdermal catheter intended to enable local therapeutic agents access to injury site. RESULTS: An experimental model of paraplegia was consistently developed by adding a supplementary catheter for local therapeutic agents access to injury site. CONCLUSION: An animal model of spinal cord injury and a system for local therapeutic agents access can be reproduced for the study of different modifiers of the regenerative response in a model of rats with spinal cord injury.Um modelo experimental de lesão raquimedular com localização precisa e reproduzível é uma ferramenta extremamente importante para o estudo de novas terapias em lesões raquimedulares. OBJETIVOS: Desenvolver um modelo experimental de lesão raquimedular em ratos que produza lesão completa (paraplegia) com o posicionamento de um sistema que permita o acesso de agentes próximo ao local da lesão para testar agentes terapêuticos locais. MÉTODOS: Quinze ratos Wistar foram submetidos à transecção cirúrgica da medula espinhal, realizada com o uso de tesoura ao nível dos corpos vertebrais de T-13 a L-3 e, ao final do procedimento, à implantação de um cateter subcutâneo para o acesso de agentes terapêuticos locais ao local da lesão. RESULTADOS: Um modelo experimental de paraplegia foi consistentemente desenvolvido com a adição suplementar de um cateter para o acesso de agentes terapêuticos locais ao local da lesão. CONCLUSÃO: Um modelo animal de lesão raquimedular e um sistema para o acesso de agentes terapêuticos locais pode ser reproduzido para o estudo de diferentes modificadores da resposta regenerativa em um modelo de ratos com lesão raquimedular.UNIFESPUNIFESPSciEL

A Gpr120-selective agonist improves insulin resistance and chronic inflammation in obese mice.

It is well known that the ω-3 fatty acids (ω-3-FAs; also known as n-3 fatty acids) can exert potent anti-inflammatory effects. Commonly consumed as fish products, dietary supplements and pharmaceuticals, ω-3-FAs have a number of health benefits ascribed to them, including reduced plasma triglyceride levels, amelioration of atherosclerosis and increased insulin sensitivity. We reported that Gpr120 is the functional receptor for these fatty acids and that ω-3-FAs produce robust anti-inflammatory, insulin-sensitizing effects, both in vivo and in vitro, in a Gpr120-dependent manner. Indeed, genetic variants that predispose to obesity and diabetes have been described in the gene encoding GPR120 in humans (FFAR4). However, the amount of fish oils that would have to be consumed to sustain chronic agonism of Gpr120 is too high to be practical, and, thus, a high-affinity small-molecule Gpr120 agonist would be of potential clinical benefit. Accordingly, Gpr120 is a widely studied drug discovery target within the pharmaceutical industry. Gpr40 is another lipid-sensing G protein-coupled receptor, and it has been difficult to identify compounds with a high degree of selectivity for Gpr120 over Gpr40 (ref. 11). Here we report that a selective high-affinity, orally available, small-molecule Gpr120 agonist (cpdA) exerts potent anti-inflammatory effects on macrophages in vitro and in obese mice in vivo. Gpr120 agonist treatment of high-fat diet-fed obese mice causes improved glucose tolerance, decreased hyperinsulinemia, increased insulin sensitivity and decreased hepatic steatosis. This suggests that Gpr120 agonists could become new insulin-sensitizing drugs for the treatment of type 2 diabetes and other human insulin-resistant states in the future