A Comprehensive Evaluation of Cross-Omics Blood-Based Biomarkers for Neuropsychiatric Disorders

The identification of peripheral multi-omics biomarkers of brain disorders has long been hindered by insufficient sample size and confounder influence. This study aimed to compare biomarker potential for different molecules and diseases. We leveraged summary statistics of five blood quantitative trait loci studies (N = 1980 to 22,609) and genome-wide association studies (N = 9725 to 500,199) from 14 different brain disorders, such as Schizophrenia (SCZ) and Alzheimer’s Disease (AD). We applied summary-based and two-sample Mendelian Randomization to estimate the associations between blood molecules and brain disorders. We identified 524 RNA, 807 methylation sites, 29 proteins, seven cytokines, and 22 metabolites having a significant association with at least one of 14 brain disorders. Simulation analyses indicated that a cross-omics combination of biomarkers had better performance for most disorders, and different disorders could associate with different omics. We identified an 11-methylation-site model for SCZ diagnosis (Area Under Curve, AUC = 0.74) by analyzing selected candidate markers in published datasets (total N = 6098). Moreover, we constructed an 18-methylation-sites model that could predict the prognosis of elders with mild cognitive impairment (hazard ratio = 2.32). We provided an association landscape between blood cross-omic biomarkers and 14 brain disorders as well as a suggestion guide for future clinical discovery and application.

Establishment of a 5 DNA Methylation Site Prognostic Signature Associated with N6-Methyladenosine in Lung Adenocarcinoma

Background: There is a high incidence of lung adenocarcinoma (LUAD). Even with surgery, targeted therapy and immunotherapy, the survival rate of LUAD patients is still low. N6-methyladenosine (m6A) and DNA methylation markers can help with the diagnosis and treatment of LUAD patients. Therefore, it is necessary to identify a novel m6A-related DNA methylation sites signature to predict the survival of patients with LUAD. Methods: In this study, we screened 15 m6A-related genes and their 217 methylation sites. RNA sequencing data of 15 genes and the clinicopathological parameters of TCGA-LUAD were obtained from the TCGA database (http://cancergenome.nih.gov/). The LUAD-DNA CpG site information was obtained from the Illumina Human Methylation 450 BeadChip (Illumina, San Diego, CA, United States). The methylation sites related to prognosis were screened using univariate COX analysis, and the independent predictors of LUAD patients were identified using multivariate COX analysis of least absolute shrinkage and selection operator (LASSO) Cox regression analysis. Finally, a model with 5 methylation sites as the main body to predict the prognosis of OS in patients with LUAD was obtained. According to the risk grouping of the prediction model, Kaplan-Meier curve and the receiver operating characteristic (ROC) curve were performed in the test and training sets to assess the predicted capacity of the model. In addition, a nomogram constructed by combining the risk score of methylation group and other related clinicopathological factors to verify the reliability of our model.Results: We constructed a m6A-related 5-DNA methylation site model to predict OS in LUAD patients. According to the results of the Kaplan-Meier curve, both the test set and the training set, the high-risk group showed a worse prognosis. The AUCs of the 5 DNA methylation signature at 1, 5 and 10 years in test datasets were 0.730, 0.649 and 0.726, respectively, and 0.679, 0.656 and 0.732 in training datasets. Finally, we constructed a nomogram to further verify the reliability of the model.Conclusion: In this study, we analyzed the methylation sites of m6A-related genes and established a m6A-related 5-DNA methylation site model to predict OS in LUAD patients.

Integration of ERT, IP and SP Methods in Hard Rock Engineering

Investigation of a hard rock site for the development of engineered structures mainly depends on the delineation of weathered and unweathered rock, and the fractures/faults. Traditionally, borehole tests are used in such investigations. However, such approaches are expensive and time-consuming, require more equipment, cannot be conducted in steep topographic areas, and provide low coverage of the area with point measurements only. Conversely, geophysical methods are non-invasive, economical, and provide large coverage of an area through both vertical and lateral imaging of the subsurface. The geophysical method, electrical resistivity tomography (ERT), can reduce a significant number of expensive drilling tests in geotechnical investigations. However, a geophysical method alone may provide ambiguity in the interpretation of the subsurface, such as electrical resistivity cannot differentiate between water and clay content. Such uncertainty can be improved by the integration of ERT with induced polarization (IP). Similarly, self-potential (SP) can be integrated with other geophysical methods to delineate the groundwater flow. In this contribution, we integrated three geophysical methods (ERT, IP and SP) to delineate the weathered and unweathered rock including the weathered/unweathered transition zone, to detect the fractures/faults, and to map the groundwater flow. Based on ERT, IP and SP results, we develop a geophysical conceptual site model which can be used by site engineers to interpret/implement the findings for build-out. Our approach fills the gaps between the well data and geological model and suggests the most suitable places for the development of engineered structures in the hard rock terrains.

