3D GRID-based pharmacophore and Metadynamics approaches for the rational design of N-Methyl β-sheet breaker peptides as inhibitors of the Alzheimer's Aβ-amyloid fibrillogenesis

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the loss of the cognitive functions and dementia. Several scientific evidences report that a central role in the pathogenesis of AD is played by the brain deposition of insoluble aggregates of β-amyloid protein (Aβ) proteins, thus causing neuronal cell death [1]. For this reason, one of the promising approach is to inhibit the aggregation of Aβ peptides. Because Aβ is self-assembling, one possible strategy to prevent this process is to use short peptide fragments homologous to the full-length wild-type Aβ protein. From this consideration, several short synthetic peptides were designed as beta-sheet breakers (BSB) [2]. In particular, the pentapetide Ac-LPFFD-NH2 (iAβ5p) exhibited a certain capability to inhibit Aβ fibrillogenesis [3]. iAβ5p analogs [4] were, then, designed by introducing N-Methylation at the amide bond nitrogen were also promising BSB. Here, we describe the methodological approach, which combines 3D GRID-based pharmacophore peptide screening with Well-Tempered Metadynamics simulations aimed to the discovery of novel N-Methylated BSB. This approach led us to identify two promising, cell permeable, N-Methylated peptides that were further evaluated for their BSB properties showing a significant improvement of the fibrillogenesis inhibition with respect to the lead iAβ5p

Evidence for stratospheric sudden warming effects on the upper thermosphere derived from satellite orbital decay data during 1967–2013

We investigate possible impact of stratospheric sudden warmings (SSWs) on the thermosphere by using long-term data of the global average thermospheric total mass density derived from satellite orbital drag during 1967–2013. Residuals are analyzed between the data and empirical Global Average Mass Density Model (GAMDM) that takes into account density variability due to solar activity, season, geomagnetic activity, and long-term trend. A superposed epoch analysis of 37 SSW events reveals a density reduction of 3–7% at 250–575 km around the time of maximum polar vortex weakening. The relative density perturbation is found to be greater at higher altitudes. The temperature perturbation is estimated to be −7.0 K at 400 km. We show that the density reduction can arise from enhanced wave forcing from the lower atmosphere

Development and Validation of the Whole Atmosphere Community Climate Model With Thermosphere and Ionosphere Extension (WACCM‐X 2.0)

Key developments have been made to the NCAR Whole Atmosphere Community Climate Model with thermosphere and ionosphere extension (WACCM‐X). Among them, the most important are the self‐consistent solution of global electrodynamics, and transport of O+ in the F‐region. Other ionosphere developments include time‐dependent solution of electron/ion temperatures, metastable O+ chemistry, and high‐cadence solar EUV capability. Additional developments of the thermospheric components are improvements to the momentum and energy equation solvers to account for variable mean molecular mass and specific heat, a new divergence damping scheme, and cooling by O(3P) fine structure. Simulations using this new version of WACCM‐X (2.0) have been carried out for solar maximum and minimum conditions. Thermospheric composition, density, and temperatures are in general agreement with measurements and empirical models, including the equatorial mass density anomaly and the midnight density maximum. The amplitudes and seasonal variations of atmospheric tides in the mesosphere and lower thermosphere are in good agreement with observations. Although global mean thermospheric densities are comparable with observations of the annual variation, they lack a clear semiannual variation. In the ionosphere, the low‐latitude E × B drifts agree well with observations in their magnitudes, local time dependence, seasonal, and solar activity variations. The prereversal enhancement in the equatorial region, which is associated with ionospheric irregularities, displays patterns of longitudinal and seasonal variation that are similar to observations. Ionospheric density from the model simulations reproduces the equatorial ionosphere anomaly structures and is in general agreement with observations. The model simulations also capture important ionospheric features during storms

Improving ionospheric predictability requires accurate simulation of the mesospheric polar vortex

The mesospheric polar vortex (MPV) plays a critical role in coupling the atmosphere-ionosphere system, so its accurate simulation is imperative for robust predictions of the thermosphere and ionosphere. While the stratospheric polar vortex is widely understood and characterized, the mesospheric polar vortex is much less well-known and observed, a short-coming that must be addressed to improve predictability of the ionosphere. The winter MPV facilitates top-down coupling via the communication of high energy particle precipitation effects from the thermosphere down to the stratosphere, though the details of this mechanism are poorly understood. Coupling from the bottom-up involves gravity waves (GWs), planetary waves (PWs), and tidal interactions that are distinctly different and important during weak vs. strong vortex states, and yet remain poorly understood as well. Moreover, generation and modulation of GWs by the large wind shears at the vortex edge contribute to the generation of traveling atmospheric disturbances and traveling ionospheric disturbances. Unfortunately, representation of the MPV is generally not accurate in state-of-the-art general circulation models, even when compared to the limited observational data available. Models substantially underestimate eastward momentum at the top of the MPV, which limits the ability to predict upward effects in the thermosphere. The zonal wind bias responsible for this missing momentum in models has been attributed to deficiencies in the treatment of GWs and to an inaccurate representation of the high-latitude dynamics. In the coming decade, simulations of the MPV must be improved

Solved and unsolved riddles about low-latitude daytime valley region plasma waves and 150-km echoes

The Earth’s atmosphere near both the geographic and magnetic equators and at altitudes between 120 and 200 km is called the low-latitude valley region (LLVR) and is among the least understood regions of the ionosphere/thermosphere due to its complex interplay of neutral dynamics, electrodynamics, and photochemistry. Radar studies of the region have revealed puzzling daytime echoes scattered from between 130 and 170 km in altitude. The echoes are quasi-periodic and are observed in solar-zenith-angle dependent layers. Populations with two distinct types of spectral features are observed. A number of radars have shown scattering cross-sections with different seasonal and probing-frequency dependencies. The sources and configurations of the so-called 150-km echoes and the related irregularities have been long-standing riddles for which some solutions are finally starting to emerge as will be described in this review paper. Although the 150-km echoes were discovered in the early 1960s, their practical significance and implications were not broadly recognized until the early 1990s, and no compelling explanations of their generation mechanisms and observed features emerged until about a decade ago. Now, more rapid progress is being made thanks to a multi-disciplinary team effort described here and recent developments in kinetic simulations and theory: 18 of 27 riddles to be described in this paper stand solved (and a few more partially solved) at this point in time. The source of the irregularities is no longer a puzzle as compelling evidence has emerged from simulations and theory, presented since 2016 that they are being caused by photoelectrons driving an upper hybrid plasma instability process. Another resolved riddle concerns the persistent gaps observed between the 150-km scattering layers—we now understand that they are likely to be the result of enhanced thermal Landau damping of the upper hybrid instability process at upper hybrid frequencies matching the harmonics of the electron gyrofrequency. The remaining unsolved riddles, e.g., minute-scale variability, multi-frequency dependence, to name a few, are still being explored observationally and theoretically—they are most likely unidentified consequences of interplay between plasma physics, photochemistry, and lower atmospheric dynamic processes governing the LLVR