Prospective evaluation of multiplicative hybrid earthquake forecasting models in California

The Regional Earthquake Likelihood Models (RELM) experiment, conducted within the Collaboratory for the Study of Earthquake Predictability (CSEP), showed that the smoothed seismicity (HKJ) model by Helmstetter et al. was the most informative time-independent earthquake model in California during the 2006–2010 evaluation period. The diversity of competing forecast hypotheses and geophysical data sets used in RELM was suitable for combining multiple models that could provide more informative earthquake forecasts than HKJ. Thus, Rhoades et al. created multiplicative hybrid models that involve the HKJ model as a baseline and one or more conjugate models. In retrospective evaluations, some hybrid models showed significant information gains over the HKJ forecast. Here, we prospectively assess the predictive skills of 16 hybrids and 6 original RELM forecasts at a 0.05 significance level, using a suite of traditional and new CSEP tests that rely on a Poisson and a binary likelihood function. In addition, we include consistency test results at a Bonferroni-adjusted significance level of 0.025 to address the problem of multiple tests. Furthermore, we compare the performance of each forecast to that of HKJ. The evaluation data set contains 40 target events recorded within the CSEP California testing region from 2011 January 1 to 2020 December 31, including the 2016 Hawthorne earthquake swarm in southwestern Nevada and the 2019 Ridgecrest sequence. Consistency test results show that most forecasting models overestimate the number of earthquakes and struggle to explain the spatial distribution of epicenters, especially in the case of seismicity clusters. The binary likelihood function significantly reduces the sensitivity of spatial log-likelihood scores to clustering, however; most models still fail to adequately describe spatial earthquake patterns. Contrary to retrospective analyses, our prospective test results show that none of the models are significantly more informative than the HKJ benchmark forecast, which we interpret to be due to temporal instabilities in the fit that forms hybrids. These results suggest that smoothing high-resolution, small earthquake data remains a robust method for forecasting moderate-to-large earthquakes over a period of 5–15 yr in California.This project has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement no. 821115, Real-time earthquake rIsk reduction for a reSilient Europe (RISE), http://www.rise-eu.org). Additionally, this research was supported by the Southern California Earthquake Center (contribution no. 11011). SCEC is funded by NSF Cooperative agreement EAR-1600087 and USGS Cooperative agreement G17AC00047

Mycobacterial trehalose dimycolate reprograms macrophage global gene expression and activates matrix metalloproteinases.

Trehalose 6,6′-dimycolate (TDM) is a cell wall glycolipid and an important virulence factor of mycobacteria. In order to study the role of TDM in the innate immune response to Mycobacterium tuberculosis, microarray analysis was used to examine gene regulation in murine bone marrow-derived macrophages in response to 90-μm-diameter polystyrene microspheres coated with TDM. A large number of genes, particularly those involved in the immune response and macrophage function, were up- or downregulated in response to these TDM-coated beads compared to control beads. Genes involved in the immune response were specifically upregulated in a myeloid differentiation primary response gene 88 (MyD88)-dependent manner. The complexity of the transcriptional response also increased greatly between 2 and 24 h. Matrix metalloproteinases (MMPs) were significantly upregulated at both time points, and this was confirmed by quantitative real-time reverse transcription-PCR (RT-PCR). Using an in vivo Matrigel granuloma model, the presence and activity of MMP-9 were examined by immunohistochemistry and in situ zymography (ISZ), respectively. We found that TDM-coated beads induced MMP-9 expression and activity in Matrigel granulomas. Macrophages were primarily responsible for MMP-9 expression, as granulomas from neutrophil-depleted mice showed staining patterns similar to that for wild-type mice. The relevance of these observations to human disease is supported by the similar induction of MMP-9 in human caseous tuberculosis (TB) granulomas. Given that MMPs likely play an important role in both the construction and breakdown of tuberculous granulomas, our results suggest that TDM may drive MMP expression during TB pathogenesis

Mammalian microRNAs predominantly act to decrease target mRNA levels

MicroRNAs (miRNAs) are endogenous ~22-nucleotide RNAs that mediate important gene-regulatory events by pairing to the mRNAs of protein-coding genes to direct their repression. Repression of these regulatory targets leads to decreased translational efficiency and/or decreased mRNA levels, but the relative contributions of these two outcomes have been largely unknown, particularly for endogenous targets expressed at low-to-moderate levels. Here, we use ribosome profiling to measure the overall effects on protein production and compare these to simultaneously measured effects on mRNA levels. For both ectopic and endogenous miRNA regulatory interactions, lowered mRNA levels account for most (≥84%) of the decreased protein production. These results show that changes in mRNA levels closely reflect the impact of miRNAs on gene expression and indicate that destabilization of target mRNAs is the predominant reason for reduced protein output.National Institutes of Health (U.S.

