Coarse graining molecular dynamics with graph neural networks

Coarse graining enables the investigation of molecular dynamics for larger systems and at longer timescales than is possible at an atomic resolution. However, a coarse graining model must be formulated such that the conclusions we draw from it are consistent with the conclusions we would draw from a model at a finer level of detail. It has been proved that a force matching scheme defines a thermodynamically consistent coarse-grained model for an atomistic system in the variational limit. Wang et al. [ACS Cent. Sci. 5, 755 (2019)] demonstrated that the existence of such a variational limit enables the use of a supervised machine learning framework to generate a coarse-grained force field, which can then be used for simulation in the coarse-grained space. Their framework, however, requires the manual input of molecular features to machine learn the force field. In the present contribution, we build upon the advance of Wang et al. and introduce a hybrid architecture for the machine learning of coarse-grained force fields that learn their own features via a subnetwork that leverages continuous filter convolutions on a graph neural network architecture. We demonstrate that this framework succeeds at reproducing the thermodynamics for small biomolecular systems. Since the learned molecular representations are inherently transferable, the architecture presented here sets the stage for the development of machine-learned, coarse-grained force fields that are transferable across molecular systems

Gene-rich UV sex chromosomes harbor conserved regulators of sexual development

Centro de Investigación Forestal (CIFOR)Nonrecombining sex chromosomes, like the mammalian Y, often lose genes and accumulate transposable ele ments, a process termed degeneration. The correlation between suppressed recombination and degeneration is clear in animal XY systems, but the absence of recombination is confounded with other asymmetries between the X and Y. In contrast, UV sex chromosomes, like those found in bryophytes, experience symmetrical population genetic conditions. Here, we generate nearly gapless female and male chromosome-scale reference genomes of the moss Ceratodon purpureus to test for degeneration in the bryophyte UV sex chromosomes. We show that the moss sex chromosomes evolved over 300 million years ago and expanded via two chromosomal fusions. Although the sex chromosomes exhibit weaker purifying selection than autosomes, we find that suppressed recombination alone is insufficient to drive degeneration. Instead, the U and V sex chromosomes harbor thousands of broadly expressed genes, including numerous key regulators of sexual development across land plants.This work was supported by NSF DEB-1541005 and 1542609 and start-up funds from UF to S.F.M.; microMORPH Cross-Disciplinary Training Grant, Sigma-Xi Grant-In-Aid of Research, and Society for the Study of Evolution Rosemary Grant Award to S.B.C.; NSF DEB-1239992 to N.J.W.; the Emil Aaltonen Foundation and the University of Turku to S.O.; and NSF DEB-1541506 to J.G.B. and S.F.M. The work conducted by the U.S. Department of Energy Joint Genome Institute was supported by the Office of Science of the U.S. Department of Energy under contract no. DE-AC02-05CH11231.Peer reviewed12 Pág. Supplementary material for this article is available at http://advances.sciencemag.org/cgi/ content/full/7/27/eabh2488/DC

Primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is an immune-mediated chronic cholestatic liver disease with a slowly progressive course. Without treatment, most patients eventually develop fibrosis and cirrhosis of the liver and may need liver transplantation in the late stage of disease. PBC primarily affects women (female preponderance 9–10:1) with a prevalence of up to 1 in 1,000 women over 40 years of age. Common symptoms of the disease are fatigue and pruritus, but most patients are asymptomatic at first presentation. The diagnosis is based on sustained elevation of serum markers of cholestasis, i.e., alkaline phosphatase and gamma-glutamyl transferase, and the presence of serum antimitochondrial antibodies directed against the E2 subunit of the pyruvate dehydrogenase complex. Histologically, PBC is characterized by florid bile duct lesions with damage to biliary epithelial cells, an often dense portal inflammatory infiltrate and progressive loss of small intrahepatic bile ducts. Although the insight into pathogenetic aspects of PBC has grown enormously during the recent decade and numerous genetic, environmental, and infectious factors have been disclosed which may contribute to the development of PBC, the precise pathogenesis remains enigmatic. Ursodeoxycholic acid (UDCA) is currently the only FDA-approved medical treatment for PBC. When administered at adequate doses of 13–15 mg/kg/day, up to two out of three patients with PBC may have a normal life expectancy without additional therapeutic measures. The mode of action of UDCA is still under discussion, but stimulation of impaired hepatocellular and cholangiocellular secretion, detoxification of bile, and antiapoptotic effects may represent key mechanisms. One out of three patients does not adequately respond to UDCA therapy and may need additional medical therapy and/or liver transplantation. This review summarizes current knowledge on the clinical, diagnostic, pathogenetic, and therapeutic aspects of PBC

INFLUENCING FACTORS ON TRAIN PUNCTUALITY: RESULTS FROM SOME NORWEGIAN STUDIES

A key performance indicator for the railroad industry is train punctuality. This paper discusses the concept of train punctuality, influencing factors and strategies for improving punctuality. An overview of important elements to consider in the preparation of train punctuality improvements is considered, supported by empirical results from studies in Norway. A high capacity utilization is widely assumed to reduce punctuality. However, the studies from the Oslo area show that capacity utilization alone cannot explain all variations in punctuality during the day. The number of passengers in the trains can also be an additional explanation factor. This study and previous research imply that the key success factor for punctuality on local and regional trains in congested areas in the management of boarding and alighting passengers. However, on single track lines, such as long distance lines and regional lines in non-congested areas, the key success factor seems to lie in the management of train crossings. Precision versus slack strategies are also considered as a means of improving punctuality

Markov field models: Scaling molecular kinetics approaches to large molecular machines

With recent advances in structural biology, including experi-mental techniques and deep learning-enabled high-precision structure predictions, molecular dynamics methods that scale up to large biomolecular systems are required. Current state-of-the-art approaches in molecular dynamics modeling focus on encoding global configurations of molecular systems as distinct states. This paradigm commands us to map out all possible structures and sample transitions between them, a task that becomes impossible for large-scale systems such as biomolecular complexes. To arrive at scalable molecular models, we suggest moving away from global state de-scriptions to a set of coupled models that each describe the dynamics of local domains or sites of the molecular system. We describe limitations in the current state-of-the-art global -state Markovian modeling approaches and then introduce Markov field models as an umbrella term that includes models from various scientific communities, including Independent Markov decomposition, Ising and Potts models, and (dynamic) graphical models, and evaluate their use for computational molecular biology. Finally, we give a few examples of early adoptions of these ideas for modeling molecular kinetics and thermodynamics

Impact of spontaneous emission noise of optical amplifiers on the channel capacity of coherent SCM systems

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Discovery of a hidden transient state in all bromodomain families

Bromodomains (BDs) are small protein modules that interact with acetylated marks in histones. These posttranslational modifications are pivotal to regulate gene expression, making BDs promising targets to treat several diseases. While the general structure of BDs is well known, their dynamical features and their interplay with other macromolecules are poorly understood, hampering the rational design of potent and selective inhibitors. Here, we combine extensive molecular dynamics simulations, Markov state modeling, and available structural data to reveal a transiently formed state that is conserved across all BD families. It involves the breaking of two backbone hydrogen bonds that anchor the ZA-loop with the alpha(A) helix, opening a cryptic pocket that partially occludes the one associated to histone binding. By analyzing more than 1,900 experimental structures, we unveil just two adopting the hidden state, explaining why it has been previously unnoticed and providing direct structural evidence for its existence. Our results suggest that this state is an allosteric regulatory switch for BDs, potentially related to a recently unveiled BD-DNA-binding mode