Role of water in Protein Aggregation and Amyloid Polymorphism

A variety of neurodegenerative diseases are associated with the formation of amyloid plaques. Our incomplete understanding of this process underscores the need to decipher the principles governing protein aggregation. Most experimental and simulation studies have been interpreted largely from the perspective of proteins: the role of solvent has been relatively overlooked. In this Account, we provide a perspective on how interactions with water affect folding landscapes of A$\beta$ monomers, A$\beta_{16-22}$ oligomer formation, and protofilament formation in a Sup35 peptide. Simulations show that the formation of aggregation-prone structures (N$^*$) similar to the structure in the fibril requires overcoming high desolvation barrier. The mechanism of protofilament formation in a polar Sup35 peptide fragment illustrates that water dramatically slows down self-assembly. Release of water trapped in the pores as water wires creates protofilament with a dry interface. Similarly, one of the main driving force for addition of a solvated monomer to a preformed fibril is the entropy gain of released water. We conclude by postulating that two-step model for protein crystallization must also hold for higher order amyloid structure formation starting from N$^*$. Multiple N$^*$ structures with varying water content results in a number of distinct water-laden polymorphic structures. In predominantly hydrophobic sequences, water accelerates fibril formation. In contrast, water-stabilized metastable intermediates dramatically slow down fibril growth rates in hydrophilic sequences.Comment: 27 pages, 4 figures; Accounts of Chemical Research, 201

Flow over a cylinder with a hinged-splitter plate

Previous work on rigid splitter plates in the wake of a bluff body has shown that the primary vortex shedding can be suppressed for sufficiently long splitter plates. In the present work, we study the problem of a hinged-splitter plate in the wake of a circular cylinder. The splitter plate can rotate about the hinge at the base of the cylinder due to the unsteady fluid forces acting on it, and hence the communication between the two sides of the wake is not totally disrupted as in the rigid splitter plate case. In our study, we investigate this problem in the limit where the stiffness and internal damping associated with the hinge are negligible, and the mass ratio of the splitter plate is small. The experiments show that the splitter plate oscillations increase with Reynolds numbers at low values of Re, and are found to reach a saturation amplitude level at higher Re, Re>4000. This type of saturation amplitude level that appears to continue indefinitely with Re, appears to be related to the fact that there is no structural restoring force, and has been observed previously for transversely oscillating cylinders with no restoring force. In the present case, the saturation tip amplitude level can be up to 0.45D, where D is the cylinder diameter. For this hinged-rigid splitter plate case, it is found that the splitter plate length to cylinder diameter ratio (L/D) is crucial in determining the character and magnitude of the oscillations. For small splitter plate lengths (L/D≤ 3.0), the oscillations appear to be nearly periodic with tip amplitudes of about 0.45D nearly independent of L/D. The nondimensional oscillation frequencies (fD/U) on the other hand are found to continuously vary with L/D from fD/U≈ 0.2 at L/D=1 to fD/U≈ 0.1 at L/D=3. As the splitter plate length is further increased beyond L/D≥ 4.0, the character of the splitter plate oscillations suddenly changes. The oscillations become aperiodic with much smaller amplitudes. In this long splitter plate regime, the spectra of the oscillations become broadband, and are reminiscent of the change in character of the wake oscillations seen in the earlier fixed-rigid splitter plate case for L/D≥ 5.0. In the present case of the hinged-splitter plate, the sudden transition seen as the splitter plate length (L/D) is increased from 3 to 4 may be attributed to the fact that the wake vortices are no longer able to synchronize with the plate motions for larger splitter plate lengths. Hence, as observed in other vortex-induced vibration problems, the oscillations become aperiodic and the amplitude reduces dramatically

Operational Probabilistic Fog Prediction Based on Ensemble Forecast System: A Decision Support System for Fog

One of the well-known challenges of fog forecasting is the high spatio-temporal variability of fog. An ensemble forecast aims to capture this variability by representing the uncertainty in the initial/lateral boundary conditions (ICs/BCs) and model physics. The present study highlights a new operational Ensemble Forecast System (EFS) developed by the Indian Institute of Tropical Meteorology (IITM), Pune, to predict the fog over the Indo-Gangetic Plain (IGP) region using the visibility (Vis) diagnostic algorithm. The EFS framework comprises the WRF model with a 4 km horizontal resolution, initialized by 21 ICs/BCs. The advantages of probabilistic fog forecasting have been demonstrated by comparing control (CNTL) and ensemble-based fog forecasts. The forecast is verified using fog observations from the Indira Gandhi International (IGI) airport during the winter months of 2020–2021 and 2021–2022. The results show that with a probability threshold of 50%, the ensemble forecasts perform better than the CNTL forecasts. The skill scores of EFS are relatively promising, with a Hit Rate of 0.95 and a Critical Success Index of 0.55; additionally, the False Alarm Rate and Missing Rate are low, with values of 0.43 and 0.04, respectively. The EFS could correctly predict more fog events (37 out of 39) compared with the CNTL forecast (31 out of 39) and shows the potential skill. Furthermore, EFS has a substantially reduced error in predicting fog onset and dissipation (mean onset and dissipation error of 1 h each) compared to the CNTL forecasts

Operational Probabilistic Fog Prediction Based on Ensemble Forecast System: A Decision Support System for Fog

One of the well-known challenges of fog forecasting is the high spatio-temporal variability of fog. An ensemble forecast aims to capture this variability by representing the uncertainty in the initial/lateral boundary conditions (ICs/BCs) and model physics. The present study highlights a new operational Ensemble Forecast System (EFS) developed by the Indian Institute of Tropical Meteorology (IITM), Pune, to predict the fog over the Indo-Gangetic Plain (IGP) region using the visibility (Vis) diagnostic algorithm. The EFS framework comprises the WRF model with a 4 km horizontal resolution, initialized by 21 ICs/BCs. The advantages of probabilistic fog forecasting have been demonstrated by comparing control (CNTL) and ensemble-based fog forecasts. The forecast is verified using fog observations from the Indira Gandhi International (IGI) airport during the winter months of 2020–2021 and 2021–2022. The results show that with a probability threshold of 50%, the ensemble forecasts perform better than the CNTL forecasts. The skill scores of EFS are relatively promising, with a Hit Rate of 0.95 and a Critical Success Index of 0.55; additionally, the False Alarm Rate and Missing Rate are low, with values of 0.43 and 0.04, respectively. The EFS could correctly predict more fog events (37 out of 39) compared with the CNTL forecast (31 out of 39) and shows the potential skill. Furthermore, EFS has a substantially reduced error in predicting fog onset and dissipation (mean onset and dissipation error of 1 h each) compared to the CNTL forecasts