The sensory hairs of the Venus flytrap (Dionaea muscipula Ellis) detect mechanical stimuli imparted by their prey and fire bursts of electrical signals called action potentials (APs). APs are elicited when the hairs are sufficiently stimulated and two consecutive APs can trigger closure of the trap. Earlier experiments have identified thresholds for the relevant stimulus parameters, namely the angular displacement \(\theta \) and angular velocity \(\omega \). However, these experiments could not trace the deformation of the trigger hair’s sensory cells, which are known to transduce the mechanical stimulus. To understand the kinematics at the cellular level, we investigate the role of two relevant mechanical phenomena: viscoelasticity and intercellular fluid transport using a multi-scale numerical model of the sensory hair. We hypothesize that the combined influence of these two phenomena and \(\omega \) contribute to the flytrap’s rate-dependent response to stimuli. In this study, we firstly perform sustained deflection tests on the hair to estimate the viscoelastic material properties of the tissue. Thereafter, through simulations of hair deflection tests at different loading rates, we were able to establish a multi-scale kinematic link between \(\omega \) and the cell wall stretch \(\delta \). Furthermore, we find that the rate at which \(\delta \) evolves during a stimulus is also proportional to \(\omega \). This suggests that mechanosensitive ion channels, expected to be stretch-activated and localized in the plasma membrane of the sensory cells, could be additionally sensitive to the rate at which stretch is applied.
Mutations in RNA binding proteins (RBPs) and in genes regulating autophagy are frequent causes of familial amyotrophic lateral sclerosis (fALS). The P56S mutation in vesicle-associated membrane protein-associated protein B (VAPB) leads to fALS (ALS8) and spinal muscular atrophy (SMA). While VAPB is primarily involved in the unfolded protein response (UPR), vesicular trafficking and in initial steps of the autophagy pathway, the effect of mutant P56S-VAPB on autophagy regulation in connection with RBP homeostasis has not been explored yet. Examining the muscle biopsy of our index ALS8 patient of European origin revealed globular accumulations of VAPB aggregates co-localised with autophagy markers LC3 and p62 in partially atrophic and atrophic muscle fibres. In line with this skin fibroblasts obtained from the same patient showed accumulation of P56S-VAPB aggregates together with LC3 and p62. Detailed investigations of autophagic flux in cell culture models revealed that P56S-VAPB alters both initial and late steps of the autophagy pathway. Accordingly, electron microscopy complemented with live cell imaging highlighted the impaired fusion of accumulated autophagosomes with lysosomes in cells expressing P56S-VAPB. Consistent with these observations, neuropathological studies of brain and spinal cord of P56S-VAPB transgenic mice revealed signs of neurodegeneration associated with altered protein quality control and defective autophagy. Autophagy and RBP homeostasis are interdependent, as demonstrated by the cytoplasmic mis-localisation of several RBPs including pTDP-43, FUS, Matrin 3 which often sequestered with P56S-VAPB aggregates both in cell culture and in the muscle biopsy of the ALS8 patient. Further confirming the notion that aggregation of the RBPs proceeds through the stress granule (SG) pathway, we found persistent G3BP- and TIAR1-positive SGs in P56S-VAPB expressing cells as well as in the ALS8 patient muscle biopsy. We conclude that P56S-VAPB-ALS8 involves a cohesive pathomechanism of aberrant RBP homeostasis together with dysfunctional autophagy.Subject terms: Mechanisms of disease, Amyotrophic lateral sclerosis相似文献
In this study, we estimated whether changes in hydrological pathwaysduring storms could explain the large temporal variations of dissolvedorganic carbon (DOC) and nitrogen (DON) in the runoff of threecatchments: a forest and a grassland sub-catchment of 1600m2 delineated by trenches, and a headwater catchment of 0.7km2.The average annual DOC export from the sub-catchments was 185 kg DOCha–1 y–1 for the forest, 108 kg DOCha–1 y–1 for the grassland and 84 kgDOC ha–1 y–1 for the headwatercatchment. DON was the major form of the dissolved N in soil and streamwater. DON export from all catchments was approximately 6 kg Nha–1 y–1, which corresponded to 60% ofthe total N export and to 50% of the ambient wet N deposition. DOC andDON concentrations in weekly samples of stream water were positivelycorrelated with discharge. During individual storms, concentrations andproperties of DOC and DON changed drastically. In all catchments, DOCconcentrations increased by 6 to 7 mg DOC l–1 comparedto base flow, with the largest relative increment in the headwatercatchment (+350%). Concentrations of DON, hydrolysable amino acids, andphenolics showed comparable increases, whereas the proportion ofcarbohydrates in DOC decreased at peak flow. Prediction of DOC and DONconcentrations by an end-member mixing analysis (EMMA) on the base ofinorganic water chemistry showed that changes in water flow pathslargely explained these temporal variability. According to the EMMA, thecontribution of throughfall to the runoff peaked in the initial phase ofthe storm, while water from the subsoil dominated during base flow only.EMMA indicated that the contribution of the DOC and DON-rich topsoil washighest in the later stages of the storm, which explained the highestDOC and DON concentrations as the hydrograph receded. Discrepanciesbetween observed and predicted concentrations were largest for thereactive DOC compounds such as carbohydrates and phenolics. Theyoccurred at base flow and in the initial phase of storms. This suggeststhat other mechanisms such as in-stream processes or a time-variantrelease of DOC also played an important role. 相似文献