Miracle-dz/UniFAR-FTUs huggingface dataset:
Activation of c-Src: A hub for exogenous prooxidant-induced activation of Toll-like receptor 4 signaling

Summary To study the role of c-Src kinase in prooxidant-induced stimulation of TLR4, we used LPS-EK and MPLA as TLR4 specific agonists and positive controls, and SIN-1 and PPC as prooxidant sources. We used HEK-Blue mTLR4 cell line that is stably transfected with mouse TLR4 and that expresses optimized SEAP reporter under the control of a promoter inducible by NF- κ B transcription factor. The level of SEAP released due to TLR4 stimulation was a measure of NF- κ B activation. Treatment with either the prooxidants or LPS-EK increased SEAP release and TNF- α production in these cells. These treatments also increased intracellular ROS accumulation with an enhanced production of nitric oxide and TBARS to confirm oxidant stress in these cells. Pretreatment with c-Src kinase inhibitors, PP2 and CA-pY, which act by different mechanisms, decreased these parameters. Pretreatment with SSG, a c-Src activator, enhanced the effects promoted by LPS-EK and prooxidants, and rescued cells from PP2- and Ca-pY-induced effects. Curiously, prooxidants but not TLR4 agonist increased the ratio of TNF α to IL-10 released suggesting that prooxidants can initiate and maintain an imbalance of TNF α production over IL-10. To different degrees, both prooxidant and TLR4 agonist increased formation of c-Src complexes with TLR4 and I κ B- α as coimmunoprecipitates. Both prooxidant and TLR4 agonist increased c-Src phosphorylation of Tyr-42 residue in I κ B- α , but prooxidant-induced effect was more robust and much longer lasting. Taken together, these studies provide a mechanism whereby c-Src assumes a central role in prooxidant-induced NF- κ B activation in TLR4 signaling. Prooxidant-induced activation of TLR4 through c-Src/NF κ B/I κ B- α coupling provides a basis for a molecular dissection of the initiation and maintenance of sterile inflammation that may serve as a “pathophysiologic primer” for many diseases. high efficiency [38, 39], we have hypothesized that c-Src amongst the SFKs plays a dominant role in NF- κ B activation induced by exogenous prooxidants through TLR4 signaling. Here we present evidence that integrates exposure to prooxidants with c-Src/ TLR4-coupled signaling to increased c-Src/I κ B α -induced effects in the NF- κ B activation pathway (as compared with that induced by LPS-EK, a specific agonist for TLR4). We hypothesize that the product of the oxidant-induced c-Src/TLR4/NF- κ B-coupled pathway has a potential to initiate and maintain long-lasting “sterile” inflammatory processes that may serve as a primer for different disease states.
Engineering Bacterial Cytochrome P450 (P450) BM3 into a Prototype with Human P450 Enzyme Activity Using Indigo Formation

Human cytochrome P450 (P450) enzymes metabolize a variety of endogenous and xenobiotic compounds, including steroids, drugs, and environmental chemicals. In this study, we examine the possibility that bacterial P450 BM3 (CYP102A1) mutants with indole oxidation activity have the catalytic activities of human P450 enzymes. Error-prone polymerase chain reaction was carried out on the heme domain-coding region of the wild-type gene to generate a CYP102A1 DNA library. The library was transformed into Escherichia coli for expression of the P450 mutants. A colorimetric colony-based method was adopted for primary screening of the mutants. When the P450 activities were measured at the whole-cell level, some of the blue colonies, but not the white colonies, possessed apparent oxidation activity toward coumarin and 7-ethoxycoumarin, which are typical human P450 substrates that produce fluorescent products. Coumarin is oxidized by the CYP102A1 mutants to produce two metabolites, 7-hydroxycoumarin and 3-hydroxycoumarin. In addition, 7-ethoxycoumarin is simultaneously oxidized to 7-hydroxycoumarin by O-deethylation reaction and to 3-hydroxy,7-ethoxycoumarin by 3-hydroxylation reactions. Highly active mutants are also able to metabolize several other human P450 substrates, including phenacetin, ethoxyresorufin, and chlorzoxazone. These results indicate that indigo formation provides a simple assay for identifying CYP102A1 mutants with a greater potential for human P450 activity. Furthermore, our computational findings suggest a correlation between the stabilization of the binding site and the catalytic efficiency of CYP102A1 mutants toward coumarin: the more stable the structure in the binding site, the lower the energy barrier and the higher the catalytic efficiency.
An Online Updating Approach for Testing the Proportional Hazards Assumption with Streams of Big Survival Data.

