Extending and validating bubble nucleation rate predictions in a Lennard-Jones fluid with enhanced sampling methods and transition state theory.

We calculate bubble nucleation rates in a Lennard-Jones fluid through explicit molecular dynamics simulations. Our approach-based on a recent free energy method (dubbed reweighted Jarzynski sampling), transition state theory, and a simple recrossing correction-allows us to probe a fairly wide range of rates in several superheated and cavitation regimes in a consistent manner. Rate predictions from this approach bridge disparate independent literature studies on the same model system. As such, we find that rate predictions based on classical nucleation theory, direct brute force molecular dynamics simulations, and seeding are consistent with our approach and one another. Published rates derived from forward flux sampling simulations are, however, found to be outliers. This study serves two purposes: First, we validate the reliability of common modeling techniques and extrapolation approaches on a paradigmatic problem in materials science and chemical physics. Second, we further test our highly generic recipe for rate calculations, and establish its applicability to nucleation processes.

Nucleation rates from small scale atomistic simulations and transition state theory.

The evaluation of nucleation rates from molecular dynamics trajectories is hampered by the slow nucleation time scale and impact of finite size effects. Here, we show that accurate nucleation rates can be obtained in a very general fashion relying only on the free energy barrier, transition state theory, and a simple dynamical correction for diffusive recrossing. In this setup, the time scale problem is overcome by using enhanced sampling methods, in casu metadynamics, whereas the impact of finite size effects can be naturally circumvented by reconstructing the free energy surface from an appropriate ensemble. Approximations from classical nucleation theory are avoided. We demonstrate the accuracy of the approach by calculating macroscopic rates of droplet nucleation from argon vapor, spanning 16 orders of magnitude and in excellent agreement with literature results, all from simulations of very small (512 atom) systems.

Reweighted Jarzynski Sampling: Acceleration of Rare Events and Free Energy Calculation with a Bias Potential Learned from Nonequilibrium Work.

We introduce a simple enhanced sampling approach for the calculation of free energy differences and barriers along a one-dimensional reaction coordinate. First, a small number of short nonequilibrium simulations are carried out along the reaction coordinate, and the Jarzynski equality is used to learn an approximate free energy surface from the nonequilibrium work distribution. This free energy estimate is represented in a compact form as an artificial neural network and used as an external bias potential to accelerate rare events in a subsequent molecular dynamics simulation. The final free energy estimate is then obtained by reweighting the equilibrium probability distribution of the reaction coordinate sampled under the influence of the external bias. We apply our reweighted Jarzynski sampling recipe to four processes of varying scales and complexities─spanning chemical reaction in the gas phase, pair association in solution, and droplet nucleation in supersaturated vapor. In all cases, we find reweighted Jarzynski sampling to be a very efficient strategy, resulting in rapid convergence of the free energy to high precision.

Significant Growth by Rickettsia Species within Human Macrophage-Like Cells Is a Phenotype Correlated with the Ability to Cause Disease in Mammals.

Rickettsia are significant sources of tick-borne diseases in humans worldwide. In North America, two species in the spotted fever group of Rickettsia have been conclusively associated with disease of humans: Rickettsia rickettsii, the causative agent of Rocky Mountain spotted fever, and Rickettsia parkeri, the cause of R. parkeri rickettsiosis. Previous work in our lab demonstrated non-endothelial parasitism by another pathogenic SFG Rickettsia species, Rickettsia conorii, within THP-1-derived macrophages, and we have hypothesized that this growth characteristic may be an underappreciated aspect of rickettsial pathogenesis in mammalian hosts. In this work, we demonstrated that multiple other recognized human pathogenic species of Rickettsia, including R. rickettsii, R. parkeri, Rickettsia africae, and Rickettsiaakari can grow within target endothelial cells as well as within PMA-differentiated THP-1 cells. In contrast, Rickettsia bellii, a Rickettsia species not associated with disease of humans, and R. rickettsii strain Iowa, an avirulent derivative of pathogenic R. rickettsii, could invade both cell types but proliferate only within endothelial cells. Further analysis revealed that similar to previous studies on R. conorii, other recognized pathogenic Rickettsia species could grow within the cytosol of THP-1-derived macrophages and avoided localization with two different markers of lysosomal compartments; LAMP-2 and cathepsin D. R. bellii, on the other hand, demonstrated significant co-localization with lysosomal compartments. Collectively, these findings suggest that the ability of pathogenic rickettsial species to establish a niche within macrophage-like cells could be an important factor in their ability to cause disease in mammals. These findings also suggest that analysis of growth within mammalian phagocytic cells may be useful to predict the pathogenic potential of newly isolated and identified Rickettsia species.

