DNA quadruplex folding formalism--a tutorial on quadruplex topologies.

Quadruplexes of DNA adopt a large variety of topologies that are dependent on their environment. We have been developing a formalism for quadruplex folding based on the relationship between base and its sugar--as defined by the glycosidic bond angle. By reducing the quadruplex stem to a description based on two finite states of the range of angles the glycosidic bond angle may adopt, the description of the relationships of type of loop and groove widths of a quadruplex stem are possible. In its current form this formalism has allowed for the prediction of some unimolecular quadruplex topologies. Its rules, whilst developed for unimolecular quadruplexes of three loops, are of general utility in understanding the interdependency of structural characteristics of multimolecular folds, as well as unimolecular quadruplexes of more than three loops. Here we describe current understanding of the interdependent structural features that define the quadruplex fold, and provide a tutorial for the use and application of this formalism.

Prevalence of multidrug resistance in Pseudomonas spp. isolated from wild bird feces in an urban aquatic environment.

Antimicrobial resistance (AMR) has been detected in the microbiota of wildlife, yet little is known about the origin and impact within the ecosystem. Due to the shortage of nonepizootic surveillance, there is limited understanding of the natural prevalence and circulation of AMR bacteria in the wild animal population, including avian species. In this surveillance study, feces from wild birds in proximity to the River Cam, Cambridge, England, were collected and Pseudomonas spp. were isolated. Of the 115 samples collected, 24 (20.9%; 95% CI, 12.6%‒29.2%) harbored Pseudomonas spp. of which 18 (75%; 95% CI, 58%‒92%) had a multiple antibiotic resistance (MAR) index greater than 0.2. No Pseudomonas spp. isolate in this study was pansusceptible. Resistance was found among the 24 isolates against ciprofloxacin (87.5%; 95% CI, 74.3%‒100%) and cefepime (83.3%; 95% CI, 68.4%‒98.2%), both of which are extensively used to treat opportunistic Pseudomonas spp. infections. The prevalence of Pseudomonas spp. in the wild bird feces sampled during this study is greater than previous, similar studies. Additionally, their multidrug resistance profile provides insight into the potential risk for ecosystem contamination. It further highlights the importance of a One Health approach, including ongoing surveillance efforts that help to develop the understanding of how wildlife, including avifauna, may contribute and disperse AMR across the ecosystem.

Consequences Matter: Compassion in Conservation Means Caring for Individuals, Populations and Species.

Human activity affecting the welfare of wild vertebrates, widely accepted to be sentient, and therefore deserving of moral concern, is widespread. A variety of motives lead to the killing of individual wild animals. These include to provide food, to protect stock and other human interests, and also for sport. The acceptability of such killing is widely believed to vary with the motive and method. Individual vertebrates are also killed by conservationists. Whether securing conservation goals is an adequate reason for such killing has recently been challenged. Conventional conservation practice has tended to prioritise ecological collectives, such as populations and species, when their interests conflict with those of individuals. Supporters of the 'Compassionate Conservation' movement argue both that conservationists have neglected animal welfare when such conflicts arise and that no killing for conservation is justified. We counter that conservationists increasingly seek to adhere to high standards of welfare, and that the extreme position advocated by some supporters of 'Compassionate Conservation', rooted in virtue ethics, would, if widely accepted, lead to considerable negative effects for conservation. Conservation practice cannot afford to neglect consequences. Moreover, the do-no-harm maxim does not always lead to better outcomes for animal welfare.

Magnetically responsive microbubbles as delivery vehicles for targeted sonodynamic and antimetabolite therapy of pancreatic cancer.

Magnetically responsive microbubbles (MagMBs), consisting of an oxygen gas core and a phospholipid coating functionalised with Rose Bengal (RB) and/or 5-fluorouracil (5-FU), were assessed as a delivery vehicle for the targeted treatment of pancreatic cancer using combined antimetabolite and sonodynamic therapy (SDT). MagMBs delivering the combined 5-FU/SDT treatment produced a reduction in cell viability of over 50% when tested against a panel of four pancreatic cancer cell lines in vitro. Intravenous administration of the MagMBs to mice bearing orthotopic human xenograft BxPC-3 tumours yielded a 48.3% reduction in tumour volume relative to an untreated control group (p<0.05) when the tumour was exposed to both external magnetic and ultrasound fields during administration of the MagMBs. In contrast, application of an external ultrasound field alone resulted in a 27% reduction in tumour volume. In addition, activated caspase and BAX protein levels were both observed to be significantly elevated in tumours harvested from animals treated with the MagMBs in the presence of magnetic and ultrasonic fields when compared to expression of those proteins in tumours from either the control or ultrasound field only groups (p<0.05). These results suggest MagMBs have considerable potential as a platform to enable the targeted delivery of combined sonodynamic/antimetabolite therapy in pancreatic cancer.