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Background: Exposure to plastic-associated endocrine disrupting chemicals (EDCs) has been associated with an increased risk of cardiovascular disease (CVD) in humans. However, the underlying mechanisms for this association are unclear. Many EDCs have been shown to function as ligands of the nuclear receptor pregnane X receptor (PXR), which functions as xenobiotic sensor but also has pro-atherogenic effects in vivo. Objective: We sought to investigate the contribution of PXR to the adverse effects dicyclohexyl phthalate (DCHP), a widely used phthalate plasticizer, on lipid homeostasis and CVD risk factors. Methods: Cell-based assays, primary organoid cultures, and PXR conditional knockout and PXR-humanized mouse models were used to investigate the impact of DCHP exposure on PXR activation and lipid homeostasis in vitro and in vivo. Targeted lipidomics were performed to measure circulating ceramides, novel predictors for CVD. Results: DCHP was identified as a potent PXR-selective agonist that led to higher plasma cholesterol levels in wild- type mice. DCHP was then demonstrated to activate intestinal PXR to elicit hyperlipidemia by using tissue-specific PXR-deficient mice. Interestingly, DCHP exposure also led to higher circulating ceramides in a PXR-dependent manner. DCHP-mediated PXR activation stimulated the expression of intestinal genes mediating lipogenesis and ceramide synthesis. Given that PXR exhibits considerable species-specific differences in receptor pharmacology, PXR-humanized mice were also used to replicate these findings. Discussion: Although the adverse health effects of several well-known phthalates have attracted considerable attention, little is known about the potential impact of DCHP on human health. Our studies demonstrate that DCHP activated PXR to induce hypercholesterolemia and ceramide production in mice. These results indicate a potentially important role of PXR in contributing to the deleterious effects of plastic-associated EDCs on cardiovascular health in humans. Testing PXR activation should be considered for risk assessment of phthalates and other EDCs., Introduction Atherosclerotic cardiovascular disease (CVD) is still the leading cause of mortality and morbidity worldwide despite advanced diagnosis and treatments (Helsley and Zhou 2017; Roth et al. 2015). In the [...]

BACKGROUND: The concept of chemical agents having properties that confer potential hazard called key characteristics (KCs) was first developed to identify carcinogenic hazards. Identification of KCs of cardiovascular (CV) toxicants could facilitate the systematic assessment of CV hazards and understanding of assay and data gaps associated with current approaches. OBJECTIVES: We sought to develop a consensus-based synthesis of scientific evidence on the KCs of chemical and nonchemical agents known to cause CV toxicity along with methods to measure them. METHODS: An expert working group was convened to discuss mechanisms associated with CV toxicity. RESULTS: The group identified 12 KCs of CV toxicants, defined as exogenous agents that adversely interfere with function of the CV system. The KCs were organized into those primarily affecting cardiac tissue (numbers 1-4 below), the vascular system (5-7), or both (8-12), as follows: 1) impairs regulation of cardiac excitability, 2) impairs cardiac contractility and relaxation, 3) induces cardiomyocyte injury and death, 4) induces proliferation of valve stroma, 5) impacts endothelial and vascular function, 6) alters hemostasis, 7) causes dyslipidemia, 8) impairs mitochondrial function, 9) modifies autonomic nervous system activity, 10) induces oxidative stress, 11) causes inflammation, and 12) alters hormone signaling. DISCUSSION: These 12 KCs can be used to help identify pharmaceuticals and environmental pollutants as CV toxicants, as well as to better understand the mechanistic underpinnings of their toxicity. For example, evidence exists that fine particulate matter [PM [less than or equal to]2.5 [micro]m in aerodynamic diameter (P[M.sub.2.5])] air pollution, arsenic, anthracycline drugs, and other exogenous chemicals possess one or more of the described KCs. In conclusion, the KCs could be used to identify potential CV toxicants and to define a set of test methods to evaluate CV toxicity in a more comprehensive and standardized manner than current approaches. https://doi.org/10.1289/EHP9321, Introduction According to the World Health Organization, cardiovascular disease (CVD) is the leading cause of death worldwide, taking 1.7 million lives annually (WHO 2017). Four of five of those deaths [...]

