A unified web cloud computing platform MiMedSurv for microbiome causal mediation analysis with survival responses.

In human microbiome studies, mediation analysis has recently been spotlighted as a practical and powerful analytic tool to survey the causal roles of the microbiome as a mediator to explain the observed relationships between a medical treatment/environmental exposure and a human disease. We also note that, in a clinical research, investigators often trace disease progression sequentially in time; as such, time-to-event (e.g., time-to-disease, time-to-cure) responses, known as survival responses, are prevalent as a surrogate variable for human health or disease. In this paper, we introduce a web cloud computing platform, named as microbiome mediation analysis with survival responses (MiMedSurv), for comprehensive microbiome mediation analysis with survival responses on user-friendly web environments. MiMedSurv is an extension of our prior web cloud computing platform, named as microbiome mediation analysis (MiMed), for survival responses. The two main features that are well-distinguished are as follows. First, MiMedSurv conducts some baseline exploratory non-mediational survival analysis, not involving microbiome, to survey the disparity in survival response between medical treatments/environmental exposures. Then, MiMedSurv identifies the mediating roles of the microbiome in various aspects: (i) as a microbial ecosystem using ecological indices (e.g., alpha and beta diversity indices) and (ii) as individual microbial taxa in various hierarchies (e.g., phyla, classes, orders, families, genera, species). To illustrate its use, we survey the mediating roles of the gut microbiome between antibiotic treatment and time-to-type 1 diabetes. MiMedSurv is freely available on our web server ( http://mimedsurv.micloud.kr ).

MiMultiCat: A Unified Cloud Platform for the Analysis of Microbiome Data with Multi-Categorical Responses.

The field of the human microbiome is rapidly growing due to the recent advances in high-throughput sequencing technologies. Meanwhile, there have also been many new analytic pipelines, methods and/or tools developed for microbiome data preprocessing and analytics. They are usually focused on microbiome data with continuous (e.g., body mass index) or binary responses (e.g., diseased vs. healthy), yet multi-categorical responses that have more than two categories are also common in reality. In this paper, we introduce a new unified cloud platform, named MiMultiCat, for the analysis of microbiome data with multi-categorical responses. The two main distinguishing features of MiMultiCat are as follows: First, MiMultiCat streamlines a long sequence of microbiome data preprocessing and analytic procedures on user-friendly web interfaces; as such, it is easy to use for many people in various disciplines (e.g., biology, medicine, public health). Second, MiMultiCat performs both association testing and prediction modeling extensively. For association testing, MiMultiCat handles both ecological (e.g., alpha and beta diversity) and taxonomical (e.g., phylum, class, order, family, genus, species) contexts through covariate-adjusted or unadjusted analysis. For prediction modeling, MiMultiCat employs the random forest and gradient boosting algorithms that are well suited to microbiome data while providing nice visual interpretations. We demonstrate its use through the reanalysis of gut microbiome data on obesity with body mass index categories. MiMultiCat is freely available on our web server.

Comprehensive microbiome causal mediation analysis using MiMed on user-friendly web interfaces.

It is a central goal of human microbiome studies to see the roles of the microbiome as a mediator that transmits environmental, behavioral, or medical exposures to health or disease outcomes. Yet, mediation analysis is not used as much as it should be. One reason is because of the lack of carefully planned routines, compilers, and automated computing systems for microbiome mediation analysis (MiMed) to perform a series of data processing, diversity calculation, data normalization, downstream data analysis, and visualizations. Many researchers in various disciplines (e.g. clinicians, public health practitioners, and biologists) are not also familiar with related statistical methods and programming languages on command-line interfaces. Thus, in this article, we introduce a web cloud computing platform, named as MiMed, that enables comprehensive MiMed on user-friendly web interfaces. The main features of MiMed are as follows. First, MiMed can survey the microbiome in various spheres (i) as a whole microbial ecosystem using different ecological measures (e.g. alpha- and beta-diversity indices) or (ii) as individual microbial taxa (e.g. phyla, classes, orders, families, genera, and species) using different data normalization methods. Second, MiMed enables covariate-adjusted analysis to control for potential confounding factors (e.g. age and gender), which is essential to enhance the causality of the results, especially for observational studies. Third, MiMed enables a breadth of statistical inferences in both mediation effect estimation and significance testing. Fourth, MiMed provides flexible and easy-to-use data processing and analytic modules and creates nice graphical representations. Finally, MiMed employs ChatGPT to search for what has been known about the microbial taxa that are found significantly as mediators using artificial intelligence technologies. For demonstration purposes, we applied MiMed to the study on the mediating roles of oral microbiome in subgingival niches between e-cigarette smoking and gingival inflammation. MiMed is freely available on our web server (http://mimed.micloud.kr).