The Cox model, which remains as the first choice in analyzing time-to-event data even for large datasets, relies on the proportional hazards assumption. When the data size exceeds the computer memory, the standard statistics for testing the proportional hazards assumption can no longer b e easily calculated. We propose an online up dating approach with minimal storage requirement that up dates the standard test statistic as each new block of data becomes available. Under the null hypothesis of proportional hazards, the proposed statistic is shown to have the same asymptotic distribution as the standard version if it could be computed with a super computer. In simulation studies, the test and its variant based on most recent data blocks maintain their sizes when the proportional hazards assumption holds and have substantial power to detect different violations of the proportional hazards assumption. The approach is illustrated with the survival analysis of patients with lymphoma cancer from the Surveillance, Epidemiology, and End Results Program. The proposed test promptly identified deviation from the proportional hazards assumption that was not captured by the test based on the entire data.
Accelerated Monte Carlo Rendering of Finite-Time Lyapunov Exponents

Time-dependent fluid flows often contain numerous hyperbolic Lagrangian coherent structures, which act as transport barriers that guide the advection. The finite-time Lyapunov exponent is a commonly-used approximation to locate these repelling or attracting structures. Especially on large numerical simulations, the FTLE ridges can become arbitrarily sharp and very complex. Thus, the discrete sampling onto a grid for a subsequent direct volume rendering is likely to miss sharp ridges in the visualization. For this reason, an unbiased Monte Carlo-based rendering approach was recently proposed that treats the FTLE field as participating medium with single scattering. This method constructs a ground truth rendering without discretization, but it is prohibitively slow with render times in the order of days or weeks for a single image. In this paper, we accelerate the rendering process significantly, which allows us to compute video sequence of high-resolution FTLE animations in a much more reasonable time frame. For this, we follow two orthogonal approaches to improve on the rendering process: the volumetric light path integration in gradient domain and an acceleration of the transmittance estimation. We analyze the convergence and performance of the proposed method and demonstrate the approach by rendering complex FTLE fields in several 3D vector fields.
Basaltic accumulation instability and chaotic plate motion in the earliest mantle inferred from numerical experiments

[1] A series of self-consistent numerical models of mantle convection with magmatism and moving plates are presented to clarify the dynamics of the strongly heated mantle of the earliest Earth. Broad hot accumulations of subducted basaltic crusts develop on the core-mantle boundary and remain there for geologic time only when the internal heating rate is below a threshold. Above the threshold, the basaltic accumulations become unstable. Instead, the thermal buoyancy induced by the strong internal heating repeatedly causes a massive upwelling, or burst, of hot materials from deep mantle. The mantle burst induces vigorous magmatic activity on the surface. The magmatic activity, in turn, damages the lithosphere and disintegrates it into smaller fragments. In contrast to the well-ordered plate motion observed below the threshold, the lithospheric fragments chaotically move and new subduction zones sporadically develop. The mantle burst and chaotic motion of lithospheric fragments effectively stir the mantle, and the mantle remains chemically rather homogeneous in spite of the chemical differentiation due to the vigorous magmatism. The Earth's mantle convection has probably changed its regime from one dominated by frequent mantle bursts and chaotic motion of lithospheric fragments to one dominated by stable basaltic accumulations and well-ordered plate motion, as the internal heat source decays. The suggested regime transition fits in with the Earth's tectonic evolution inferred from geologic observations of the continents of various ages.
Patterns in the Evolution of Nares Size and Secondary Palate Length in Anomodont Therapsids (Synapsida): Implications for Hypoxia as a Cause of End-Permian Tetrapod Extinctions

