A dramatic expansion of road building is underway in the Congo Basin fuelled by private enterprise, international aid, and government aspirations. Among the great wilderness areas on earth, the Congo ...Basin is outstanding for its high biodiversity, particularly mobile megafauna including forest elephants (Loxodonta africana cyclotis). The abundance of many mammal species in the Basin increases with distance from roads due to hunting pressure, but the impacts of road proliferation on the movements of individuals are unknown. We investigated the ranging behaviour of forest elephants in relation to roads and roadless wilderness by fitting GPS telemetry collars onto a sample of 28 forest elephants living in six priority conservation areas. We show that the size of roadless wilderness is a strong determinant of home range size in this species. Though our study sites included the largest wilderness areas in central African forests, none of 4 home range metrics we calculated, including core area, tended toward an asymptote with increasing wilderness size, suggesting that uninhibited ranging in forest elephants no longer exists. Furthermore we show that roads outside protected areas which are not protected from hunting are a formidable barrier to movement while roads inside protected areas are not. Only 1 elephant from our sample crossed an unprotected road. During crossings her mean speed increased 14-fold compared to normal movements. Forest elephants are increasingly confined and constrained by roads across the Congo Basin which is reducing effective habitat availability and isolating populations, significantly threatening long term conservation efforts. If the current road development trajectory continues, forest wildernesses and the forest elephants they contain will collapse.
Abstract
Objectives
Drug resistance exists to all current and investigational antimalarial drug classes. Consequently, we have set out to develop chemically and mechanistically discrete ...antimalarials. Here we report on the development of thiosemicarbazone (TSC) antimalarials, with TSC3 as the most advanced lead.
Methods
Thiosemicarbazones were generated through simple condensation reactions of thiosemicarbazides and ketones. TSC3 was selected and tested for in vitro antimalarial activities against MDR Plasmodium falciparum lines using the 3Hhypoxanthine growth assay, in vitro cytotoxicity against mammalian cell lines using the alamarBlue fluorescence cell viability assay, in vivo potency in the mouse–Plasmodium berghei model and blood exposure in mice measured by LC-MS for pharmacokinetic analysis.
Results
TSC3 showed potent in vitro activity against atovaquone-, dihydroartemisinin-, chloroquine- and mefloquine-resistant P. falciparum lines (EC50 <15 nM). The selectivity index (EC50 cells/EC50Pf W2 line) of TSC3 was >500 in two of three mammalian cell lines. In P. berghei-infected mice, TSC3 showed potent activity in the Peters 4 day suppression test (ED50 1.2 mg/kg/day) and was as potent as artesunate and chloroquine in the curative modified Thompson test. A single oral dose of TSC3 at 16 mg/kg in healthy mice achieved a mean maximum blood concentration of 1883 ng/mL at 1 h after dosing and an elimination half-life of 48.7 h in groups of five mice.
Conclusions
TSC3 shows promise as a persistent, potent and orally effective antimalarial. This, coupled with the extremely low cost of synthesis, suggests that the further development of antimalarial thiosemicarbazones is clearly warranted.
Thermo‐responsive monomers were designed to contain a Diels‐Alder (DA) adduct such that cyclo‐reversion would yield either the maleimide or the furan unit attached to the polymer chain. These ...thermally responsive monomers were then copolymerized with N‐isopropylacrylamide (NIPAM) via reversible addition‐fragmentation chain‐transfer (RAFT) polymerization to yield linear gradient‐copolymer structures as a comparison to existing nanogel/starlike systems to understand how polymer topology and composition influence solution‐state properties. Using UV–Vis spectroscopy, it was determined that solution‐state properties were thermally dependent and influenced by a number of variables such as comonomer feed ratio, polymer chain end functionality, and polymer backbone length and composition. Manipulation of the feed ratio allowed for control over the cloud point, including the breadth and location of phase separation. Thermal treatment of these copolymers revealed tunable and predictable variations in previously observed transitions, directly correlated to cleavage of the DA adducts and change in polymer backbone composition. Finally, on cooling cycles, a double sigmoid was sometimes observed, indicating a complex globule to random coil transition correlated to polymer chain end composition. These studies help understand how to untie the “monkey's fist.”
The predicted relationship between home-range size and group mass in primates developed by Clutton-Brock and Harvey (1977) has proved extremely robust in describing the use of space by most primate ...species. However, mandrills (Mandrillus sphinx) are now known to have an extreme group mass in the wild, far larger than that of the species used originally to generate that relationship, and so it was unknown whether this relationship would be robust for this species. We investigated the home-range size and use of a wild horde of ca. 700 mandrills in Lopé National Park, Gabon, using radiotelemetry. The total area the horde used over a 6-yr period 100% minimum convex polygon (MCP) was 182 km², including 89 km² of suitable forest habitat. Mandrills used gallery forests and isolated forest fragments with high botanical diversity far more intensively that the continuous forest and completely avoided savanna and marsh. Peeled polygons and fixed kernel contours revealed multiple centres of use, with the horde spending more than half its time in <10% of the total documented range, typical of a frugivore using a patchy environment. Home-range size and internal structure varied considerably between years, but total home range fitted the predicted relationship between group mass and home range size, despite being an outlier to the dataset. We discuss the conservation implications of the species' space requirements, in light of current pressures on land use in their range.
The mammary gland is one of the few adult tissues that strongly induce de novo fatty acid synthesis upon physiological stimulation, suggesting that fatty acid is important for milk production during ...lactation. The committed enzyme to perform this function is fatty acid synthase (FASN). To determine whether de novo fatty acid synthesis is obligatory or dietary fat is sufficient for mammary gland development and function during lactation, Fasn was specifically knocked out in mouse mammary epithelial cells. We found that deletion of Fasn hindered the development and induced the premature involution of the lactating mammary gland and significantly decreased medium- and long-chain fatty acids and total fatty acid contents in the milk. Consequently, pups nursing from Fasn knockout mothers experienced growth retardation and preweanling death, which was rescued by cross-fostering pups to a lactating wild-type mother. These results demonstrate that FASN is essential for the development, functional competence, and maintenance of the lactating mammary gland.
Neocortical layer 1 (L1) is a site of convergence between pyramidal-neuron dendrites and feedback axons where local inhibitory signaling can profoundly shape cortical processing. Evolutionary ...expansion of human neocortex is marked by distinctive pyramidal neurons with extensive L1 branching, but whether L1 interneurons are similarly diverse is underexplored. Using Patch-seq recordings from human neurosurgical tissue, we identified four transcriptomic subclasses with mouse L1 homologs, along with distinct subtypes and types unmatched in mouse L1. Subclass and subtype comparisons showed stronger transcriptomic differences in human L1 and were correlated with strong morphoelectric variability along dimensions distinct from mouse L1 variability. Accompanied by greater layer thickness and other cytoarchitecture changes, these findings suggest that L1 has diverged in evolution, reflecting the demands of regulating the expanded human neocortical circuit.
If the shoe fits: TMC435, a noncovalent small‐molecule inhibitor of the hepatitis C virus (HCV) NS3/NS4A protease, is currently undergoing clinical evaluation as an HCV therapeutic. In the crystal ...structure of the noncovalent NS3/NS4A protease–TMC435 complex the bound inhibitor exploits induced‐fit binding. The new structure is consistent with the emerging view of viral resistance to NS3/NS4A protease inhibitors.
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