MiSurv: an Integrative Web Cloud Platform for User-Friendly Microbiome Data Analysis with Survival Responses.

Investigators have studied the treatment effects on human health or disease, the treatment effects on human microbiome, and the roles of the microbiome on human health or disease. Especially, in a clinical trial, investigators commonly trace disease status over a lengthy period to survey the sequential disease progression for different treatment groups (e.g., treatment versus placebo, new treatment versus old treatment). Hence, disease responses are often available in the form of survival (i.e., time-to-event) responses stratified by treatment groups. While the recent web cloud platforms have enabled user-friendly microbiome data processing and analytics, there is currently no web cloud platform to analyze microbiome data with survival responses. Therefore, we introduce here an integrative web cloud platform, called MiSurv, for comprehensive microbiome data analysis with survival responses. IMPORTANCE MiSurv consists of a data processing module and its following four data analytic modules: (i) Module 1: Comparative survival analysis between treatment groups, (ii) Module 2: Comparative analysis in microbial composition between treatment groups, (iii) Module 3: Association testing between microbial composition and survival responses, (iv) Module 4: Prediction modeling using microbial taxa on survival responses. We demonstrate its use through an example trial on the effects of antibiotic use on the survival rate against type 1 diabetes (T1D) onset and gut microbiome composition, respectively, and the effects of the gut microbiome on the survival rate against T1D onset. MiSurv is freely available on our web server (http://misurv.micloud.kr) or can alternatively run on the user's local computer (https://github.com/wg99526/MiSurvGit).

Integrative web cloud computing and analytics using MiPair for design-based comparative analysis with paired microbiome data.

Pairing (or blocking) is a design technique that is widely used in comparative microbiome studies to efficiently control for the effects of potential confounders (e.g., genetic, environmental, or behavioral factors). Some typical paired (block) designs for human microbiome studies are repeated measures designs that profile each subject's microbiome twice (or more than twice) (1) for pre and post treatments to see the effects of a treatment on microbiome, or (2) for different organs of the body (e.g., gut, mouth, skin) to see the disparity in microbiome between (or across) body sites. Researchers have developed a sheer number of web-based tools for user-friendly microbiome data processing and analytics, though there is no web-based tool currently available for such paired microbiome studies. In this paper, we thus introduce an integrative web-based tool, named MiPair, for design-based comparative analysis with paired microbiome data. MiPair is a user-friendly web cloud service that is built with step-by-step data processing and analytic procedures for comparative analysis between (or across) groups or between baseline and other groups. MiPair employs parametric and non-parametric tests for complete or incomplete block designs to perform comparative analyses with respect to microbial ecology (alpha- and beta-diversity) and taxonomy (e.g., phylum, class, order, family, genus, species). We demonstrate its usage through an example clinical trial on the effects of antibiotics on gut microbiome. MiPair is an open-source software that can be run on our web server ( http://mipair.micloud.kr ) or on user's computer ( https://github.com/yj7599/mipairgit ).

Utilization of a combined EEG/NIRS system to predict driver drowsiness.

The large number of automobile accidents due to driver drowsiness is a critical concern of many countries. To solve this problem, numerous methods of countermeasure have been proposed. However, the results were unsatisfactory due to inadequate accuracy of drowsiness detection. In this study, we introduce a new approach, a combination of EEG and NIRS, to detect driver drowsiness. EEG, EOG, ECG and NIRS signals have been measured during a simulated driving task, in which subjects underwent both awake and drowsy states. The blinking rate, eye closure, heart rate, alpha and beta band power were used to identify subject's condition. Statistical tests were performed on EEG and NIRS signals to find the most informative parameters. Fisher's linear discriminant analysis method was employed to classify awake and drowsy states. Time series analysis was used to predict drowsiness. The oxy-hemoglobin concentration change and the beta band power in the frontal lobe were found to differ the most between the two states. In addition, these two parameters correspond well to an awake to drowsy state transition. A sharp increase of the oxy-hemoglobin concentration change, together with a dramatic decrease of the beta band power, happened several seconds before the first eye closure.

Exploring Neuro-Physiological Correlates of Drivers' Mental Fatigue Caused by Sleep Deprivation Using Simultaneous EEG, ECG, and fNIRS Data.