Abstract Seemingly consistent proportional differences in several palatal structures have been noted between Permian and Triassic anomodont therapsids for nearly a century. These patterns have been cited as evidence in support of a decline in atmospheric oxygen concentrations that may have contributed to end-Permian terrestrial extinctions. However, it is not known whether the observed differences are significant, or whether they stem from continued directional selection. If they are not significant, or if their timing does not match that proposed for the oxygen decline, support for the hypoxia-based extinction scenario would be weakened. We tested whether the internal nares and bony secondary palate, two palatal features proposed to be related to respiratory efficiency, are significantly larger in Triassic anomodonts, and whether the variation can be attributed to a long-term tendency for increase. Results based on raw data indicate that Triassic anomodonts have significantly larger secondary palates than Permian anomodonts. They also have significantly larger internal nares, but only when primitive, morphologically-divergent specimens are not considered. Although nares and palate size are correlated with stratigraphic occurrence, available data reject the hypothesis that the observed differences were the result of a long-term trend. Most of these findings are consistent with the predictions of the hypoxia scenario. However, removing the effects of body size and phylogeny causes some of the differences to break down, indicating that if selection for increased respiratory efficiency affected these characters, it was most likely not the only factor to do so. Therefore, the characters provide only weak evidence in support of the hypoxia scenario, and we recommend against their use for this purpose. Our results emphasize the need for caution when invoking presumed differences between Permian and Triassic vertebrates as support for hypoxia, or other extinction scenarios, without a rigorous study of the character(s) in question.
Comparison of body composition changes between low calorie high protein diet to standard protein in obese individuals with

The world prevalence of obesity in adult population in 2014 was Background: nearly 13% while in Indonesia, it has reached 32.9% in the same year. Obesity is an established risk factors for cardiovascular diseases. A large proportion of people who had succeeded to reduce body weight failed to maintain it (weight cycling). Studies were inconclusive about the best composition in the diet for such people. The purpose of this research was to evaluate the body composition changes resulted from low calorie high protein and standard protein diet programme in obese people with history of weight cycling. This is an open-randomized clinical trial of weight loss program as a Methods: part of a larger study researching the effect of low calorie high protein diet to body composition, oxidative stress, inflammation marker and metabolic syndrome in obese with weight cycling. A total of 61 adult obese men and women with history of weight cycling were recruited. Subjects were assigned to low calorie diet and were randomly distributed into two intervention groups, namely high protein group (22-30 % of total calories intake) and standard protein group (12-20%). Anthropometry and body composition data were taken at baseline and at the end of the study. Subjects were followed up to 8 weeks with daily reminder and weekly counselling. Fourty five participants completed the study. There were significant Results: reductions in in body weight and body mass index (BMI), fat mass, fat mass percentage, muscle mass, and gain in muscle mass percentage occurred in both groups (Standard protein: P<0.001; High protein: P<0.001 for all variables except for fat mass P= 0,001) with no difference between group (P>0.05). Calories deficit with either high protein or standard protein for 8 Conclusion: weeks brought about significant reduction in body composition
Integration of water resources modelling approaches for varying levels of decision-making.

