Using nonequilibrium fluctuation theorems to understand and correct errors in equilibrium and nonequilibrium discrete Langevin dynamics simulations

Common algorithms for computationally simulating Langevin dynamics must discretize the stochastic differential equations of motion. These resulting finite time step integrators necessarily have several practical issues in common: Microscopic reversibility is violated, the sampled stationary distribution differs from the desired equilibrium distribution, and the work accumulated in nonequilibrium simulations is not directly usable in estimators based on nonequilibrium work theorems. Here, we show that even with a time-independent Hamiltonian, finite time step Langevin integrators can be thought of as a driven, nonequilibrium physical process. Once an appropriate work-like quantity is defined -- here called the shadow work -- recently developed nonequilibrium fluctuation theorems can be used to measure or correct for the errors introduced by the use of finite time steps. In particular, we demonstrate that amending estimators based on nonequilibrium work theorems to include this shadow work removes the time step dependent error from estimates of free energies. We also quantify, for the first time, the magnitude of deviations between the sampled stationary distribution and the desired equilibrium distribution for equilibrium Langevin simulations of solvated systems of varying size. While these deviations can be large, they can be eliminated altogether by Metropolization or greatly diminished by small reductions in the time step. Through this connection with driven processes, further developments in nonequilibrium fluctuation theorems can provide additional analytical tools for dealing with errors in finite time step integrators.Comment: 11 pages, 4 figure

Dry Soil - A Problem for 1956

We\u27re entering 1956 with a shortage of soil moisture in many parts of the state. Past weather is influencing our future. But armed with foreknowledge, you may want to consider possible crop and practice adjustments

Peeling Bifurcations of Toroidal Chaotic Attractors

Chaotic attractors with toroidal topology (van der Pol attractor) have counterparts with symmetry that exhibit unfamiliar phenomena. We investigate double covers of toroidal attractors, discuss changes in their morphology under correlated peeling bifurcations, describe their topological structures and the changes undergone as a symmetry axis crosses the original attractor, and indicate how the symbol name of a trajectory in the original lifts to one in the cover. Covering orbits are described using a powerful synthesis of kneading theory with refinements of the circle map. These methods are applied to a simple version of the van der Pol oscillator.Comment: 7 pages, 14 figures, accepted to Physical Review

Indications for liver transplantation in the cyclosporine era

One hundred seventy orthotopic liver transplants were performed under conventional immunosuppression with azathioprine and steroids with 1- and 5-year survivals of 32.9% and 20.0%, respectively. Since the introduction of cyclosporine-prednisone therapy in March 1980, 313 primary orthotopic liver transplants have been performed. Actuarial survivals at 1 and 5 years have improved to 69.7% and 62.8%, respectively. Biliary atresia is now the most common indication for liver replacement. In adults, primary biliary cirrhosis and sclerosing cholangitis have become more common indications for transplantation, and alcoholic cirrhosis and primary liver malignancy as indications have declined. Early enthusiasm for liver transplantation in patients with hepatic cancer has been tempered by the finding that recurrence is both common and rapid. An increasing number of patients with inborn errors of metabolism originating in the liver are receiving transplants, including patients with Wilson's disease, tyrosinemia, alpha-1-antitrypsin deficiency, glycogen storage disease, familial hypercholesterolemia, and hemochromatosis. Survival in this group of patients has been excellent (74.4% at 1 and 5 years). A hemophiliac who received a transplant for postnecrotic cirrhosis has survived and may have been cured of his hemophilia. About 20% of patients require retransplantation for rejection, technical failure, or primary graft failure. Only 4 of the patients receiving retransplants under conventional immunosuppression survived beyond 6 months, and all died within 14 months of retransplantation. Sixty-eight patients have received retransplants under cyclosporine-prednisone. Thirty-one patients are surviving, all for at least 1 year. Six of the 12 patients requiring a third transplant are alive 2 to 3 years after the primary operation. An aggressive approach to retransplantation in the patient with a failed graft is justified

Fundamental properties of the mammalian innate immune system revealed by multispecies comparison of type I interferon responses

