Testing whether all eigenstates obey the Eigenstate Thermalization Hypothesis

We ask whether the Eigenstate Thermalization Hypothesis (ETH) is valid in a strong sense: in the limit of an infinite system, {\it every} eigenstate is thermal. We examine expectation values of few-body operators in highly-excited many-body eigenstates and search for `outliers', the eigenstates that deviate the most from ETH. We use exact diagonalization of two one-dimensional nonintegrable models: a quantum Ising chain with transverse and longitudinal fields, and hard-core bosons at half-filling with nearest- and next-nearest-neighbor hopping and interaction. We show that even the most extreme outliers appear to obey ETH as the system size increases, and thus provide numerical evidences that support ETH in this strong sense. Finally, periodically driving the Ising Hamiltonian, we show that the eigenstates of the corresponding Floquet operator obey ETH even more closely. We attribute this better thermalization to removing the constraint of conservation of the total energy.Comment: 9 pages, 6 figures. Updated references and clarified some argument

Diverse small molecule inhibitors of human apurinic/apyrimidinic endonuclease APE1 identified from a screen of a large public collection.

The major human apurinic/apyrimidinic endonuclease APE1 plays a pivotal role in the repair of base damage via participation in the DNA base excision repair (BER) pathway. Increased activity of APE1, often observed in tumor cells, is thought to contribute to resistance to various anticancer drugs, whereas down-regulation of APE1 sensitizes cells to DNA damaging agents. Thus, inhibiting APE1 repair endonuclease function in cancer cells is considered a promising strategy to overcome therapeutic agent resistance. Despite ongoing efforts, inhibitors of APE1 with adequate drug-like properties have yet to be discovered. Using a kinetic fluorescence assay, we conducted a fully-automated high-throughput screen (HTS) of the NIH Molecular Libraries Small Molecule Repository (MLSMR), as well as additional public collections, with each compound tested as a 7-concentration series in a 4 µL reaction volume. Actives identified from the screen were subjected to a panel of confirmatory and counterscreen tests. Several active molecules were identified that inhibited APE1 in two independent assay formats and exhibited potentiation of the genotoxic effect of methyl methanesulfonate with a concomitant increase in AP sites, a hallmark of intracellular APE1 inhibition; a number of these chemotypes could be good starting points for further medicinal chemistry optimization. To our knowledge, this represents the largest-scale HTS to identify inhibitors of APE1, and provides a key first step in the development of novel agents targeting BER for cancer treatment

Spatiotemporal variability in the O-18-salinity relationship of seawater across the tropical Pacific Ocean

The relationship between salinity and the stable oxygen isotope ratio of seawater (δ18Osw) is of utmost importance to the quantitative reconstruction of past changes in salinity from δ18O values of marine carbonates. This relationship is often considered to be uniform across water masses, but the constancy of the δ18Osw-salinity relationship across space and time remains uncertain, as δ18Osw responds to varying atmospheric vapor sources and pathways, while salinity does not. Here we present new δ18Osw-salinity data from sites spanning the tropical Pacific Ocean. New data from Palau, Papua New Guinea, Kiritimati, and Galápagos show slopes ranging from 0.09 ‰/psu in the Galápagos to 0.32‰/psu in Palau. The slope of the δ18Osw-salinity relationship is higher in the western tropical Pacific versus the eastern tropical Pacific in observations and in two isotope-enabled climate model simulations. A comparison of δ18Osw-salinity relationships derived from short-term spatial surveys and multiyear time series at Papua New Guinea and Galápagos suggests spatial relationships can be substituted for temporal relationships at these sites, at least within the time period of the investigation. However, the δ18Osw-salinity relationship varied temporally at Palau, likely in response to water mass changes associated with interannual El Niño–Southern Oscillation (ENSO) variability, suggesting nonstationarity in this local δ18Osw-salinity relationship. Applying local δ18Osw-salinity relationships in a coral δ18O forward model shows that using a constant, basinwide δ18Osw-salinity slope can both overestimate and underestimate the contribution of δ18Osw to carbonate δ18O variance at individual sites in the western tropical Pacific.We are grateful for the dedicated water samplers who enabled this research: Lori J. Bell and Gerda Ucharm of the Coral Reef Research Foundation, Palau; Rosa Maritza Motoche Gonzalez and the Fuerza Aerea Ecuatoriana, Santa Cruz, Galapagos, Ecuador; Taonateiti Kabiri and the students of Tennessee Primary School, London, Kiritimati; and the Manus Weather Observers, U.S. Department of Energy ARM Climate Research Facility, Manus, Papua New Guinea. We would like to thank the Galapagos National Park, the Kiritimati Ministry of Environment Lands and Agricultural Development for sample permits, and the Charles Darwin Research Station for logistical support. Funding sources for this work includes NSF-AGS-PF 1049664 to J.L.C., NSF P2C2-1203785 to K.M.C., J.L.C., and D.N. This research was also supported by the Office of Biological and Environment Research of the U.S. Department of Energy as part of the Atmospheric Radiation Measurement Climate Research Facility. Isotope data are available as supporting information associated with the manuscript. (1049664 - NSF-AGS-PF; P2C2-1203785 - NSF; Office of Biological and Environment Research of the U.S. Department of Energy as part of the Atmospheric Radiation Measurement Climate Research Facility

