13 research outputs found
Mitigating hERG Inhibition: Design of Orally Bioavailable CCR5 Antagonists as Potent Inhibitors of R5 HIV-1 Replication
A series of CCR5 antagonists representing the thiophene-3-yl-methyl
ureas were designed that met the pharmacological criteria for HIV-1
inhibition and mitigated a human ether-a-go-go related gene (hERG)
inhibition liability. Reducing lipophilicity was the main design criteria
used to identify compounds that did not inhibit the hERG channel,
but subtle structural modifications were also important. Interestingly,
within this series, compounds with low hERG inhibition prolonged the
action potential duration (APD) in dog Purkinje fibers, suggesting
a mixed effect on cardiac ion channels
A Deterministic Model to Quantify Risk and Guide Mitigation Strategies to Reduce Bluetongue Virus Transmission in California Dairy Cattle
The global distribution of bluetongue virus (BTV) has been changing recently, perhaps as a result of climate change. To evaluate the risk of BTV infection and transmission in a BTV-endemic region of California, sentinel dairy cows were evaluated for BTV infection, and populations of Culicoides vectors were collected at different sites using carbon dioxide. A deterministic model was developed to quantify risk and guide future mitigation strategies to reduce BTV infection in California dairy cattle. The greatest risk of BTV transmission was predicted within the warm Central Valley of California that contains the highest density of dairy cattle in the United States. Temperature and parameters associated with Culicoides vectors (transmission probabilities, carrying capacity, and survivorship) had the greatest effect on BTV's basic reproduction number, R0. Based on these analyses, optimal control strategies for reducing BTV infection risk in dairy cattle will be highly reliant upon early efforts to reduce vector abundance during the months prior to peak transmission
Genetic diversity and kelp forest vulnerability to climatic stress
© 2018 The Author(s). Genetic diversity confers adaptive capacity to populations under changing conditions but its role in mediating impacts of climate change remains unresolved for most ecosystems. This lack of knowledge is particularly acute for foundation species, where impacts may cascade throughout entire ecosystems. We combined population genetics with eco-physiological and ecological field experiments to explore relationships among latitudinal patterns in genetic diversity, physiology and resilience of a kelp ecosystem to climate stress. A subsequent 'natural experiment' illustrated the possible influence of latitudinal patterns of genetic diversity on ecosystem vulnerability to an extreme climatic perturbation (marine heatwave). There were strong relationships between physiological versatility, ecological resilience and genetic diversity of kelp forests across latitudes, and genetic diversity consistently outperformed other explanatory variables in contributing to the response of kelp forests to the marine heatwave. Population performance and vulnerability to a severe climatic event were thus strongly related to latitudinal patterns in genetic diversity, with the heatwave extirpating forests with low genetic diversity. Where foundation species control ecological structure and function, impacts of climatic stress can cascade through the ecosystem and, consequently, genetic diversity could contribute to ecosystem vulnerability to climate change
Design of Substituted Imidazolidinylpiperidinylbenzoic Acids as Chemokine Receptor 5 Antagonists: Potent Inhibitors of R5 HIV‑1 Replication
The
redesign of the previously reported thiophene-3-yl-methyl urea
series, as a result of potential cardiotoxicity, was successfully
accomplished, resulting in the identification of a novel potent series
of CCR5 antagonists containing the imidazolidinylpiperidinyl scaffold.
The main redesign criteria were to reduce the number of rotatable
bonds and to maintain an acceptable lipophilicity to mitigate hERG
inhibition. The structure–activity relationship (SAR) that
was developed was used to identify compounds with the best pharmacological
profile to inhibit HIV-1. As a result, five advanced compounds, <b>6d</b>, <b>6e</b>, <b>6i</b>, <b>6h</b>, and <b>6k</b>, were further evaluated for receptor selectivity, antiviral
activity against CCR5 using (R5) HIV-1 clinical isolates, and in vitro
and in vivo safety. On the basis of these results, <b>6d</b> and <b>6h</b> were selected for further development
Detecting conservation benefits in spatially protected fish populations with meta-analysis of long-term monitoring data
Marine protected areas (MPA) produce a
positive effect on fish populations, but this may be difficult
to identify due to the high temporal variability of
populations. Meta-analysis is an option for analysing
data from different sources and sampling designs and it
can address problems related to temporal and spatial
variability in fish populations. We analysed fish abundance
data from visual counts conducted in summer,
from 1996 to 2002, in the MPA of Tabarca (Alicante,
Spain). The results showed an overall positive effect of
protection at the species and family levels. Overall
abundance of fishes inside the reserve was, on average,
1.22 times higher than outside the reserve boundaries.
Positive effect of protection was found for Boops
boops, Diplodus annularis, Diplodus cervinus, Epinephelus
marginatus, Epinephelus costae and Epinephelus
aenus. Species of Labrids were not affected by
protection, except for Thalassoma pavo and Symphodus
ocellatus. Meta-analysis of temporal data allows
evaluation of the protection MPA provide and is particularly
useful when data sources have different experimental
designs or sampling programs. The Tabarca
MPA has benefited fish populations by increasing their
abundance and we suggest that meta-analysis is a complementary
tool for the management of MPAs