We previously reported that microRNA (miR)23a and miR30b are selectively sorted into exosomes derived from rickettsia‐infected endothelial cells (R‐ECExos). Yet, the mechanism remains unknown. Cases of spotted fever rickettsioses have been increasing, and infections with these bacteria cause life‐threatening diseases by targeting brain and lung tissues. Therefore, the goal of the present study is to further dissect the molecular mechanism underlying R‐ECExos‐induced barrier dysfunction of normal recipient microvascular endothelial cells (MECs), depending on their exosomal RNA cargos. Infected ticks transmit the rickettsiae to human hosts following a bite and injections of the bacteria into the skin. In the present study, we demonstrate that treatment with R‐ECExos, which were derived from spotted fever group R parkeri infected human dermal MECs, induced disruptions of the paracellular adherens junctional protein VE‐cadherin, and breached the paracellular barrier function in recipient pulmonary MECs (PMECs) in an exosomal RNA‐dependent manner. We did not detect different levels of miRs in parent dermal MECs following rickettsial infections. However, we demonstrated that the microvasculopathy‐relevant miR23a‐27a‐24 cluster and miR30b are selectively enriched in R‐ECExos. Bioinformatic analysis revealed that common sequence motifs are shared exclusively among the exosomal, selectively‐enriched miR23a cluster and miR30b at different levels. Taken together, these data warrant further functional identification and characterization of a monopartition, bipartition, or tripartition among ACA, UCA, and CAG motifs that guide recognition of microvasculopathy‐relevant miR23a‐27a‐24 and miR30b, and subsequently results in their selective enrichments in R‐ECExos. [ABSTRACT FROM AUTHOR]

Renal ischemia–reperfusion injury (IRI) is a significant cause of acute kidney injury (AKI) and usually brings severe public health consequences. Adipose-derived endothelial progenitor cell (AdEPCs) transplantation is beneficial for AKI but suffers from low delivery efficiency. This study was conducted to explore the protective effects of magnetically delivered AdEPCs on the repair of renal IRI. Two types of magnetic delivery methods, namely the endocytosis magnetization (EM) method and the immunomagnetic (IM) method were fabricated using PEG@Fe3O4 and CD133@Fe3O4, and their cytotoxicities in AdEPCs were assessed. In the renal IRI rat model, magnetic AdEPCs were injected via the tail vein and a magnet was placed beside the injured kidney for magnetic guidance. The distribution of transplanted AdEPCs, renal function, and tubular damage were evaluated. Our results suggested that CD133@Fe3O4 had the minimum negative effects on the proliferation, apoptosis, angiogenesis, and migration of AdEPCs compared with PEG@Fe3O4. Renal magnetic guidance could significantly enhance the transplantation efficiency and the therapeutic outcomes of AdEPCs–PEG@Fe3O4 and AdEPCs–CD133@Fe3O4 in the injured kidneys. However, under renal magnetic guidance, AdEPCs–CD133@Fe3O4 had stronger therapeutic effects than PEG@Fe3O4 after renal IRI. The immunomagnetic delivery of AdEPCs with CD133@Fe3O4 could be a promising therapeutic strategy for renal IRI. [ABSTRACT FROM AUTHOR]

The loss of drilling fluids often occurs during reservoir extraction in fractured formations, and the prediction of natural fracture loss rate is vital for controlling drilling fluids loss. However, the coupling of loss model to wellbore flow has rarely been considered. Based on the non-Newtonian fluid loss dynamics theory, this study considers Herschel–Buckley fluid and develops an updated numerical model to couple the loss of fracture with wellbore flow. The roughness of the fracture is characterized using the continuous random accumulation method. The coupling model is verified by field data, and its simulated results show the average relative and maximum relative errors were 4.76% and 12.8%, respectively. A linear throttle valve is introduced to simulate the effect of regulating wellhead back pressure and pump displacement on drilling fluids loss in managed pressure drilling, and the results indicate that the impact of regulating wellhead back pressure is better than that of pump displacement. This paper studies the pressure fluctuates of the fractured borehole breathing mechanism in detail and has proposed two possible scenarios that may cause borehole breathing. Increasing the wellhead back pressure can convert the overflow into loss, while reducing the wellhead back pressure by too much at once may also turn a loss into an overflow. The orthogonal experiment design is performed to study the influence of eight parameters on the loss rate, and the order of influence is as follows: fracture width, fluidity index, fracture area, consistency factor, yield stress, drilling fluids density, circulating displacement, and fracture dip. [ABSTRACT FROM AUTHOR]

