Explore the vast range of titles available.

A small-molecule inhibitor of the type III phosphatidylinositol 3-kinase, Vps34, binds the ATP binding pocket and prevents vesicle trafficking and autophagy. Vps34 is a phosphoinositide 3-kinase (PI3K) class III isoform that has attracted major attention over the recent years because of its role in autophagy. Herein we describe the biological characterization of SAR405, which is a low-molecular-mass kinase inhibitor of Vps34 ( K D 1.5 nM). This compound has an exquisite protein and lipid kinase selectivity profile that is explained by its unique binding mode and molecular interactions within the ATP binding cleft of human Vps34. To the best of our knowledge, this is the first potent and specific Vps34 inhibitor described so far. Our results demonstrate that inhibition of Vps34 kinase activity by SAR405 affects both late endosome-lysosome compartments and prevents autophagy. Moreover, we show that the concomitant inhibition of Vps34 and mTOR, with SAR405 and the US Food and Drug Administration–approved mTOR inhibitor everolimus, results in synergistic antiproliferative activity in renal tumor cell lines, indicating a potential clinical application in cancer.

Animals in urban environments face challenging situations and have to cope with human activities. This study investigated the ecology and behaviour of a population of European hamsters (Cricetus cricetus) living in the city centre of Vienna (Austria). We recorded the surface activities of 35 hamsters in May 2015. Each focal animal was observed for 15 minutes, and a total of 66 focal samples were analysable. As a prey species in an environment teeming with human activities, we predicted a high level of vigilance by the hamsters. The results show that while animals dedicated a lot of time to vigilance, most of their time was spent foraging. The study also explores whether the frequency of vigilance behaviours differ between males and females. We found that vigilance behaviours were expressed in a different manner by males and females. Finally, we investigated the distribution of the burrows on green spaces depending on proximity to trees and on noise levels. We found a biased distribution of burrows, with a spatial preference for location protected by the vegetation and distant to noise sources. Although burrows were located preferentially under vegetation cover, levels of noise did not determine their positions. Moreover, this species does not respond to disturbances like daily urban noises, probably due to habituation. The common hamster is an endangered species; our results lead to a greater knowledge of its behaviour in a persistent urban population.

Animals in urban environments face challenging situations and have to cope with human activities. This study investigated the ecology and behaviour of a population of European hamsters (Cricetus cricetus) living in the city centre of Vienna (Austria). We recorded the surface activities of 35 hamsters in May 2015. Each focal animal was observed for 15 minutes, and a total of 66 focal samples were analysable. As a prey species in an environment teeming with human activities, we predicted a high level of vigilance by the hamsters. The results show that while animals dedicated a lot of time to vigilance, most of their time was spent foraging. The study also explores whether the frequency of vigilance behaviours differ between males and females. We found that vigilance behaviours were expressed in a different manner by males and females. Finally, we investigated the distribution of the burrows on green spaces depending on proximity to trees and on noise levels. We found a biased distribution of burrows, with a spatial preference for location protected by the vegetation and distant to noise sources. Although burrows were located preferentially under vegetation cover, levels of noise did not determine their positions. Moreover, this species does not respond to disturbances like daily urban noises, probably due to habituation. The common hamster is an endangered species; our results lead to a greater knowledge of its behaviour in a persistent urban population.

Infection of mice with Rift Valley fever virus (RVFV) reproduces major pathological features of severe human disease, notably the early-onset hepatitis and delayed-onset encephalitis. We previously reported that the Rvfs2 locus from the susceptible MBT/Pas strain reduces survival time after RVFV infection. Here, we used BALB/cByJ (BALB) mice congenic for Rvfs2 (C.MBT- Rvfs2 ) to investigate the pathophysiological mechanisms impacted by Rvfs2 . Clinical, biochemical and histopathological features indicated similar liver damage in BALB and C.MBT- Rvfs2 mice until day 5 after infection. However, while C.MBT- Rvfs2 mice succumbed from acute liver injury, most BALB mice recovered and died later of encephalitis. Hepatocytes of BALB infected liver proliferated actively on day 6, promoting organ regeneration and recovery from liver damage. By comparison with C.MBT- Rvfs2 , BALB mice had up to 100-fold lower production of infectious virions in the peripheral blood and liver, strongly decreased RVFV protein in liver and reduced viral replication in primary cultured hepatocytes, suggesting that the BALB Rvfs2 haplotype limits RVFV pathogenicity through decreased virus replication. Moreover, bone marrow chimera experiments showed that both hematopoietic and non-hematopoietic cells are required for the protective effect of the BALB Rvfs2 haplotype. Altogether, these results indicate that Rvfs2 controls critical events which allow survival to RVFV-induced hepatitis.

The systemic inoculation of mice with Rift Valley fever virus (RVFV) reproduces major pathological features of severe human disease, notably the acute-onset hepatitis and delayed-onset encephalitis. We previously reported that a genomic interval (Rvfs2) derived from the susceptible MBT/Pas strain is associated with reduced survival time after RVFV infection. In this study, we investigated the pathophysiological mechanisms by which Rvfs2 confers increased susceptibility to BALB/c mice that are congenic for Rvfs2 (C.MBT Rvfs2) after infection with virulent RVFV. Clinical traits, biochemical parameters, and histopathological features indicated similar liver damage in BALB/c and C.MBT Rvfs2 mice between the third and fifth days after infection. However, C.MBT Rvfs2 mice died at that point from acute liver injury while most BALB/c mice recovered from this condition but eventually died of encephalitis. We observed that hepatocytes proliferated actively within the infected liver of BALB/c mice on the sixth day after infection, promoting organ regeneration on the eighth day after infection and recovery from liver damage. We found that the production of infectious virions was up to 100-fold lower in the peripheral blood and liver of BALB/c compared to C.MBT Rvfs2 mice. Likewise, RVFV protein amounts were much lower in BALB/c liver compared to C.MBT Rvfs2 liver. Primary cultured hepatocytes showed higher viral replication rate in C.MBT Rvfs2 which could contribute to the susceptibility conferred by Rvfs2. Using bone marrow chimera experiments, we uncovered that both hematopoietic and non-hematopoietic cells are required for the BALB/c allele of Rvfs2 to exert its protective effects against the RVFV-induced acute liver disease. Taken together, we have established that Rvfs2 acts as an important RVFV restriction factor by limiting virus multiplication in mice.