Renin inhibitors for the treatment of hypertension: design and optimization of a novel series of tertiary alcohol-bearing piperidines

The design and optimization of a novel series of renin inhibitor is described herein. Strategically, by committing the necessary resources to the development of synthetic sequences and scaffolds that were most amenable for late stage structural diversification, even as the focus of the SAR campaign moved from one end of the molecule to another, highly potent renin inhibitors could be rapidly identified and profiled.     

Peripartum cardiomyopathy: a global effort to find the cause and cure for the rare and little understood disease

In this review, we present our current understanding of peripartum cardiomyopathy (PPCM) based on reports of the incidence, diagnosis and current treatment options. We summarise opinions on whether PPCM is triggered by vascular and/or hormonal causes and examine the influence of comorbidities such as preeclampsia. Two articles published in 2021 strongly support the hypothesis that PPCM may be a familial disease. Using large cohorts of PPCM patients, they summarised the available genomic DNA sequence data that are expressed in human cardiomyocytes. While PPCM is considered a disease predominately affecting the left ventricle, there are data to suggest that some cases also involve right ventricular failure. Finally, we conclude that there is sufficient evidence to warrant an RNAseq investigation and that this would be most informative if performed at the cardiomyocytes level rather than analysing genomic DNA from the peripheral circulation. Given the rarity of PPCM, the combined resources of international human heart tissue biobanks have assembled 30 ventricular tissue samples from PPCM patients, and we are actively seeking to enlarge this patient base by collaborating with human heart tissue banks and research laboratories who would like to join this endeavour.     

Individual differences in den maintenance effort in a communally dwelling mammal: the Eurasian badger

Group living has potential costs in terms of relative fitness for individuals that invest effort in activities providing general benefit, if other competing individuals exploit those activities and accrue similar benefits at no cost. We examined the roles of individual badgers, Meles meles, in the den maintenance activities of digging and bedding collection at their communal setts. Twenty per cent of adults and yearlings were responsible for 60-90% of the observed digging and bedding collection effort. Overall males tended to dig more than females, while durations of bedding collection were similar. Among adult and yearling males and females, individuals with a high percentage of days observed at the sett (high site fidelity) performed more digging and collected more bedding than transients and badgers of low site fidelity. Males of high status (large, mature, frequently copulating individuals) were more likely to dig than males of low status. Principal component analysis indicated negligibly low correlation between status and site fidelity for males. We hypothesize that while highly resident adult females benefit from extending the sett to avoid direct reproductive competition, males of high status and site fidelity might extend the sett to encourage receptive breeding females in their home group to stay and/or to improve survivorship of sired litters. Other categories of individual depend on the sett for shelter but, perhaps having less to gain from extending it, adopt a less active role in sett maintenance. Copyright 1999 The Association for the Study of Animal Behaviour.     

A difference in optomotor behaviour of two Antarctic nototheniid fishes is correlated with the presence of a choroid<Emphasis Type="Italic"> rete mirabile</Emphasis> and Root effect

The hypothesis that fish vision is influenced by the presence of a choroid rete mirabile (an oxygen-concentrating apparatus in the eye) and the Root effect was tested using the optomotor response in two nototheniid species from Antarctica. Pagothenia borchgrevinki, an active cryopelagic zooplanktivore, does not exhibit a major Root effect and the rete is absent. In contrast, the sluggish, benthic nototheniid, Trematomus bernacchii, possesses both a rete and a significant Root effect. Whole-eye ocular PO2 was higher in T. bernacchii (18.6 kPa) than in P. borchgrevinki (18.1 kPa) and the optomotor response of T. bernacchii was positively influenced by subtended angle on a moving background whereas P. borchgrevinki did not respond to any subtended angle (0–600 min of arc). The optomotor response of T. bernacchii may therefore have been facilitated by elevated ocular PO2 due to the presence of the choroid rete and the Root effect.     

Patch-clamp experiments with porins extracted from a marine bacterium (Photobacterium profundum strain SS9) and reconstituted in liposomes

The reconstitution of bacterial porins in liposome bilayers for patch-clamp recording is well established. However, the solutions used in the dehydration, rehydration, and osmotic swelling of the liposomes have been developed for porins from enteric bacteria. Porins from marine bacteria normally function in contact with seawater whose ionic composition and osmotic pressure would appear to be incompatible with the established methods. Here, we show that, contrary to expectation, an established reconstitution and patch-clamp method works well with porins, mainly OmpH and OmpL, extracted from the deep-sea marine bacterium Photobacterium profundum strain SS9 and that seawater can be introduced at a supplementary stage.     

Rabies in Zimbabwe: reservoir dogs and the implications for disease control.

Using detailed field study observations of the side-striped jackal (Canis adustus) and a simple stochastic model of the transmission dynamics of the virus and host demography, we discuss the epidemiology of rabies virus infection in the jackal population of Zimbabwe. Of the two jackal species in Zimbabwe, the other being the black-backed jackal (Canis mesomelas), the bulk of notified rabies cases are in side-striped jackals. Specifically, we show that the side-striped jackal population itself does not seem able to support rabies infection endemically, i.e. without frequent reintroduction from outside sources of infection. We argue that this is probably because the overall average jackal population density is too low to maintain the chain of infection. This study suggests that the disease is regularly introduced to jackals by rabid dogs from populations associated with human settlements. Given the rapidly rising dog population in Zimbabwe, estimates are derived of the future incidence of jackal rabies based on different dog-vaccination scenarios.