Genetic mapping of complex traits by minimizing integrated square errors

<p>Abstract</p> <p>Background</p> <p>Genetic mapping has been used as a tool to study the genetic architecture of complex traits by localizing their underlying quantitative trait loci (QTLs). Statistical methods for genetic mapping rely on a key assumption, that is, traits obey a parametric distribution. However, in practice real data may not perfectly follow the specified distribution.</p> <p>Results</p> <p>Here, we derive a robust statistical approach for QTL mapping that accommodates a certain degree of misspecification of the true model by incorporating integrated square errors into the genetic mapping framework. A hypothesis testing is formulated by defining a new test statistics - energy difference.</p> <p>Conclusions</p> <p>Simulation studies were performed to investigate the statistical properties of this approach and compare these properties with those from traditional maximum likelihood and non-parametric QTL mapping approaches. Lastly, analyses of real examples were conducted to demonstrate the usefulness and utilization of the new approach in a practical genetic setting.</p

Equivalence of Discrete Fracture Network and Porous Media Models by Hydraulic Tomography

Hydraulic tomography (HT) has emerged as a potentially viable method for mapping fractures in geologic media as demonstrated by recent studies. However, most of the studies adopted equivalent porous media (EPM) models to generate and invert hydraulic interference test data for HT. While these models assign significant different hydraulic properties to fractures and matrix, they may not fully capture the discrete nature of the fractures in the rocks. As a result, HT performance may have been overrated. To explore this issue, this study employed a discrete fracture network (DFN) model to simulate hydraulic interference tests. HT with the EPM model was then applied to estimate the distributions of hydraulic conductivity (K) and specific storage (S-s) of the DFN. Afterward, the estimated fields were used to predict the observed heads from DFN models, not used in the HT analysis (i.e., validation). Additionally, this study defined the spatial representative elementary volume (REV) of the fracture connectivity probability for the entire DFN dominant. The study showed that if this spatial REV exists, the DFN is deemed equivalent to EPM and vice versa. The hydraulic properties estimated by HT with an EPM model can then predict head fields satisfactorily over the entire DFN domain with limited monitoring wells. For a sparse DFN without this spatial REV, a dense observation network is needed. Nevertheless, HT is able to capture the dominant fractures.National Science and Technology Major Project of China [2017ZX05008-003-021]; Strategic Priority Research Program of the Chinese Academy of Sciences [XDB10030601]; Youth Innovation Promotion Association of the Chinese Academy of Sciences [2016063]; US Civilain Research and Development Foundation (CRDF) under the award: Hydraulic tomography in shallow alluvial sediments: Nile River Valley, Egypt [DAA2-15-61224-1]; Global Expert award through Tianjin Normal University from the Thousand Talents Plan of Tianjin City6 month embargo; published online: 23 April 2019This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Modelling, Simulation and Dynamic Sliding Mode Control of a MEMS Gyroscope

An adaptive dynamic sliding mode control via a backstepping approach for a microelectro mechanical system (MEMS) vibratory z-axis gyroscope is presented in this paper. The time derivative of the control input of the dynamic sliding mode controller (DSMC) is treated as a new control variable for the augmented system which is composed of the original system and the integrator. This DSMC can transfer discontinuous terms to the first-order derivative of the control input, and effectively reduce the chattering. An adaptive dynamic sliding mode controller with the method of backstepping is derived to real-time estimate the angular velocity and the damping and stiffness coefficients and asymptotical stability of the designed systems can be guaranteed. Simulation examples are investigated to demonstrate the satisfactory performance of the proposed adaptive backstepping sliding mode control

Fibrinolytic system and COVID-19: From an innovative view of epithelial ion transport

Lifeways of worldwide people have changed dramatically amid the coronavirus disease 2019 (COVID-19) pandemic, and public health is at stake currently. In the early stage of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, fibrinolytic system is mostly inhibited, which is responsible for the development of hypofibrinolysis, promoting disseminated intravascular coagulation, hyaline membrane formation, and pulmonary edema. Whereas the common feature and risk factor at advanced stage is a large amount of fibrin degradation products, including D-dimer, the characteristic of hyperfibrinolysis. Plasmin can cleave both SARS-CoV-2 spike protein and γ subunit of epithelial sodium channel (ENaC), a critical element to edematous fluid clearance. In this review, we aim to sort out the role of fibrinolytic system in the pathogenesis of COVID-19, as well as provide the possible guidance in current treating methods. In addition, the abnormal regulation of ENaC in the occurrence of SARS-CoV-2 mediated hypofibrinolysis and hyperfibrinolysis are summarized, with the view of proposing an innovative view of epithelial ion transport in preventing the dysfunction of fibrinolytic system during the progress of COVID-19

Ferulic Acid: A Review of Pharmacology, Toxicology, and Therapeutic Effects on Pulmonary Diseases

Ferulic acid (FA), a prevalent dietary phytochemical, has many pharmacological effects, including anti-oxidation and anti-inflammation effects, and has been widely used in the pharmaceutical, food, and cosmetics industries. Many studies have shown that FA can significantly downregulate the expression of reactive oxygen species and activate nuclear factor erythroid-2-related factor-2/heme oxygenase-1 signaling, exerting anti-oxidative effects. The anti-inflammatory effect of FA is mainly related to the p38 mitogen-activated protein kinase and nuclear factor-kappaB signaling pathways. FA has demonstrated potential clinical applications in the treatment of pulmonary diseases. The transforming growth factor-β1/small mothers against decapentaplegic 3 signaling pathway can be blocked by FA, thereby alleviating pulmonary fibrosis. Moreover, in the context of asthma, the T helper cell 1/2 imbalance is restored by FA. Furthermore, FA ameliorates acute lung injury by inhibiting nuclear factor-kappaB and mitogen-activated protein kinase pathways via toll-like receptor 4, consequently decreasing the expression of downstream inflammatory mediators. Additionally, there is a moderate neuraminidase inhibitory activity showing a tendency to reduce the interleukin-8 level in response to influenza virus infections. Although the application of FA has broad prospects, more preclinical mechanism-based research should be carried out to test these applications in clinical settings. This review not only covers the literature on the pharmacological effects and mechanisms of FA, but also discusses the therapeutic role and toxicology of FA in several pulmonary diseases