Within government organisations there is a hierarchy of decision making ranging from broad, strategic decisions taken at top management level, through detailed planning, to the routine operational decisions. Due to the complex nature of water resources management, some form of water resources model is required to determine how much water is available, and to balance this against water requirements, taking the variability in assurance of supply to different users into consideration. In South Africa, as in many other countries, the trend has been to develop different models aimed at advising different levels of decision making. While this has proved successful, it has led to multiple models and hence multiple databases, and inevitably to inconsistencies in the conclusions reached by adopting different scales of modelling intensity and complexity. This paper describes an approach to water resources modelling which seamlessly deals with several levels of complexity, from broad-scale, strategic planning through detailed planning (or systems analysis), to the short to medium term operation of reservoirs (including hedging strategies) to deal with droughts and unexpected situations such as over-abstraction. The initial model setup commences at a broad strategic (or reconnaissance) level. As the model user progresses to higher levels of modelling intensity he is prompted to provide the data required by these higher levels. The core of this modelling system is a database of water user and monthly naturalized hydrology, rainfall and evaporation which is used throughout all levels of modelling. The fundamental concepts of reservoir behaviour analysis forms the basis of the modelling procedure, commencing with a single iteration cascading monthly time-step simulation for strategic planning purposes and progressing to a multi-iteration solution using up to 500 stochastically generated hydrological sequences, including curtailment rules for each user, to solve complex reservoir operation problems. Comprehensive testing and application of this system has not yet been undertaken, but preliminary observations are made in this paper based on a trial application in a test catchment.
Velocity-dependent dynamic curvature gain for redirected walking

The aim of Redirected Walking (RDW) is to redirect a person along their path of travel in a Virtual Environment (VE) in order to increase the virtual space that can be explored in a given tracked area. Among other techniques, the user is redirected on a curved real-world path while visually walking straight in the VE (curvature gain). In this paper, we describe two experiments we conducted to test and extend RDW techniques. In Experiment 1, we measured the effect of walking speed on the detection threshold for curvature of the walking path. In a head-mounted display (HMD) VE, we found a decreased sensitivity for curvature for the slowest walking speed. When participants walked at 0.75 m/s, their detection threshold was approximately 0.1m−1 (radius of approximately 10m). In contrast, for faster walking speeds (>1.0m/s), we found a significantly lower detection threshold of approximately 0.036m−1 (radius of approximately 27m). In Experiment 2, we implemented many well known redirection techniques into one dynamic RDW application. We integrated a large virtual city model and investigated RDW for free exploration. Further, we implemented a dynamic RDW controller which made use of the results from Experiment 1 by dynamically adjusting the applied curvature gain depending on the actual walking velocity of the user. In addition, we investigated the possible role of avatars to slow the users down or make them rotate their heads while exploring. Both the dynamic curvature gain controller and the avatar controller were evaluated in Experiment 2. We measured the average distance that was walked before reaching the boundaries of the tracked area. The mean walked distance was significantly larger in the condition where the dynamic gain controller was applied. This distance increased from approximately 15m for static gains to approximately 22m for dynamic gains. This did not come at the cost of an increase in simulator sickness. Applying the avatar controller did reveal an effect on walking distance or simulator sickness.
Association of Hearing Loss With Total and Cause-speci�c Mortality in US Adults

Objectives We expected to explore the associations of hearing loss and hearing thresholds at different frequencies with total and cause-speci�c mortality. Methods 11,732 individuals derived from the National Health and Nutrition Examination Survey (NHANES) 1999-2012 were included in this study. Data of death was extracted from the NHANES Public-Use Linked Mortality File through December 31, 2015. Cox proportional hazards models were used to explore the associations between hearing loss, hearing thresholds at different frequencies and total or cause-speci�c mortality. Results A total of 1,253 deaths occurred with a median follow-up of 12.15 years. A signi�cant positive dose-response relationship between hearing loss in speech frequency and total mortality was observed, and the HRs and 95% CIs were 1.16 (0.91, 1.47), 1.54 (1.19, 2.00) and 1.85 (1.36, 2.50), respectively for mild, moderate and severe speech-frequency hearing loss (SFHL) with a P trend of 0.0003. In addition, moderate (HR: 1.90, 95%CI: 1.20-3.00) and greater (3.50, 1.38-8.86) SFHL signi�cantly elevated risk of heart disease mortality. (1.40, 1.44, 1.20-1.73; and 1.10-1.62, respectively) and (1.89, 1.95, 1.21-3.16; and 1.16-3.09, respectively). Preventing or inhibiting the pathogenic factors of hearing loss is important for reducing the of 12.33% (1,447/11,732) and 10.97% (1,287/11,732) showed mild, moderate and severe HFHL, respectively. Meanwhile, 13.41% (1,573/11,732), 7.05% (827/11,732) and 2.57% (302/11,732) had mild, moderate and severe SFHL, respectively. There were signi�cant differences in BMI, PIR, Married status, smoking status, drinking status, Epidemiology of Hearing Loss Study. The discrepancy might due to different race/ethnicity, different sample sizes, and follow-up time. The Rao-Scott χ2 test was used to compare for categorical variables and analysis of variance adjusted for sampling weights was used to compare for continuous variables. Categorical variables were expressed as number (percentage) and continuous variables were shown as mean/median (95%CI). Abbreviation: HFHL: high-frequency hearing loss; SFHL: speech-frequency hearing loss; CI: con�dence interval.
Lack of Palliative Mortality Prediction Tools for People with a Hematological Malignancy: Call for Action

