A smoothed stochastic earthquake rate model considering seismicity and fault moment release for Europe

We present a time-independent gridded earthquake rate forecast for the European region including Turkey. The spatial component of our model is based on kernel density estimation techniques, which we applied to both past earthquake locations and fault moment release on mapped crustal faults and subduction zone interfaces with assigned slip rates. Our forecast relies on the assumption that the locations of past seismicity is a good guide to future seismicity, and that future large-magnitude events occur more likely in the vicinity of known faults. We show that the optimal weighted sum of the corresponding two spatial densities depends on the magnitude range considered. The kernel bandwidths and density weighting function are optimized using retrospective likelihood-based forecast experiments. We computed earthquake activity rates (a- and b-value) of the truncated Gutenberg-Richter distribution separately for crustal and subduction seismicity based on a maximum likelihood approach that considers the spatial and temporal completeness history of the catalogue. The final annual rate of our forecast is purely driven by the maximum likelihood fit of activity rates to the catalogue data, whereas its spatial component incorporates contributions from both earthquake and fault moment-rate densities. Our model constitutes one branch of the earthquake source model logic tree of the 2013 European seismic hazard model released by the EU-FP7 project ‘Seismic HAzard haRmonization in Europe' (SHARE) and contributes to the assessment of epistemic uncertainties in earthquake activity rates. We performed retrospective and pseudo-prospective likelihood consistency tests to underline the reliability of our model and SHARE's area source model (ASM) using the testing algorithms applied in the collaboratory for the study of earthquake predictability (CSEP). We comparatively tested our model's forecasting skill against the ASM and find a statistically significant better performance for testing periods of 10-20yr. The testing results suggest that our model is a viable candidate model to serve for long-term forecasting on timescales of years to decades for the European regio

Trial and error versus errorless learning of functional skills in patients with acute stroke

Objective: To compare the effectiveness of errorless learning versus trial and error learning for teaching activities of daily living to patients with acute stroke with or without explicit memory impairments. Design: Randomized crossover. Setting: Rehabilitation hospital. Participants: 33 adult subjects following an acute stroke. Intervention: Subjects were taught to prepare a wheelchair for a transfer and to put on a sock with a sock-donner. Tasks were taught using errorless learning or trial and error learning. Explicit memory was assessed using the Neurobehavioral Cognitive Status Exam. Main Outcome Measures: Days until subject was able to demonstrate retention of the task, and success or failure at carry-over to a similar task. Results: No significant differences were found in days to retention for either functional task when taught using errorless learning or trial and error learning in subjects with or without explicit memory impairments. Carry-over was significantly better when trial and error learning was used for learning sock donning. Conclusions: When choosing the best learning method for patients undergoing rehabilitation for stroke, the nature of the task should be considered. Additional research is needed to identify the best approach for teaching activities of daily living and facilitating carry-over of learning in individuals with acute stroke

Prevalence and clinical correlates of YMDD variants during lamivudine therapy for patients with chronic hepatitis B

YMDD variants of hepatitis B virus (HBV) emerge in some patients with chronic hepatitis B who receive lamivudine. YMDD variants were examined in 794 patients in 4 controlled studies of 1 year's duration. The long-term effects of YMDD variants were examined in a subset of patients treated up to 4 years. YMDD variants were detected by polymerase chain reaction (PCR) and restriction fragment-length polymorphism assays. After 1 year, YMDD variants were detected in 81 (24%) of 335 patients. In these patients, the median serum HBV DNA concentration at 1 year was <20% of the baseline level, and serum alanine transaminase (ALT) levels and liver histologic findings had significantly improved. In patients with YMDD variants who were treated for up to 4 years, median HBV DNA and ALT levels showed improvements. Sex, baseline body mass index, and HBV DNA level were associated with emergence of YMDD variants. Patients with YMDD variants losing clinical response with a significant increase in the HBV DNA and ALT levels may require additional therapy.published_or_final_versio

Binding, domain orientation, and dynamics of the Lck SH3-SH2 domain pair and comparison with other Src-family kinases

The catalytic activity of Src-family kinases is regulated by association with its SH3 and SH2 domains. Activation requires displacement of intermolecular contacts by SH3/SH2 binding ligands resulting in dissociation of the SH3 and SH2 domains from the kinase domain. To understand the contribution of the SH3-SH2 domain pair to this regulatory process, the binding of peptides derived from physiologically relevant SH2 and SH3 interaction partners was studied for Lck and its relative Fyn by NMR spectroscopy. In contrast to Fyn, activating ligands do not induce communication between SH2 and SH3 domains in Lck. This can be attributed to the particular properties of the Lck SH3-SH2 linker which is shown to be extremely flexible thus effectively decoupling the behavior of the SH3 and SH2 domains. Measurements on the SH32 tandem from Lck further revealed a relative domain orientation that is distinctly different from that found in the Lck SH32 crystal structure and in other Src kinases. These data suggest that flexibility between SH2 and SH3 domains contributes to the adaptation of Src-family kinases to specific environments and distinct functions

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

Aftershock Sequences Modeled with 3-D Stress Heterogeneity and Rate-State Seismicity Equations: Implications for Crustal Stress Estimation