Investigations of the neuro-physiological correlates of mental loads, or states, have attracted significant attention recently, as it is particularly important to evaluate mental fatigue in drivers operating a motor vehicle. In this research, we collected multimodal EEG/ECG/EOG and fNIRS data simultaneously to develop algorithms to explore neuro-physiological correlates of drivers' mental states. Each subject performed simulated driving under two different conditions (well-rested and sleep-deprived) on different days. During the experiment, we used 68 electrodes for EEG/ECG/EOG and 8 channels for fNIRS recordings. We extracted the prominent features of each modality to distinguish between the well-rested and sleep-deprived conditions, and all multimodal features, except EOG, were combined to quantify mental fatigue during driving. Finally, a novel driving condition level (DCL) was proposed that distinguished clearly between the features of well-rested and sleep-deprived conditions. This proposed DCL measure may be applicable to real-time monitoring of the mental states of vehicle drivers. Further, the combination of methods based on each classifier yielded substantial improvements in the classification accuracy between these two conditions.

Herbal Extracts That Reduce Ocular Oxidative Stress May Enhance Attentive Performance in Humans.

We used herbal extracts in this study to investigate the effects of blue-light-induced oxidative stress on subjects' attentive performance, which is also associated with work performance. We employed an attention network test (ANT) to measure the subjects' work performance indirectly and used herbal extracts to reduce ocular oxidative stress. Thirty-two subjects participated in either an experimental group (wearing glasses containing herbal extracts) or a control group (wearing glasses without herbal extracts). During the ANT experiment, we collected electroencephalography (EEG) and electrooculography (EOG) data and measured button responses. In addition, electrocardiogram (ECG) data were collected before and after the experiments. The EOG results showed that the experimental group exhibited a reduced number of eye blinks per second during the experiment and faster button responses with a smaller variation than did the control group; this group also showed relatively more sustained tension in their ECG results. In the EEG analysis, the experimental group had significantly greater cognitive processing, with larger P300 and parietal 2-6 Hz activity, an orienting effect with neural processing of frontal area, high beta activity in the occipital area, and an alpha and beta recovery process after the button response. We concluded that reducing blue-light-induced oxidative stress with herbal extracts may be associated with reducing the number of eye blinks and enhancing attentive performance.

27-hydroxycholesterol induces production of tumor necrosis factor-alpha from macrophages.

Enhanced production of TNF-α from macrophages promotes development and instability of atherosclerotic plaques, but involvement of lipid component in TNF-α production has not been clarified in atherosclerosis. We attempted to determine whether cholesterol oxidation products (oxysterols) could modify TNF-α production. Treatment of THP-1 cells with 27-hydroxycholesterol (27OHChol) or 7α-hydroxycholesterol (7αOHChol) resulted in a profound increase in TNF-α transcription, while treatment with an identical concentration of cholesterol and 7-ketochoelsterol did not lead to any change in TNF-α expression. Treatment with 27OHChol resulted in increased synthesis, as well as secretion, of TNF-α, while 7αOHChol led to increased synthesis of TNF-α without affecting secretion of the cytokine. Co-treatment with 7αOHChol or 27OHChol and LPS resulted in synergistically enhanced or augmented secretion of TNF-α. Treatment with TO-901317, pertussis toxin, PP2, and LY294002 resulted not only in attenuated transcription of TNF-α induced by 27OHChol and 7αOHChol, but also secretion of TNF-α enhanced by 27OHChol. This is the first report demonstrating enhanced production of TNF-α in macrophages by treatment with oxysterols which are detected in abundance in atheromatous lesions; in addition, results of the current study provide evidence indicating that certain types of oxysterols contribute to development of atherosclerosis by promoting production of proinflammatory cytokines.

Roles of 7-ketocholesterol on the homeostasis of intracellular cholesterol level.

Atherosclerotic plaque contains materials, such as cholesterol, oxysterols, cell debris, modified fatty acids, and infiltrated cells. Among them, cholesterol is the major component in plaque. Cholesterol is known to originate from the influx of extracellular materials, but this explanation is not enough for the cholesterol accumulation observed in atherosclerotic plaque. This study examined the origins of cholesterols in plaques. The main focus was to determine if the intracellular cholesterol levels are affected by oxysterols in human vascular smooth muscle cells. The results showed that the cholesterol levels increased in response to a 7-ketocholesterol (7K)-treatment in a dose-dependent manner. Eight enzymes involved in cholesterol biosynthesis were examined. Among them, squalene epoxidase (SQLE) was increased by 7K but not by 7α-hydroxycholesterol, 27-hydroxycholesterol (27OH-chol), or cholesterol. The 7K-induced SQLE expression was suppressed in the presence of the enzyme inhibitor SB203580 but not by UO126 and SP600125. The SQLE immunoreactivity was detected in the atherosclerotic plaque of the aortic roots from apoE mice. In addition, 7K increased the cholesterol level and SQLE expression in murine bone marrow-derived macrophages. This suggests that 7K increases the intracellular cholesterol level through an elevation of SQLE expression, which might affect the progress of cholesterol accumulation in the atherosclerotic lipid core.