A Granger Causality Measure for Point Process Models of Ensemble Neural Spiking Activity

The ability to identify directional interactions that occur among multiple neurons in the brain is crucial to an understanding of how groups of neurons cooperate in order to generate specific brain functions. However, an optimal method of assessing these interactions has not been established. Granger causality has proven to be an effective method for the analysis of the directional interactions between multiple sets of continuous-valued data, but cannot be applied to neural spike train recordings due to their discrete nature. This paper proposes a point process framework that enables Granger causality to be applied to point process data such as neural spike trains. The proposed framework uses the point process likelihood function to relate a neuron’s spiking probability to possible covariates, such as its own spiking history and the concurrent activity of simultaneously recorded neurons. Granger causality is assessed based on the relative reduction of the point process likelihood of one neuron obtained excluding one of its covariates compared to the likelihood obtained using all of its covariates. The method was tested on simulated data, and then applied to neural activity recorded from the primary motor cortex (MI) of a Felis catus subject. The interactions present in the simulated data were predicted with a high degree of accuracy, and when applied to the real neural data, the proposed method identified causal relationships between many of the recorded neurons. This paper proposes a novel method that successfully applies Granger causality to point process data, and has the potential to provide unique physiological insights when applied to neural spike trains.National Institutes of Health (U.S.) (Grant DP1-OD003646)National Institutes of Health (U.S.) (Grant R01-EB006385

The pheromone-induced nuclear accumulation of the Fus3 MAPK in yeast depends on its phosphorylation state and on Dig1 and Dig2

BACKGROUND: Like mammalian MAP kinases, the mating-specific Fus3 MAPK of yeast accumulates in the nuclei of stimulated cells. Because Fus3 does not appear to be subjected to active nucleo-cytoplasmic transport, it is not clear how its activation by mating pheromone effects the observed change in its localization. One possibility is that the activation of Fus3 changes its affinity for nuclear and cytoplasmic tethers. RESULTS: Dig1, Dig2, and Ste12 are nuclear proteins that interact with Fus3. We found that the pheromone-induced nuclear accumulation of a Fus3-GFP reporter is reduced in cells lacking Dig1 or Dig2, whereas Fus3T180AY182A-GFP localization was unaffected by the absence of these proteins. This suggests that Dig1 and Dig2 contribute to the retention of phosphorylated Fus3 in the nucleus. Moreover, overexpression of Ste12 caused the hyper-accumulation of Fus3-GFP (but not Fus3T180AY182A-GFP) in the nuclei of pheromone-treated cells, suggesting that Ste12 also plays a role in the nuclear retention of phosphorylated Fus3, either by directly interacting with it or by transcribing genes whose protein products are Fus3 tethers. We have previously reported that overexpression of the Msg5 phosphatase inhibits the nuclear localization of Fus3. Here we show that this effect depends on the phosphatase activity of Msg5, and provide evidence that both nuclear and cytoplasmic Msg5 can affect the localization of Fus3. CONCLUSION: Our data are consistent with a model in which the pheromone-induced phosphorylation of Fus3 increases its affinity for nuclear tethers, which contributes to its nuclear accumulation and is antagonized by Msg5

The Forestecology R Package for Fitting and Assessing Neighborhood Models of the Effect of Interspecific Competition on the Growth of Trees

Neighborhood competition models are powerful tools to measure the effect of interspecific competition. Statistical methods to ease the application of these models are currently lacking. We present the forestecology package providing methods to (a) specify neighborhood competition models, (b) evaluate the effect of competitor species identity using permutation tests, and (cs) measure model performance using spatial cross-validation. Following Allen and Kim (PLoS One, 15, 2020, e0229930), we implement a Bayesian linear regression neighborhood competition model. We demonstrate the package\u27s functionality using data from the Smithsonian Conservation Biology Institute\u27s large forest dynamics plot, part of the ForestGEO global network of research sites. Given ForestGEO’s data collection protocols and data formatting standards, the package was designed with cross-site compatibility in mind. We highlight the importance of spatial cross-validation when interpreting model results. The package features (a) tidyverse-like structure whereby verb-named functions can be modularly “piped” in sequence, (b) functions with standardized inputs/outputs of simple features sf package class, and (c) an S3 object-oriented implementation of the Bayesian linear regression model. These three facts allow for clear articulation of all the steps in the sequence of analysis and easy wrangling and visualization of the geospatial data. Furthermore, while the package only has Bayesian linear regression implemented, the package was designed with extensibility to other methods in mind