In this paper, we present a model for studying aftershock sequences that integrates Coulomb static stress change analysis, seismicity equations based on rate-state friction nucleation of earthquakes, slip of geometrically complex faults, and fractal-like, spatially heterogeneous models of crustal stress. In addition to modeling instantaneous aftershock seismicity rate patterns with initial clustering on the Coulomb stress increase areas and an approximately 1/t diffusion back to the pre-mainshock background seismicity, the simulations capture previously unmodeled effects. These include production of a significant number of aftershocks in the traditional Coulomb stress shadow zones and temporal changes in aftershock focal mechanism statistics. The occurrence of aftershock stress shadow zones arises from two sources. The first source is spatially heterogeneous initial crustal stress, and the second is slip on geometrically rough faults, which produces localized positive Coulomb stress changes within the traditional stress shadow zones. Temporal changes in simulated aftershock focal mechanisms result in inferred stress rotations that greatly exceed the true stress rotations due to the main shock, even for a moderately strong crust (mean stress 50 MPa) when stress is spatially heterogeneous. This arises from biased sampling of the crustal stress by the synthetic aftershocks due to the non-linear dependence of seismicity rates on stress changes. The model indicates that one cannot use focal mechanism inversion rotations to conclusively demonstrate low crustal strength (≤10 MPa); therefore, studies of crustal strength following a stress perturbation may significantly underestimate the mean crustal stress state for regions with spatially heterogeneous stress

Dynamic and influential interaction of cancer cells with normal epithelial cells in 3D culture

BACKGROUND: The cancer microenvironment has a strong impact on the growth and dynamics of cancer cells. Conventional 2D culture systems, however, do not reflect in vivo conditions, impeding detailed studies of cancer cell dynamics. This work aims to establish a method to reveal the interaction of cancer and normal epithelial cells using 3D time-lapse. METHODS: GFP-labelled breast cancer cells, MDA-MB-231, were co-cultured with mCherry-labelled non-cancerous epithelial cells, MDCK, in a gel matrix. In the 3D culture, the epithelial cells establish a spherical morphology (epithelial sphere) thus providing cancer cells with accessibility to the basal surface of epithelia, similar to the in vivo condition. Cell movement was monitored using time-lapse analyses. Ultrastructural, immunocytochemical and protein expression analyses were also performed following the time-lapse study. RESULTS: In contrast to the 2D culture system, whereby most MDA-MB-231 cells exhibit spindle-shaped morphology as single cells, in the 3D culture the MDA-MB-231 cells were found to be single cells or else formed aggregates, both of which were motile. The single MDA-MB-231 cells exhibited both round and spindle shapes, with dynamic changes from one shape to the other, visible within a matter of hours. When co-cultured with epithelial cells, the MDA-MB-231 cells displayed a strong attraction to the epithelial spheres, and proceeded to surround and engulf the epithelial cell mass. The surrounded epithelial cells were eventually destroyed, becoming debris, and were taken into the MDA-MB-231 cells. However, when there was a relatively large population of normal epithelial cells, the MDA-MB-231 cells did not engulf the epithelial spheres effectively, despite repeated contacts. MDA-MB-231 cells co-cultured with a large number of normal epithelial cells showed reduced expression of monocarboxylate transporter-1, suggesting a change in the cell metabolism. A decreased level of gelatin-digesting ability as well as reduced production of matrix metaroproteinase-2 was also observed. CONCLUSIONS: This culture method is a powerful technique to investigate cancer cell dynamics and cellular changes in response to the microenvironment. The method can be useful for various aspects such as; different combinations of cancer and non-cancer cell types, addressing the organ-specific affinity of cancer cells to host cells, and monitoring the cellular response to anti-cancer drugs. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12935-014-0108-6) contains supplementary material, which is available to authorized users

Association between circulating osteocalcin and cardiometabolic risk factors following a 4-week leafy green vitamin K-rich diet

© 2020 S. Karger AG, Basel. Copyright: All rights reserved. Background: Evidence suggests that lower serum undercarboxylated osteocalcin (ucOC) may be negatively associated with cardiometabolic health. We investigated whether individuals with a suppression of ucOC following an increase in dietary vitamin K1 exhibit a relative worsening of cardiometabolic risk factors. Materials and Methods: Men (n = 20) and women (n = 10) aged 62 ± 10 years participated in a randomized, controlled, crossover study. The primary analysis involved using data obtained from participants following a high vitamin K1 diet (HK; 4-week intervention of increased leafy green vegetable intake). High and low responders were defined based on the median percent reduction (30%) in ucOC following the HK diet. Blood pressure (resting and 24 h), arterial stiffness, plasma glucose, lipid concentrations, and serum OC forms were assessed. Results: Following the HK diet, ucOC and ucOC/tOC were suppressed more (p \u3c 0.01) in high responders (41 and 29%) versus low responders (12 and 10%). The reduction in ucOC and ucOC/tOC was not associated with changes in blood pressure, arterial stiffness, plasma glucose, or lipid concentrations in the high responders (p \u3e 0.05). Discussion/Conclusion: Suppression of ucOC via consumption of leafy green vegetables has no negative effects on cardiometabolic health, perhaps, in part, because of cross-talk mechanisms