Overwintering and migration behaviour of post-spawned Atlantic salmon Salmo salar in a large hydropower-regulated river and reservoir

Tracking 47 post-spawned adult Atlantic salmon Salmo salar L. in a hydropower-regulated river through autumn, winter and spring revealed that winter survival was 56% and 75% in two study years, respectively, with higher mortality of males than females (50% vs. 33% and 100% vs. 13%, respectively). Some kelts (n = 7) displayed nondirected movements that were interpreted as a reconditioning period for an average of 9–17 days prior to directed downstream movements indicating the initiation of migration. Survival after the initiation of migration in spring was 83% and 94% to the hydropower dam in the first and second study years, and decreased to 60 and 63%, respectively, after dam passage. There were no further losses in the downriver reach in the second year, with the first year having a cumulative survival estimate of 53% to the river mouth. Kelts approached the dam when the spillway gates were available as a passage option most of the time (64%–75%), but some kelts arrived at the dam or had not yet passed when spillways were closed (n = 6) and the only remaining passage option was restricted to the turbines. However, all but one kelt that must have passed via turbine were successful in reaching the river mouth. Migratory delay presumably due to searching behaviour caused by low water flow was estimated at approximately 6 days as migration rates were significantly slower in the reservoir (median ± s.e. 8.5 ± 2.5 km day⁻¹) than up- (29.7 ± 5.0 km day⁻¹) or downriver (22.1 ± 3.1 km day⁻¹). The proportion of time (median 30%) that kelts spent swimming upstream (searching behaviour) in the reservoir was a significant variable for migration success.     

The N2A region of titin has a unique structural configuration

The N2A segment of titin is a main signaling hub in the sarcomeric I-band that recruits various signaling factors and processing enzymes. It has also been proposed to play a role in force production through its Ca²⁺-regulated association with actin. However, the molecular basis by which N2A performs these functions selectively within the repetitive and extensive titin chain remains poorly understood. Here, we analyze the structure of N2A components and their association with F-actin. Specifically, we characterized the structure of its Ig domains by elucidating the atomic structure of the I81-I83 tandem using x-ray crystallography and computing a homology model for I80. Structural data revealed these domains to present heterogeneous and divergent Ig folds, where I81 and I83 have unique loop structures. Notably, the I81-I83 tandem has a distinct rotational chain arrangement that confers it a unique multi-domain topography. However, we could not identify specific Ca²⁺-binding sites in these Ig domains, nor evidence of the association of titin N2A components with F-actin in transfected C2C12 myoblasts or C2C12-derived myotubes. In addition, F-actin cosedimentation assays failed to reveal binding to N2A. We conclude that N2A has a unique architecture that predictably supports its selective recruitment of binding partners in signaling, but that its mechanical role through interaction with F-actin awaits validation.     

The pharmacokinetics and drug-drug interactions of ivermectin in Aedes aegypti mosquitoes

Mosquitoes are vectors of major diseases such as dengue fever and malaria. Mass drug administration of endectocides to humans and livestock is a promising complementary approach to current insecticide-based vector control measures. The aim of this study was to establish an insect model for pharmacokinetic and drug-drug interaction studies to develop sustainable endectocides for vector control. Female Aedes aegypti mosquitoes were fed with human blood containing either ivermectin alone or ivermectin in combination with ketoconazole, rifampicin, ritonavir, or piperonyl butoxide. Drug concentrations were quantified by LC-MS/MS at selected time points post-feeding. Primary pharmacokinetic parameters and extent of drug-drug interactions were calculated by pharmacometric modelling. Lastly, the drug effect of the treatments was examined. The mosquitoes could be dosed with a high precision (%CV: ≤13.4%) over a range of 0.01–1 μg/ml ivermectin without showing saturation (R²: 0.99). The kinetics of ivermectin were characterised by an initial lag phase of 18.5 h (CI_90%: 17.0–19.8 h) followed by a slow zero-order elimination rate of 5.5 pg/h (CI_90%: 5.1–5.9 pg/h). By contrast, ketoconazole, ritonavir, and piperonyl butoxide were immediately excreted following first order elimination, whereas rifampicin accumulated over days in the mosquitoes. Ritonavir increased the lag phase of ivermectin by 11.4 h (CI_90%: 8.7–14.2 h) resulting in an increased exposure (+29%) and an enhanced mosquitocidal effect. In summary, this study shows that the pharmacokinetics of drugs can be investigated and modulated in an Ae. aegypti animal model. This may help in the development of novel vector-control interventions and further our understanding of toxicology in arthropods.     

Neuronal Differentiation of LUHMES Cells Induces Substantial Changes of the Proteome

Neuronal cell lines are important model systems to study mechanisms of neurodegenerative diseases. One example is the Lund Human Mesencephalic (LUHMES) cell line, which can differentiate into dopaminergic‐like neurons and is frequently used to study mechanisms of Parkinson's disease and neurotoxicity. Neuronal differentiation of LUHMES cells is commonly verified with selected neuronal markers, but little is known about the proteome‐wide protein abundance changes during differentiation. Using mass spectrometry and label‐free quantification (LFQ), the proteome of differentiated and undifferentiated LUHMES cells and of primary murine midbrain neurons are compared. Neuronal differentiation induced substantial changes of the LUHMES cell proteome, with proliferation‐related proteins being strongly down‐regulated and neuronal and dopaminergic proteins, such as L1CAM and α‐synuclein (SNCA) being up to 1,000‐fold up‐regulated. Several of these proteins, including MAPT and SYN1, may be useful as new markers for experimentally validating neuronal differentiation of LUHMES cells. Primary midbrain neurons are slightly more closely related to differentiated than to undifferentiated LUHMES cells, in particular with respect to the abundance of proteins related to neurodegeneration. In summary, the analysis demonstrates that differentiated LUHMES cells are a suitable model for studies on neurodegeneration and provides a resource of the proteome‐wide changes during neuronal differentiation. (ProteomeXchange identifier PXD020044).