Regional groundwater flow pattern in Beishan, Hexi Corridor and Qilian Mountain

Groundwater flow in mountainous areas is controlled by climate conditions, topography, geological structure, and other factors.Due to the restrictions such as data acquisition, the groundwater flow pattern and control mechanism in mountainous areas are still not clearly understood.Taking Beishan area as an example, which locates the pre-selected area of the Geological Repository for High-Level radioactive Waste in China, groundwater flow pattern is of great significance for the safety of the repository on the ten-thousand-year time scale.In this study, characteristics of the hydrogeological structure and permeability in Beishan area, Hexi Corridor, and Qilian Mountains were obtained based on regional remote sensing interpretation, geological structure evolution analysis, geophysical exploration, and hydrogeological drilling.A conceptual model was proposed through comprehensive hydrogeological survey, hydrogeochemical and isotope analysis.In addition, regional groundwater flow numerical models and multi-scenario simulations were used to understand the groundwater flow patterns in the Beishan-Hexi Corridor-Qilian Mountains in Gansu.Results show that topography plays a dominant role in the groundwater flow pattern in the area.Groundwater from Qilian Mountains is difficult to pass through the Hexi Corridor to discharge in the Beishan Mountains.With the lowest altitude in the region, the Hexi Corridor can be regarded as the boundary of the groundwater system between the Qilian Mountains and the Beishan Mountain.Under the control of topography and lithology, the groundwater in Beishan mountain area only develops local flow systems and the flow velocity is small.At the same time, due to the blocking effect of the faults in this area, the groundwater from Xinchang, the key pre-selected high level radioactive waste disposal site in Beishan, cannot flow directly to the south into the Huahai Basin.In addition, its length of the flow path is greatly increased.Only the groundwater on the south side of the F95 fault can discharge to the Huahai Basin, but due to the limited catchment basin, slow flow velocity and poor circulation condition, the discharge is weak.This study investigates the mountain-basin groundwater circulation pattern, and provides a scientific basis for the site evaluation of the geological repository for high-level radioactive waste in Beishan, Gansu

Characteristics of hydraulic conductivity in mountain block systems and its effects on mountain block recharge: Insights from field investigation and numerical modeling

International audienceThe process wherein groundwater flowing from mountain bedrock into lowland and adjacent alluvial aquifers, known as mountain-block recharge (MBR), is found across various climatic and geological settings. An understanding of the potential groundwater flow paths in mountain block systems is necessary for comprehending MBR spatial distribution. However, poorly characterized mountain block hydraulic properties, and especially a lack of direct measurements of hydraulic conductivity (K) at depths >200 m, limit the characterization and quantifications of the MBR processes. In this study, we analyze hydraulic data set, namely 555 in-situ K measurements at various depths from two borehole sections extending from mountain block to mountain front in a potential disposal site for high-level radioactive waste. The K dataset was categorized into two groups: one for bedrock and another for fault zones, which was further classified into fault core K, damage zone K, and general fault zone K. Using a permeability conceptual model and multiple scenarios numerical modelling, this study examined the potential flow paths of MBR processes, mainly focusing on the characteristics of K in bedrocks and the hydraulic role of fault zones in mountain block systems. The distribution of Bedrock K supports the assumption of decreased trend with depth. A logarithmic fit through Bedrock K and depth pairs resulted in Log(K) = -1.62*Log(z) - 6.52, with low predictive power. This study illustrated the localized effects and spatially variable roles of fault zones in MBR within this particular hydrogeological configuration in Beishan, China. Our results provide insights into the MBR process in crystalline mountain block systems. Additionally, the hydraulic conductivity presented here provides data on the subsurface properties of mountain block systems in a crystalline area, and further facilitates the characterization and quantification of mountain-block recharge

8-Methoxyflindersine-Induced Apoptosis and Cell Cycle Disorder Involving MAPK Signaling Activation in Human Colorectal Cancer Cells

Colorectal cancer (CRC) is one of the most common malignant tumors with a high lethal rate globally, and novel strategies for its prevention and therapy are urgently needed. In our previous work, 8-methoxyflindersine (8-MF), a quinoline alkaloid, was isolated from the Dictamni cortex, and its bioactivities were largely unknown. In this study, we found that 8-MF significantly inhibited cell viability in the CRC cell lines LoVo and RKO. The 8-MF-induced CRC cell apoptosis, as well as cell cycle disorder, were further verified by cyclins dysregulation in mRNA and protein levels. Further, the activation of MAPK family members p38 and ERK1/2 was observed after 8-MF treatment. Moreover, the protein–protein interaction of 8-MF with cyclins and MAPKs was demonstrated using the STRING database. The 8-MF could bind to p38 and ERK1/2 proteins in molecular docking. Taken together, we found that 8-MF induced apoptosis and cell cycle disorder involving MAPK signaling activation in CRC cells, indicating 8-MF as a novel lead compound candidate for the development of anti-tumor drugs for CRC