Reaction mechanisms of C(3PJ) and C+(2PJ) with benzene in the interstellar medium from quantum mechanical molecular dynamics simulations.

While spectroscopic data on small hydrocarbons in interstellar media in combination with crossed molecular beam (CMB) experiments have provided a wealth of information on astrochemically relevant species, much of the underlying mechanistic pathways of their formation remain elusive. Therefore, in this work, the chemical reaction mechanisms of C(3PJ) + C6H6 and C+(2P) + C6H6 systems using the quantum mechanical molecular dynamics (QMMD) technique at the PBE0-D3(BJ) level of theory is investigated, mimicking a CMB experiment. Both the dynamics of the reactions as well as the electronic structure for the purpose of the reaction network are evaluated. The method is validated for the first reaction by comparison to the available experimental data. The reaction scheme for the C(3PJ) + C6H6 system covers the literature data, e.g. the major products are the 1,2-didehydrocycloheptatrienyl radical (C7H5) and benzocyclopropenyl radical (C6H5-CH), and it reveals the existence of less common pathways for the first time. The chemistry of the C+(2PJ) + C6H6 system is found to be much richer, and we have found that this is because of more exothermic reactions in this system in comparison to those in the C(3PJ) + C6H6 system. Moreover, using the QMMD simulation, a number of reaction paths have been revealed that produce three distinct classes of reaction products with different ring sizes. All in all, at all the collision energies and orientations, the major product is the heptagon molecular ion for the ionic system. It is also revealed that the collision orientation has a dominant effect on the reaction products in both systems, while the collision energy mostly affects the charged system. These simulations both prove the applicability of this approach to simulate crossed molecular beams, and provide fundamental information on reactions relevant for the interstellar medium.

The continuum of carbon-hydrogen (C-H) activation mechanisms and terminology.

As a rapidly growing field across all areas of chemistry, C-H activation/functionalisation is being used to access a wide range of important molecular targets. Of particular interest is the development of a sustainable methodology for alkane functionalisation as a means for reducing hydrocarbon emissions. This Perspective aims to give an outline to the community with respect to commonly used terminology in C-H activation, as well as the mechanisms that are currently understood to operate for (cyclo)alkane activation/functionalisation.

Free energy barriers from biased molecular dynamics simulations.

Atomistic simulation methods for the quantification of free energies are in wide use. These methods operate by sampling the probability density of a system along a small set of suitable collective variables (CVs), which is, in turn, expressed in the form of a free energy surface (FES). This definition of the FES can capture the relative stability of metastable states but not that of the transition state because the barrier height is not invariant to the choice of CVs. Free energy barriers therefore cannot be consistently computed from the FES. Here, we present a simple approach to calculate the gauge correction necessary to eliminate this inconsistency. Using our procedure, the standard FES as well as its gauge-corrected counterpart can be obtained by reweighing the same simulated trajectory at little additional cost. We apply the method to a number of systems-a particle solvated in a Lennard-Jones fluid, a Diels-Alder reaction, and crystallization of liquid sodium-to demonstrate its ability to produce consistent free energy barriers that correctly capture the kinetics of chemical or physical transformations, and discuss the additional demands it puts on the chosen CVs. Because the FES can be converged at relatively short (sub-ns) time scales, a free energy-based description of reaction kinetics is a particularly attractive option to study chemical processes at more expensive quantum mechanical levels of theory.

Ensemble-Based Molecular Simulation of Chemical Reactions under Vibrational Nonequilibrium.

We present an approach to incorporate the effect of vibrational nonequilibrium in molecular dynamics (MD) simulations. A perturbed canonical ensemble, in which selected modes are excited to higher temperature while all others remain equilibrated at low temperature, is simulated by applying a specifically tailored bias potential. Our method can be readily applied to any (classical or quantum mechanical) MD setup at virtually no additional computational cost and allows the study of reactions of vibrationally excited molecules in nonequilibrium environments such as plasmas. In combination with enhanced sampling methods, the vibrational efficacy and mode selectivity of vibrationally stimulated reactions can then be quantified in terms of chemically relevant observables, such as reaction rates and apparent free energy barriers. We first validate our method for the prototypical hydrogen exchange reaction and then show how it can capture the effect of vibrational excitation on a symmetric SN2 reaction and radical addition on CO2.

