Spatial control of irreversible protein aggregation

Liquid cellular compartments spatially segregate from the cytoplasm and can regulate aberrant protein aggregation, a process linked to several medical conditions, including Alzheimer's and Parkinson's diseases. Yet the mechanisms by which these droplet-like compartments affect protein aggregation remain unknown. Here, we combine kinetic theory of protein aggregation and liquid-liquid phase separation to study the spatial control of irreversible protein aggregation in the presence of liquid compartments. We find that, even for weak interactions between the compartment constituents and the aggregating monomers, aggregates are strongly enriched inside the liquid compartment relative to the surrounding cytoplasm. We show that this enrichment is caused by a positive feedback mechanism of aggregate nucleation and growth which is mediated by a flux maintaining the phase equilibrium between the compartment and the cytoplasm. Our model predicts that the compartment volume that maximizes aggregate enrichment in the compartment is determined by the reaction orders of aggregate nucleation. The underlying mechanism of aggregate enrichment could be used to confine cytotoxic protein aggregates inside droplet-like compartments suggesting potential new avenues against aberrant protein aggregation. Our findings could also represent a common mechanism for the spatial control of irreversible chemical reactions in general

One-dimensional lattice of oscillators coupled through power-law interactions: Continuum limit and dynamics of spatial Fourier modes

We study synchronization in a system of phase-only oscillators residing on the sites of a one-dimensional periodic lattice. The oscillators interact with a strength that decays as a power law of the separation along the lattice length and is normalized by a size-dependent constant. The exponent $\alpha$ of the power law is taken in the range $0 \le \alpha <1$. The oscillator frequency distribution is symmetric about its mean (taken to be zero), and is non-increasing on $[0,\infty)$. In the continuum limit, the local density of oscillators evolves in time following the continuity equation that expresses the conservation of the number of oscillators of each frequency under the dynamics. This equation admits as a stationary solution the unsynchronized state uniform both in phase and over the space of the lattice. We perform a linear stability analysis of this state to show that when it is unstable, different spatial Fourier modes of fluctuations have different stability thresholds beyond which they grow exponentially in time with rates that depend on the Fourier modes. However, numerical simulations show that at long times, all the non-zero Fourier modes decay in time, while only the zero Fourier mode (i.e., the "mean-field" mode) grows in time, thereby dominating the instability process and driving the system to a synchronized state. Our theoretical analysis is supported by extensive numerical simulations.Comment: 7 pages, 4 figures. v2: new simulation results added, close to the published versio

Aggregation controlled by condensate rheology

Biomolecular condensates in living cells can exhibit a complex rheology, including viscoelastic and glassy behavior. This rheological behavior of condensates was suggested to regulate polymerization of cytoskeletal filaments and aggregation of amyloid fibrils. Here, we theoretically investigate how the rheological properties of condensates can control the formation of linear aggregates. To this end, we propose a kinetic theory for linear aggregation in coexisting phases, which accounts for the aggregate size distribution and the exchange of aggregates between inside and outside of condensates. The rheology of condensates is accounted in our model via aggregate mobilities that depend on aggregate size. We show that condensate rheology determines whether aggregates of all sizes or dominantly small aggregates are exchanged between condensate inside and outside on the timescale of aggregation. As a result, the ratio of aggregate numbers inside to outside of condensates differs significantly. Strikingly, we also find that weak variations in the rheological properties of condensates can lead to a switch-like change of the number of aggregates. These results suggest a possible physical mechanism for how living cells could control linear aggregation in a switch-like fashion through variations in condensate rheology

Best Practices among Certain Classes of Pennsylvania Destination Marketing Organizations (DMOs)

The researchers originally became aware of the existence of DMOs (previously known as tourism promotion agencies or TPAs) when reading materials in the Gettysburg Times. The two student-authors plan to work in local government following graduation, and they were curious about perspectives shared in the Gettysburg Times about the local DMO. Thereafter, a representative from the Gettysburg Borough Council approached the faculty-author about conducting research on DMOs’ policies, procedures, and practices, and, relatedly, the “pillow tax,” a hotel room occupancy tax that is administered by counties and disbursed to DMOs, among others. Specifically, the Borough Council representative was curious about best practices with respect to allocation of the pillow tax; how DMOs use pillow tax revenue; and how DMOs account for such use. The Borough representative also was curious about general business practices among DMOs. The faculty-author applied for and obtained approval from the Gettysburg College Institutional Review Board for research among Pennsylvania DMOs and their representatives on these issues. This white paper briefly summarizes the history of the relationship between Pennsylvania DMOs and the pillow tax then describes the researchers’ methodology. Next, the white paper describes what Study DMOs appear to believe are best practices, or most commonly accepted practices, in six categories: Boards of Directors; Revenue; Grant Making; Spending; Assessment; and Future Planning. All data are reported in aggregate to minimize the risk of revealing individually identifiable data. These findings may inform DMO, community, and county decision-making