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The response of the equatorial Pacific Ocean to global warming

The basic pattern of sea surface temperature (SST) in the equatorial Pacific Ocean is characterized by a vast warm pool in the west (~29°C, annual mean), and a relatively narrow tongue of cold surface water extending westward from the coast of South America (~25°C, annual mean). The result is an approximately linear zonal gradient of SST where the west is ~4°C warmer than the east. A persistent change of the zonal SST gradient by a fraction of a degree centigrade was enough to cause the Dust Bowl drought of the 1930s and other major droughts (Schubert et al. 2004, Schubert 2004, Seager et al. 2005, Kumar et al. 1999). The zonal SST gradient exhibits strong seasonality that is dominated by the seasonality of the eastern equatorial Pacific (i.e., the “cold tongue”) as SSTs in the west remain fairly constant. The cold tongue is weak during March (Fig. 1a) and strong during September (Fig. 1b), resulting in a strong seasonal cycle (Fig. 1c). Because of its importance in the global climate system, the past and future change of the equatorial Pacific zonal SST gradient, as well as the atmospheric circulation to which it is coupled, has been the subject of recent climate research. A weakening of the zonal SST gradient and atmospheric circulation has been termed “El Niño–like,” and a strengthening thereof has been termed “La Niña–like. ” A theory has been proposed that global warming will result in an “El Niño–like” response, including a weakened zonal atmospheric overturning circulation and SST gradient, based on the mass and energy balances of the atmosphere (Held and Soden 2006, Vecchi and Soden 2007). Recent analysis of observed trends in annual mean sea level pressure (SLP) in the Indo–Pacific sector seem to support this theory (Vecchi et al. 2006). A more ocean–centric theory has also been proposed, wherein global warming will result in a “La Niña–like” response, because the strong upwelling in the cold tongue should dilute the warming in that region, hence resulting in a stronger contrast with the west (Clement et al. 1996, Seager and Murtugudde 1997). Observational evidence has been presented in support of this theory as well (Cane et al. 1997, Cane 2005). Although it appears that the zonal atmospheric overturning circulation of the equatorial Pacific has been weakening since the mid–1800s (Vecchi et al. 2006), no consensus has been achieved to date regarding the change in the zonal SST gradient.
Role of statistics in the validation of general circulation models

The field of statistics should play a central role in the validation of general circulation models (GCMs). Both the perspectives of climate modelers and of climate impact researchers are addressed. Confusion over what statistics can or cannot be expected to achieve is described, and an overemphasis of statistical tests of significance is identified. A compelling case is made for assessing the performance of GCMs in terms of their ability to reproduce climate variability, not just average conditions. Unsatisfactory aspects of current statistical practice are pointed out, with the problem of multiple comparisons illustrated by an example. Prospects for the future are considered, emphasizing the need for factoring statistical issues into the design of GCM experiments, as well as the possible application of new statistical techniques. Indicative of ways in which existing techniques could be used more appropriately in the validation of GCM output, an example that involves a multiple confidence interval is presented. If the appropriate role of statistics were recognized, one obstacle currently hindering the improvement of GCMs and limiting their use In climate impact studies would be removed.