Pseudo-prospective Evaluation of UCERF3-ETAS Forecasts During the 2019 Ridgecrest Sequence

The 2019 Ridgecrest sequence provides the first opportunity to evaluate Uniform California Earthquake Rupture Forecast v.3 with epidemic‐type aftershock sequences (UCERF3‐ETAS) in a pseudoprospective sense. For comparison, we include a version of the model without explicit faults more closely mimicking traditional ETAS models (UCERF3‐NoFaults). We evaluate the forecasts with new metrics developed within the Collaboratory for the Study of Earthquake Predictability (CSEP). The metrics consider synthetic catalogs simulated by the models rather than synoptic probability maps, thereby relaxing the Poisson assumption of previous CSEP tests. Our approach compares statistics from the synthetic catalogs directly against observations, providing a flexible approach that can account for dependencies and uncertainties encoded in the models. We find that, to the first order, both UCERF3‐ETAS and UCERF3‐NoFaults approximately capture the spatiotemporal evolution of the Ridgecrest sequence, adding to the growing body of evidence that ETAS models can be informative forecasting tools. However, we also find that both models mildly overpredict the seismicity rate, on average, aggregated over the evaluation period. More severe testing indicates the overpredictions occur too often for observations to be statistically indistinguishable from the model. Magnitude tests indicate that the models do not include enough variability in forecasted magnitude‐number distributions to match the data. Spatial tests highlight discrepancies between the forecasts and observations, but the greatest differences between the two models appear when aftershocks occur on modeled UCERF3‐ETAS faults. Therefore, any predictability associated with embedding earthquake triggering on the (modeled) fault network may only crystalize during the presumably rare sequences with aftershocks on these faults. Accounting for uncertainty in the model parameters could improve test results during future experiments.Maximilian J. Werner and Warner Marzocchi received funding from the European Union's Horizon 2020 research and innovation program (Number 821115, RISE: Real‐Time Earthquake Risk Reduction for a Resilient Europe). This research was supported by the Southern California Earthquake Center (SCEC; Contribution Number 10082). SCEC is funded by National Science Foundation (NSF) Cooperative Agreement EAR‐1600087 and the U.S. Geological Survey (USGS) Cooperative Agreement G17AC00047

Depressive symptom trajectories among girls in the juvenile justice system: 24-month outcomes of an RCT of Multidimensional Treatment Foster Care

Youth depression is a significant and growing international public health problem. Youth who engage in high levels of delinquency are at particularly high risk for developing problems with depression. The present study examined the impact of a behavioral intervention designed to reduce delinquency (Multidimensional Treatment Foster Care; MTFC) compared to a group care intervention (GC; i.e., services as usual) on trajectories of depressive symptoms among adolescent girls in the juvenile justice system. MTFC has documented effects on preventing girls' recidivism, but its effects on preventing the normative rise in girls' depressive symptoms across adolescence have not been examined. This indicated prevention sample included 166 girls (13-17 years at T1) who had at least one criminal referral in the past 12 months and who were mandated to out-of-home care; girls were randomized to MTFC or GC. Intent-to-treat analyses examined the main effects of MTFC on depression symptoms and clinical cut-offs, and whether benefits were greatest for girls most at risk. Depressive symptom trajectories were specified in hierarchical linear growth models over a 2 year period using five waves of data at 6 month intervals. Depression clinical cut-off scores were specified as nonlinear probability growth models. Results showed significantly greater rates of deceleration for girls in MTFC versus GC for depressive symptoms and for clinical cut-off scores. The MTFC intervention also showed greater benefits for girls with higher levels of initial depressive symptoms. Possible mechanisms of effect are discussed, given MTFC's effectiveness on targeted and nontargeted outcomes. © 2013 Society for Prevention Research

Nuclear localised more sulphur accumulation1 epigenetically regulates sulphur homeostasis in Arabidopsis thaliana

Sulphur (S) is an essential element for all living organisms. The uptake, assimilation and metabolism of S in plants are well studied. However, the regulation of S homeostasis remains largely unknown. Here, we report on the identification and characterisation of the more sulphur accumulation1 (msa1-1) mutant. The MSA1 protein is localized to the nucleus and is required for both S adenosylmethionine (SAM) production and DNA methylation. Loss of function of the nuclear localised MSA1 leads to a reduction in SAM in roots and a strong S-deficiency response even at ample S supply, causing an over- accumulation of sulphate, sulphite, cysteine and glutathione. Supplementation with SAM suppresses this high S phenotype. Furthermore, mutation of MSA1 affects genome-wide DNA methylation, including the methylation of S-deficiency responsive genes. Elevated S accumulation in msa1-1 requires the increased expression of the sulphate transporter genes SULTR1;1 and SULTR1;2 which are also differentially methylated in msa1-1. Our results suggest a novel function for MSA1 in the nucleus in regulating SAM biosynthesis and maintaining S homeostasis epigenetically via DNA methylation

Assessing managerial power theory: A meta-analytic approach to understanding the determinants of CEO compensation

Although studies about the determinants of CEO compensation are ubiquitous, the balance of evidence for one of the more controversial theoretical approaches, managerial power theory, remains inconclusive. The authors provide a meta-analysis of 219 U.S.-based studies, focusing on the relationships between indicators of managerial power and levels of CEO compensation and CEO pay-performance sensitivities. The results indicate that managerial power theory is well equipped for predicting core compensation variables such as total cash and total compensation but less so for predicting the sensitivity of pay to performance. In most situations where CEOs are expected to have power over the pay setting process, they receive significantly higher levels of total cash and total compensation. In contrast, where boards are expected to have more power, CEOs receive lower total cash and total compensation. In addition, powerful directors also appear to be able to establish tighter links between CEO compensation and firm performance and can accomplish this even in the face of powerful CEOs. The authors discuss the implications for theory and research regarding the determinants of executive compensation