Structure and Properties of Supercritical Water: Experimental and Theoretical Characterizations

Water in the supercritical region of the phase diagram exhibits a markedly different structure and properties from that at ambient conditions, which is useful in controlling chemical reactions. Nonetheless, the experimental, as well as theoretical, characterization of the substance is not easy because the region is next to the critical point. This article reviews the experimental as well as theoretical studies on water in the supercritical region and its properties as a solvent for chemical reactions, as carried out by the authors and based on small-angle X-ray scattering and the statistical mechanics theory of molecular liquids, also known as reference interaction-site model (RISM) theory.

Groundwater contamination risk assessment based on advection-dispersion equation

The consequences of contaminated groundwater can seriously affect sustainable development; present and future generations being seriously affected by inadequate drinking water quality, loss of water supply, degraded surface water systems, high remediation costs, more expenses for other water supplies, and likely health issues. Therefore, an effective way to protect groundwater resources is by assessing the risk of groundwater contamination. An assessment of groundwater pollution should be performed to determine the level of risk posed by soil and groundwater contamination and establish if remediation strategies are required to protect controlled waters from site-derived contamination. Furthermore, if remediation is deemed necessary, site-specific remedial targets should be derived. A case study is presented, where a Conceptual Site Model was derived based on a “Source-Pathway-Receptor” exposure mechanism using historical information. Primary sources of contamination at the site are residual contamination within the soil and groundwater, and samples were collected from the site and tested in the laboratory; the concentration of water samples was compared to Romanian Drinking Water Standards. The following potential migration pathways have been identified: Leaching from soil and Migration of contaminated groundwater. The Detailed Quantitative Risk Assessment (DQRA) has modelled the leaching of contaminants from the site via infiltration and vertical migration to the groundwater and subsequent lateral groundwater migration, with dilution and attenuation process active, to the compliance point, using Ogata-Banks equation. The results of this assessment indicate that the concentration of contaminants does not represent a significant risk to controlled waters.

Asymmetric Interplay Between K+ and Blocker and Atomistic Parameters From Physiological Experiments Quantify K+ Channel Blocker Release

Modulating the activity of ion channels by blockers yields information on both the mode of drug action and on the biophysics of ion transport. Here we investigate the interplay between ions in the selectivity filter (SF) of K+ channels and the release kinetics of the blocker tetrapropylammonium in the model channel KcvNTS. A quantitative expression calculates blocker release rate constants directly from voltage-dependent ion occupation probabilities in the SF. The latter are obtained by a kinetic model of single-channel currents recorded in the absence of the blocker. The resulting model contains only two adjustable parameters of ion-blocker interaction and holds for both symmetric and asymmetric ionic conditions. This data-derived model is corroborated by 3D reference interaction site model (3D RISM) calculations on several model systems, which show that the K+ occupation probability is unaffected by the blocker, a direct consequence of the strength of the ion-carbonyl attraction in the SF, independent of the specific protein background. Hence, KcvNTS channel blocker release kinetics can be reduced to a small number of system-specific parameters. The pore-independent asymmetric interplay between K+ and blocker ions potentially allows for generalizing these results to similar potassium channels.

Accurate Absorption Energy Calculations in Solution Using the Reference Interaction Site Model Self-Consistent Field Including the Constrained Spatial Electron Density Distribution

The solvation effect is an important factor determining the properties of molecules in solution. The reference interaction site model (RISM) is a powerful method to treat the solvation effect with pair-correlation functions, such as a radial distribution function. This study developed a hybrid method between quantum mechanics and RISM using the spatial electron density distributions on each atomic site (RISM-SCF-cSED). Sophisticated quantum mechanical approaches can be used to consider the solvation effect because the computational cost of RISM-SCF-cSED is reasonable. In this study, the absorption energies of 5-(dimethylamino)-2,4-pentadienal in various solutions were calculated using RISM-SCF-cSED. The experimental data were well reproduced with an average errors of ∼0.06 eV, using multi-reference perturbation theory.

Physical observables to determine the nature of membrane-less cellular sub-compartments

The spatial organization of complex biochemical reactions is essential for the regulation of cellular processes. Membrane-less structures called foci containing high concentrations of specific proteins have been reported in a variety of contexts, but the mechanism of their formation is not fully understood. Several competing mechanisms exist that are difficult to distinguish empirically, including liquid-liquid phase separation, and the trapping of molecules by multiple binding sites. Here we propose a theoretical framework and outline observables to differentiate between these scenarios from single molecule tracking experiments. In the binding site model, we derive relations between the distribution of proteins, their diffusion properties, and their radial displacement. We predict that protein search times can be reduced for targets inside a liquid droplet, but not in an aggregate of slowly moving binding sites. We use our results to reject the multiple binding site model for Rad52 foci, and find a picture consistent with a liquid-liquid phase separation. These results are applicable to future experiments and suggest different biological roles for liquid droplet and binding site foci.