Modelling molecular adsorption on charged or polarized surfaces: a critical flaw in common approaches.

A number of recent computational material design studies based on density functional theory (DFT) calculations have put forward a new class of materials with electrically switchable chemical characteristics that can be exploited in the development of tunable gas storage and electrocatalytic applications. We find systematic flaws in almost every computational study of gas adsorption on polarized or charged surfaces, stemming from an improper and unreproducible treatment of periodicity, leading to very large errors of up to 3 eV in some cases. Two simple corrective procedures that lead to consistent results are proposed, constituting a crucial course correction to the research in the field.

Magnetic switching of nanoscale antidot lattices.

We investigate the rich magnetic switching properties of nanoscale antidot lattices in the 200 nm regime. In-plane magnetized Fe, Co, and Permalloy (Py) as well as out-of-plane magnetized GdFe antidot films are prepared by a modified nanosphere lithography allowing for non-close packed voids in a magnetic film. We present a magnetometry protocol based on magneto-optical Kerr microscopy elucidating the switching modes using first-order reversal curves. The combination of various magnetometry and magnetic microscopy techniques as well as micromagnetic simulations delivers a thorough understanding of the switching modes. While part of the investigations has been published before, we summarize these results and add significant new insights in the magnetism of exchange-coupled antidot lattices.

Direct observation of realistic-temperature fuel combustion mechanisms in atomistic simulations.

Atomistic simulations can in principle provide an unbiased description of all mechanisms, intermediates, and products of complex chemical processes. However, due to the severe time scale limitation of conventional simulation techniques, unrealistically high simulation temperatures are usually applied, which are a poor approximation of most practically relevant low-temperature applications. In this work, we demonstrate the direct observation at the atomic scale of the pyrolysis and oxidation of n-dodecane at temperatures as low as 700 K through the use of a novel simulation technique, collective variable-driven hyperdynamics (CVHD). A simulated timescale of up to 39 seconds is reached. Product compositions and dominant mechanisms are found to be strongly temperature-dependent, and are consistent with experiments and kinetic models. These simulations provide a first atomic-level look at the full dynamics of the complicated fuel combustion process at industrially relevant temperatures and time scales, unattainable by conventional molecular dynamics simulations.

Merging metadynamics into hyperdynamics: accelerated molecular simulations reaching time scales from microseconds to seconds.

The hyperdynamics method is a powerful tool to simulate slow processes at the atomic level. However, the construction of an optimal hyperdynamics potential is a task that is far from trivial. Here, we propose a generally applicable implementation of the hyperdynamics algorithm, borrowing two concepts from metadynamics. First, the use of a collective variable (CV) to represent the accelerated dynamics gives the method a very large flexibility and simplicity. Second, a metadynamics procedure can be used to construct a suitable history-dependent bias potential on-the-fly, effectively turning the algorithm into a self-learning accelerated molecular dynamics method. This collective variable-driven hyperdynamics (CVHD) method has a modular design: both the local system properties on which the bias is based, as well as the characteristics of the biasing method itself, can be chosen to match the needs of the considered system. As a result, system-specific details are abstracted from the biasing algorithm itself, making it extremely versatile and transparent. The method is tested on three model systems: diffusion on the Cu(001) surface and nickel-catalyzed methane decomposition, as examples of "reactive" processes with a bond-length-based CV, and the folding of a long polymer-like chain, using a set of dihedral angles as a CV. Boost factors up to 109, corresponding to a time scale of seconds, could be obtained while still accurately reproducing correct dynamics.

On the time scale associated with Monte Carlo simulations.