Enhanced potency of aggregation inhibitors mediated by liquid condensates

Liquid condensates are membraneless organelles that form via phase separation in living cells. These condensates provide unique heterogeneous environments that have much potential in regulating a range of biochemical processes from gene expression to filamentous protein aggregation—a process linked to Alzheimer's and Parkinson's diseases. Here we theoretically study the physical interplay between protein aggregation, its inhibition, and liquid-liquid phase separation. Our key finding is that the action of protein aggregation inhibitors can be strongly enhanced by liquid condensates. The physical mechanism of this enhancement relies on the partitioning and colocalization of inhibitors with their targets inside the liquid condensate. Our theory uncovers how the physicochemical properties of condensates can be used to modulate inhibitor potency, and we provide experimentally testable conditions under which drug potency is maximal. Our findings suggest design principles for protein aggregation inhibitors with respect to their phase-separation properties

Evaluation of the Relevance of a Web-Based Ask an Expert Feature: StratSoy and Soy and Human Health Queries

StratSoy, a state-of-the-art Web-based information system, has an Ask an Expert (AE) feature that allows Web site browsers to question experts in 13 areas including Soy and Human Health (SHH). The objectives of this research were to: a) assess the use of the SHH AE feature; b) examine respondent attitudes about soy-related topics to help guide development of a Frequently Asked Questions (FAQ) section; and c) improve the information dissemination process on the Web site based on the results of this research. Study participants were 50 Web site users and 48 people who were unfamiliar with the site. The results of the study indicated topic areas of interest and additional Web site features desired by the respondents. The findings identified specific areas that may be targeted to improve the Web site

Phase shifts of synchronized oscillators and the systolic/diastolic blood pressure relation

We study the phase-synchronization properties of systolic and diastolic arterial pressure in healthy subjects. We find that delays in the oscillatory components of the time series depend on the frequency bands that are considered, in particular we find a change of sign in the phase shift going from the Very Low Frequency band to the High Frequency band. This behavior should reflect a collective behavior of a system of nonlinear interacting elementary oscillators. We prove that some models describing such systems, e.g. the Winfree and the Kuramoto models offer a clue to this phenomenon. For these theoretical models there is a linear relationship between phase shifts and the difference of natural frequencies of oscillators and a change of sign in the phase shift naturally emerges.Comment: 8 figures, 9 page

Weak charge form factor and radius of 208Pb through parity violation in electron scattering

We use distorted wave electron scattering calculations to extract the weak charge form factor F_W(q), the weak charge radius R_W, and the point neutron radius R_n, of 208Pb from the PREX parity violating asymmetry measurement. The form factor is the Fourier transform of the weak charge density at the average momentum transfer q=0.475 fm$^{-1}$. We find F_W(q) =0.204 \pm 0.028 (exp) \pm 0.001 (model). We use the Helm model to infer the weak radius from F_W(q). We find R_W= 5.826 \pm 0.181 (exp) \pm 0.027 (model) fm. Here the exp error includes PREX statistical and systematic errors, while the model error describes the uncertainty in R_W from uncertainties in the surface thickness \sigma of the weak charge density. The weak radius is larger than the charge radius, implying a "weak charge skin" where the surface region is relatively enriched in weak charges compared to (electromagnetic) charges. We extract the point neutron radius R_n=5.751 \pm 0.175 (exp) \pm 0.026 (model) \pm 0.005 (strange) fm$, from R_W. Here there is only a very small error (strange) from possible strange quark contributions. We find R_n to be slightly smaller than R_W because of the nucleon's size. Finally, we find a neutron skin thickness of R_n-R_p=0.302\pm 0.175 (exp) \pm 0.026 (model) \pm 0.005 (strange) fm, where R_p is the point proton radius.Comment: 5 pages, 1 figure, published in Phys Rev. C. Only one change in this version: we have added one author, also to metadat

Slow fluctuations in enhanced Raman scattering and surface roughness relaxation

We propose an explanation for the recently measured slow fluctuations and ``blinking'' in the surface enhanced Raman scattering (SERS) spectrum of single molecules adsorbed on a silver colloidal particle. We suggest that these fluctuations may be related to the dynamic relaxation of the surface roughness on the nanometer scale and show that there are two classes of roughness with qualitatively different dynamics. The predictions agree with measurements of surface roughness relaxation. Using a theoretical model for the kinetics of surface roughness relaxation in the presence of charges and optical electrical fields, we predict that the high-frequency electromagnetic field increases both the effective surface tension and the surface diffusion constant and thus accelerates the surface smoothing kinetics and time scale of the Raman fluctuations in manner that is linear with the laser power intensity, while the addition of salt retards the surface relaxation kinetics and increases the time scale of the fluctuations. These predictions are in qualitative agreement with the Raman experiments