The host innate immune response mediated by type I interferon (IFN) and the resulting up-regulation of hundreds of interferon-stimulated genes (ISGs) provide an immediate barrier to virus infection. Studies of the type I ‘interferome’ have mainly been carried out at a single species level, often lacking the power necessary to understand key evolutionary features of this pathway. Here, using a single experimental platform, we determined the properties of the interferomes of multiple vertebrate species and developed a webserver to mine the dataset. This approach revealed a conserved ‘core’ of 62 ISGs, including genes not previously associated with IFN, underscoring the ancestral functions associated with this antiviral host response. We show that gene expansion contributes to the evolution of the IFN system and that interferomes are shaped by lineage-specific pressures. Consequently, each mammal possesses a unique repertoire of ISGs, including genes common to all mammals and others unique to their specific species or phylogenetic lineages. An analysis of genes commonly down-regulated by IFN suggests that epigenetic regulation of transcription is a fundamental aspect of the IFN response. Our study provides a resource for the scientific community highlighting key paradigms of the type I IFN response

The Ursinus Weekly, February 10, 1964

Tickets still available for Four Freshmen • Lorelei dance February 14; Music by Lester Lanin • Dr. Allen, Ursinus prof, publishes book of poems • IS-IFC plans set for song festival • Dr. Helen T. Garrett to leave UC for Parisian sabbatical • Job interview schedule released • Weekly editors, staff hold tea for College faculty • Dr. R. Doane to speak at UC Circle meeting • Two students visit campus • Dr. Carleton Coon, anthropologist, to speak at UC Forum on Feb. 12 • Sorority rushing to begin Monday • Frats to begin Spring rush • Mr. J. Douglas Davis to conduct fourth annual European tour • Lincoln students to visit Ursinus • Students unite for Lodge • Dr. R. Fletcher, Ursinus faculty, named in D.I.B. • Our man in Sweden travels to Spain • New UC Bulletin has a new look • Fashion career fellowships available • Letters to the editor • Impending crisis in our American railroads • UC basketeers knocked from MAC top rung • Preview: Girls\u27 sports • Grapplers bow to Albright after pinning H\u27ford matmen • Alumna wins in squashhttps://digitalcommons.ursinus.edu/weekly/1263/thumbnail.jp

ALS-associated missense and nonsense TBK1 mutations can both cause loss of kinase function

Mutations in TANK binding kinase 1 (TBK1) have been linked to amyotrophic lateral sclerosis. Some TBK1 variants are nonsense and are predicted to cause disease through haploinsufficiency; however, many other mutations are missense with unknown functional effects. We exome sequenced 699 familial amyotrophic lateral sclerosis patients and identified 16 TBK1 novel or extremely rare protein-changing variants. We characterized a subset of these: p.G217R, p.R357X, and p.C471Y. Here, we show that the p.R357X and p.G217R both abolish the ability of TBK1 to phosphorylate 2 of its kinase targets, IRF3 and optineurin, and to undergo phosphorylation. They both inhibit binding to optineurin and the p.G217R, within the TBK1 kinase domain, reduces homodimerization, essential for TBK1 activation and function. Finally, we show that the proportion of TBK1 that is active (phosphorylated) is reduced in 5 lymphoblastoid cell lines derived from patients harboring heterozygous missense or in-frame deletion TBK1 mutations. We conclude that missense mutations in functional domains of TBK1 impair the binding and phosphorylation of its normal targets, implicating a common loss of function mechanism, analogous to truncation mutations

Indications for pediatric liver transplantation

Two hundred fifty pediatric (<18 years of age) patients underwent orthotopic liver transplantation because of end-stage liver disease and were given combination therapy with cyclosporine and prednisone. The most common indications for transplantation in decreasing order of frequency were biliary atresia, inborn errors of metabolism, and postnecrotic cirrhosis. The 5-year actuarial survival for the entire group was 69.2%. Age and diagnosis did not influence survival. Infections were the most common cause of death, followed by liver failure and cerebrovascular accident. The impact of retransplantation on survival depends on the indication. The survival is better when retransplantation is carried out after rejection than because of technical complications, and the latter has a better survival than does primary graft nonfunction. The difference in survival among these groups is statistically significant. The quality of life for 164 of 173 survivors is good to excellent; only nine children are currently experiencing medical problems. A persistent problem in pediatric transplantation is the scarcity of small donors. © 1987 The C. V. Mosby Company