Uniform-acceptance force-bias Monte Carlo (fbMC) methods have been shown to be a powerful technique to access longer timescales in atomistic simulations allowing, for example, phase transitions and growth. Recently, a new fbMC method, the time-stamped force-bias Monte Carlo (tfMC) method, was derived with inclusion of an estimated effective timescale; this timescale, however, does not seem able to explain some of the successes the method. In this contribution, we therefore explicitly quantify the effective timescale tfMC is able to access for a variety of systems, namely a simple single-particle, one-dimensional model system, the Lennard-Jones liquid, an adatom on the Cu(100) surface, a silicon crystal with point defects and a highly defected graphene sheet, in order to gain new insights into the mechanisms by which tfMC operates. It is found that considerable boosts, up to three orders of magnitude compared to molecular dynamics, can be achieved for solid state systems by lowering of the apparent activation barrier of occurring processes, while not requiring any system-specific input or modifications of the method. We furthermore address the pitfalls of using the method as a replacement or complement of molecular dynamics simulations, its ability to explicitly describe correct dynamics and reaction mechanisms, and the association of timescales to MC simulations in general.

Meeting enrollees' needs: how do Medicare and employer coverage stack up?

One key issue in health reform concerns the relative roles of coverage offered through private insurance and public programs. This paper compares the experiences of aged Medicare beneficiaries with those of people under age sixty-five who have private employer coverage. Compared with the employer-coverage group, people in the Medicare group report fewer problems obtaining medical care, less financial hardship due to medical bills, and higher overall satisfaction with their coverage. Although access and bill payment problems increased across the board from 2001 to 2007, the gap between Medicare and private employer coverage widened.

Confronting cisternae in canine testicular seminoma: special reference to appearance rate.

A number of confronting cisternae (CC) were found in canine testicular seminomas (SEM). The CC consisted of two or three closely attached cisternae separated by an electron-dense layer, but occasionally four or more cisternae were stacked in a similar fashion. They showed a short, straight, and direct continuity with the rER or the nuclear envelope. They were found in SEM cells of both interphase and mitotic stages. We statistically examined 18 cases of canine SEM concerning the CC appearance rate in interphase cells (CCARI) and in mitotic cells (CCARM), and the tumor mitotic index (TMI). The SEM were classified into three groups (intratubular SEM without invasion, intratubular SEM with invasion, and diffuse type SEM) using Nielsen and Lein's classification (1974). The CCARI and TMI of the diffuse type SEM were significantly higher than those of the intratubular SEM with invasion, and those of the latter group were significantly higher than those of the intratubular SEM without invasion. On the other hand, the CCARM were similar between these three groups, and this parameter showed a non-significant correlation with the TMI. The present study suggests that the increase in the number of CC in interphase canine SEM cells might be correlated with the tumor progression.

Treatable abdominal pathologic conditions and unsuspected malignant neoplasms at autopsy in veterans who received mechanical ventilation.

STUDY OBJECTIVE: To determine, in medical patients who received mechanical ventilation, the frequency and types of major unexpected diagnoses at autopsy that, if known before death, would probably have led to improved survival (class I errors) or substantively changed management but not survival (class IIB errors). DESIGN: Retrospective cohort study. SETTING: Six medical intensive care units in a Department of Veterans Affairs Cooperative Study. PATIENTS: One hundred seventy-two autopsied patients of the 401 veterans who received mechanical ventilation and died in the hospital. RESULTS: The class I error rate was 12%. Abdominal pathologic conditions--abscesses, bowel perforations, or infarction--were as frequent as pulmonary emboli as a cause of class I errors. While patients with abdominal pathologic conditions generally complained of abdominal pain, results of examination of the abdomen were considered unremarkable in most patients, and the symptom was not pursued. Six percent of patients had extensive malignant neoplasms (class IIB errors). CONCLUSIONS: Atypical presentation of potentially treatable abdominal pathologic conditions is a common cause of class I errors in veterans who receive mechanical ventilation. Conversely, several patients with unrecognized terminal conditions underwent intensive intervention. If the information gained at autopsy had been known before death, management would have probably changed substantively in 18% of patients.

[Prognosis in epilepsy and tactics in terminating antiepileptic therapy]. / Prognóza epilepsie a taktika ukoncení antiepileptické lécby.

Views on the termination of long-term antiepileptic treatment differ. The submitted paper emphasizes the importance of a correctly established prognosis for assessment of a suitable time for the termination of therapy. The correct prognosis can be established on the basis of the mutual ratio of favourable and unfavourable prognostic factors in the course of every individual case of the disease. The aim of the work made in a group of 105 patients with epilepsy was to assess the prognostic values of 31 factors which play an important role in the course of the disease. The author found statistically significant differences in the incidence of some factors in patient groups with a favourable and adverse course of the disease. In the conclusion the author describes the tactics of terminating antiepileptic treatment based on the assessed prognostic factors.