Towards a priori uncertainty quantification in coarse-grained molecular dynamics: Generalized multipole potentials.

In computational materials science, coarse-graining approaches often lack a priori uncertainty quantification (UQ) tools that estimate the accuracy of a reduced-order model before it is calibrated or deployed. This is especially the case in coarse-grained (CG) molecular dynamics (MD), where "bottom-up" methods need to run expensive atomistic simulations as part of the calibration process. As a result, scientists have been slow to adopt CG techniques in many settings because they do not know in advance whether the cost of developing the CG model is justified. To address this problem, we present an analytical method of coarse-graining rigid-body systems that yields corresponding intermolecular potentials with controllable levels of accuracy relative to their atomistic counterparts. Critically, this analysis: (i) provides a mathematical foundation for assessing the quality of a CG force field without running simulations; and (ii) provides a tool for understanding how atomistic systems can be viewed as appropriate limits of reduced-order models. Simulated results confirm the validity of this approach at the trajectory level and point to issues that must be addressed in coarse-graining fully non-rigid systems.

Predicted Role of NAD Utilization in the Control of Circadian Rhythms during DNA Damage Response.

The circadian clock is a set of regulatory steps that oscillate with a period of approximately 24 hours influencing many biological processes. These oscillations are robust to external stresses, and in the case of genotoxic stress (i.e. DNA damage), the circadian clock responds through phase shifting with primarily phase advancements. The effect of DNA damage on the circadian clock and the mechanism through which this effect operates remains to be thoroughly investigated. Here we build an in silico model to examine damage-induced circadian phase shifts by investigating a possible mechanism linking circadian rhythms to metabolism. The proposed model involves two DNA damage response proteins, SIRT1 and PARP1, that are each consumers of nicotinamide adenine dinucleotide (NAD), a metabolite involved in oxidation-reduction reactions and in ATP synthesis. This model builds on two key findings: 1) that SIRT1 (a protein deacetylase) is involved in both the positive (i.e. transcriptional activation) and negative (i.e. transcriptional repression) arms of the circadian regulation and 2) that PARP1 is a major consumer of NAD during the DNA damage response. In our simulations, we observe that increased PARP1 activity may be able to trigger SIRT1-induced circadian phase advancements by decreasing SIRT1 activity through competition for NAD supplies. We show how this competitive inhibition may operate through protein acetylation in conjunction with phosphorylation, consistent with reported observations. These findings suggest a possible mechanism through which multiple perturbations, each dominant during different points of the circadian cycle, may result in the phase advancement of the circadian clock seen during DNA damage.

Reproducibility in cytometry: Signals analysis and its connection to uncertainty quantification.

Signals analysis for cytometry remains a challenging task that has a significant impact on uncertainty. Conventional cytometers assume that individual measurements are well characterized by simple properties such as the signal area, width, and height. However, these approaches have difficulty distinguishing inherent biological variability from instrument artifacts and operating conditions. As a result, it is challenging to quantify uncertainty in the properties of individual cells and perform tasks such as doublet deconvolution. We address these problems via signals analysis techniques that use scale transformations to: (I) separate variation in biomarker expression from effects due to flow conditions and particle size; (II) quantify reproducibility associated with a given laser interrogation region; (III) estimate uncertainty in measurement values on a per-event basis; and (IV) extract the singlets that make up a multiplet. The key idea behind this approach is to model how variable operating conditions deform the signal shape and then use constrained optimization to "undo" these deformations for measured signals; residuals to this process characterize reproducibility. Using a recently developed microfluidic cytometer, we demonstrate that these techniques can account for instrument and measurand induced variability with a residual uncertainty of less than 2.5% in the signal shape and less than 1% in integrated area.

Predicted functions of MdmX in fine-tuning the response of p53 to DNA damage.

Tumor suppressor protein p53 is regulated by two structurally homologous proteins, Mdm2 and MdmX. In contrast to Mdm2, MdmX lacks ubiquitin ligase activity. Although the essential interactions of MdmX are known, it is not clear how they function to regulate p53. The regulation of tumor suppressor p53 by Mdm2 and MdmX in response to DNA damage was investigated by mathematical modeling of a simplified network. The simplified network model was derived from a detailed molecular interaction map (MIM) that exhibited four coherent DNA damage response pathways. The results suggest that MdmX may amplify or stabilize DNA damage-induced p53 responses via non-enzymatic interactions. Transient effects of MdmX are mediated by reservoirs of p53ratioMdmX and Mdm2ratioMdmX heterodimers, with MdmX buffering the concentrations of p53 and/or Mdm2. A survey of kinetic parameter space disclosed regions of switch-like behavior stemming from such reservoir-based transients. During an early response to DNA damage, MdmX positively or negatively regulated p53 activity, depending on the level of Mdm2; this led to amplification of p53 activity and switch-like response. During a late response to DNA damage, MdmX could dampen oscillations of p53 activity. A possible role of MdmX may be to dampen such oscillations that otherwise could produce erratic cell behavior. Our study suggests how MdmX may participate in the response of p53 to DNA damage either by increasing dependency of p53 on Mdm2 or by dampening oscillations of p53 activity and presents a model for experimental investigation.

Design of the DEMO Fusion Reactor Following ITER.

Runs of the NSTAB nonlinear stability code show there are many three-dimensional (3D) solutions of the advanced tokamak problem subject to axially symmetric boundary conditions. These numerical simulations based on mathematical equations in conservation form predict that the ITER international tokamak project will encounter persistent disruptions and edge localized mode (ELMS) crashes. Test particle runs of the TRAN transport code suggest that for quasineutrality to prevail in tokamaks a certain minimum level of 3D asymmetry of the magnetic spectrum is required which is comparable to that found in quasiaxially symmetric (QAS) stellarators. The computational theory suggests that a QAS stellarator with two field periods and proportions like those of ITER is a good candidate for a fusion reactor. For a demonstration reactor (DEMO) we seek an experiment that combines the best features of ITER, with a system of QAS coils providing external rotational transform, which is a measure of the poloidal field. We have discovered a configuration with unusually good quasisymmetry that is ideal for this task.

The contribution of lipid layer movement to tear film thinning and breakup.

PURPOSE: To investigate whether the tear film thinning between blinks is caused by evaporation or by tangential flow of the tear film along the surface of the cornea. Tangential flow was studied by measuring the movement of the lipid layer. METHODS: Four video recordings of the lipid layer of the tear film were made from 16 normal subjects, with the subjects keeping their eyes open for up to 30 seconds after a blink. To assess vertical and horizontal stretching of the lipid layer and underlying aqueous layer, lipid movement was analyzed at five positions, a middle position 1 mm below the corneal center, and four positions respectively 1 mm above, below, nasal, and temporal to this middle position. In addition, in 13 subjects, the thinning of the tear film after a blink was measured. RESULTS: The total upward movement could be fitted by the sum of an exponential decay plus a slow steady drift; this drift was upward in 14 of 16 subjects (P = 0.002). Areas of thick lipid were seen to expand causing upward or downward drift or horizontal movement. The velocity of the initial rapid upward movement and the time constant of upward movement were found to correlate significantly with tear film thickness but not with tear-thinning rate. CONCLUSIONS: Analysis indicated that the observed movement of the lipid layer was too slow to explain the observed thinning rate of the tear film. In the Appendix, it is shown that flow under a stationary lipid layer cannot explain the observed thinning rate. It is concluded that most of the observed tear thinning between blinks is due to evaporation.