For the shortcomings of the analytical calculation method and the design of few-piece main-auxiliary parabolic leaf springs, based on the theory of material mechanics, through analyzing the actual structural characteristics of the few-piece main-auxiliary parabolic leaf spring with root diagonal segment, an analytical calculation model of the deformation and stress for the few piece main-auxiliary parabolic leaf spring with root diagonal segment was established. The reliability of the analytical calculation model was verified by using the leaf spring mechanical characteristics test platform. The results show that the maximum deviation between the analytical calculation values of the deformation and stress obtained by the calculation model and the test value is only 4.76% and 6.06%, respectively, which can effectively characterize the mechanical characteristics of the actual few-piece main-auxiliary parabolic leaf spring. The research can quickly and accurately realize the stiffness check, strength check, and forward design of the few-piece main-auxiliary parabolic leaf spring with root diagonal segment, which provides an effective theoretical basis and technical reference for the parabolic leaf spring design. [ABSTRACT FROM AUTHOR]

Pressure waves possess many significant applications in the oil and gas drilling engineering field, such as mud pulse telemetry (MPT) and measurement while drilling (MWD). The focus of this research is to study the pressure wave propagation and attenuation characteristics of wellbore liquid-phase flow in managed pressure drilling (MPD) by fast switching throttle valve (FSTV). First, a mathematical model of transient pressure wave propagation along the wellbore in both upstream and downstream directions is proposed in MPD by FSTV based on the one-dimensional transient flow theory. The model considering the frictional shear effect between the pipe walls is solved by utilizing the method of characteristics. Meanwhile, boundary conditions at the drill string inlet and annulus outlet, at the throttle valve, at the junction of drill bit, and at the reducer are adequately taken into account according to the actual situation of fluid flow. Second, a laboratory experiment of excited pressure waves in a vertical wellbore is conducted to measure the variation of the pressure fluctuation with different pump rates by FSTV. Comparing with the measurement result, the calculation result is discovered that the overall change is consistent, where the maximum absolute relative error at the peak of the pressure wave is only 4.5%. Finally, it further analyzes influential factors affecting the propagation and attenuation behaviors of wellbore pressure waves in liquid-phase flow based on the model. The results indicate that pressure waveforms present sinusoidal wave propagation, and pump rates, pressure wave speed, excitation time, fluid type, mud density, fluid viscosity, and borehole size exert varying degrees of influence on downhole pressure fluctuations. The proposed model achieves accurate quantitative interpretation and analysis of downhole pressure wave in MPD by FSTV, which has important significance for the realization of safe and efficient drilling. [ABSTRACT FROM AUTHOR]

Simple Summary: The morbidity and mortality of renal cell carcinoma (RCC) remain high, and there is an urgent need to explore the reliable biomarker and molecular mechanism of RCC. Circ-PRKCI is a novel circRNA discovered in recent years, and has been confirmed to participate in tumor progression by acting as an miRNA sponge. However, the role of circ-PRKCI in RCC remains unclear. Here, with the aid of an online bioinformatics database and luciferase reporter assays, we found that circ-PRKCI could bind to miR-545-3p, while CCND1 served as a target of miR-545-3p. Caki-1-derived exosomes could thus inhibit miR-545-3p expression via the upregulation of circ-PRKCI. Through a series of functional experiments, we confirmed that Caki-1-derived exosomal circ-PRKCI promoted RCC proliferation by regulating the miR-545-3p/CCND1 axis. Our study will provide new insights for RCC clinical treatment. Renal cell carcinoma (RCC) originates from the epithelial cells of the renal tubules and has a high degree of malignancy and heterogeneity. Recent studies have found that exosomes regulate intercellular communication via transferring various bioactive molecules, such as circular RNAs (circRNAs), which are critical for cancer progression. However, the role of tumor cell-derived exosomal circRNAs in RCC remains unclear. In this study, we reported the high expression of circ-PRKCI in RCC tissues and serum exosomes. We also found that circ-PRKCI could be transferred exosomally from highly malignant RCC cells to relatively less malignant RCC cells. Tumor cell-derived exosomal circ-PRKCI promoted the proliferation, migration, and invasion of RCC cells, while inhibiting their apoptosis. Mechanistically, we found that circ-PRKCI promoted the proliferation of RCC via the miR-545-3p/CCND1 signaling pathway. Our study is the first to report the potential mechanisms of tumor cell-derived exosomal circ-PRKCI in RCC. In conclusion, this study will provide a new understanding about the molecular mechanisms of RCC progression. [ABSTRACT FROM AUTHOR]