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Extracts of Cyclocarya paliurus (CP) leaves, a popular sweet tea, inhibit pancreatic β cell apoptosis and have potent hypoglycemic effects, but the identities of the anti-apoptotic bioactive components are still unknown. In the present study, a method using UPLC-Q-TOF/MS based on serum pharmacochemistry combined with target cell extraction was established to rapidly identify direct-acting pancreatic protectants from CP. After orally administering a set amount of CP extract to rats, blood samples were collected to characterize the components that can be absorbed into the blood using UPLC-Q-TOF/MS. Also, target cells (pancreatic β NIT-1 cells) were incubated with CP extract for 24 hours, and cells were collected to identify the components that can bind to the cells using UPLC-Q-TOF/MS. Finally, to evaluate the protective effect of the bioactive components of CP, MTT and TUNEL assays were performed on treated NIT-1 cell induced by streptozotocin (STZ). Three potential direct-acting pancreatic protectants -- kaempferol, quercetin, quadranoside IV -- were identified, and anti-apoptotic effects of kaempferol and quercetin were confirmed in STZ-induced NIT-1 cells. The findings indicate that this combined approach is a feasible, rapid, and expedient tool for capturing potential direct-acting components from natural products such as those from CP leaves.

Introduction/Objective. Most patients with end-stage renal disease (ESRD) have hypertension. However, dialysis-related strategies to optimize blood pressure in these patients remain controversial. The current study aims to investigate the influence of dialysate sodium profiling on ambulatory blood pressure (ABP) in patients on maintenance hemodialysis, when there are no adequate dialytic and economic resources or high patient compliance. Methods. This prospective, single-center study enrolled 60 hypertensive ESRD patients. Subjects received maintenance dialysis with regular dialysate sodium concentration (140 mmol/L) during the initial three months after the enrollment, and were randomly assigned to continue regular sodium dialysate (group A) or switch to sodium profiling (group B) for duration of three months. ABP, heart rate (HR), pre-/postdialysis serum sodium levels, antihypertensive treatment dosages, and interdialytic weight gain (IDWG) etc. were recorded after treatment assignment. Results. Thirty patients each were enrolled in groups A and B. The characteristics at baseline were not significantly different between the two groups. Compared to patients in group A three months later, patients in group B had lower systolic ABP (p = 0.00), HR (p = 0.04), IDWG (p = 0.04), and antihypertensive medication dosages (p = 0.04). Throughout the treatment duration, no significant inter-group differences were observed for pre-/post-dialysis serum sodium and intradialytic complications. Additionally, no significant correlations were found between systolic or diastolic ABP and other variables studied in this study. Conclusion. In this study, we found that dialysate sodium profiling successfully ameliorated hypertension and reduced BP medications without altering natremic levels or increasing complications among patients on maintenance hemodialysis during the three months. Dialysate sodium profiling was relatively safe in this duration.

Tolvaptan is the only drug approved to slow cyst growth and preserve kidney function in patients with autosomal dominant polycystic kidney disease (ADPKD). However, its limited efficacy combined with significant side effects underscores the need to identify new and safe therapeutic drug targets to slow progression to end stage kidney disease. We identified Discoidin Domain Receptor 1 (DDR1) as receptor tyrosine kinase upregulated in vivo in 3 mouse models of ADPKD using a novel mass spectrometry approach to identify kinases upregulated in ADPKD. Previous studies demonstrating critical roles for DDR1 to cancer progression, its potential role in the pathogenesis of a variety of other kidney disease, along with the possibility that DDR1 could provide new insight into how extracellular matrix impacts cyst growth led us to study the role of DDR1 in ADPKD pathogenesis. However, genetic deletion of DDR1 using CRISPR/Cas9 failed to slow cyst growth or preserve kidney function in both a rapid and slow mouse model of ADPKD demonstrating that DDR1 does not play a role in PKD pathogenesis and is thus a not viable drug target. In spite of the negative results, our studies will be of interest to the nephrology community as it will prevent others from potentially conducting similar experiments on DDR1 and reinforces the potential of performing unbiased screens coupled with in vivo gene editing using CRISPR/Cas9 to rapidly identify and confirm new potential drug targets for ADPKD.

In order to improve the heat dissipation performance and study the factors affecting the heat dissipation effect of a two-dimensional ordered porous structure, a thermal analysis of the radiator in the power module of a DC charging pile was carried out. Based on the thermal analysis of the grid-type radiator, the square-hole radiator is subjected to a thermal analysis, the heat dissipation performance of the two radiators is compared, and the factors affecting the heat dissipation effect of the square-hole radiator are explored. Research shows that the heat dissipation effect of the square-hole radiator, which represents a twodimensional ordered porous structure, is better than that of the grid-type radiator. The factors affecting the heat dissipation effect of the square-hole radiator are mainly related to the height of the radiator and are positively related to the heat dissipation effect of the radiator.

Cross linking of the IgE receptor (FcεRI) on mast cells plays a critical role in IgE-dependent allergy including allergic rhinitis, asthma, anaphylaxis, and delayed type hypersensitivity reactions. The Ca2+ activated K+ channel, KCa3.1, plays a critical role in IgE-stimulated Ca2+ entry and degranulation in mast cells by helping to maintain a negative membrane potential, which provides an electrochemical gradient to drive Ca2+ influx. Of the 3 classes of PI3K, the class II PI3Ks are the least studied and little is known about the roles for class II PI3Ks in vivo in the context of the whole organism under normal and pathological conditions. Studying bone marrow derived mast cells (BMMC) isolated from PI3KC2β-/- mice, we now show that the class II PI3KC2β is critical for FcεRI stimulated KCa3.1 channel activation and the subsequent activation of mast cells. We found FcεRI-stimulated Ca2+ entry, cytokine production, and degranulation are decreased in BMMC isolated from PI3KC2β-/- mice. In addition, PI3KC2β-/- mice are markedly resistant to both passive cutaneous and passive systemic anaphylaxis. These findings identify PI3KC2β as a new pharmacologic target to treat IgE-mediated disease.

KCa2.1, KCa2.2, KCa2.3 and KCa3.1 constitute a family of mammalian small- to intermediate-conductance potassium channels that are activated by calcium-calmodulin. KCa3.1 is unique among these four channels in that activation requires, in addition to calcium, phosphorylation of a single histidine residue (His358) in the cytoplasmic region, by nucleoside diphosphate kinase-B (NDPK-B). The mechanism by which KCa3.1 is activated by histidine phosphorylation is unknown. Histidine phosphorylation is well characterized in prokaryotes but poorly understood in eukaryotes. Here, we demonstrate that phosphorylation of His358 activates KCa3.1 by antagonizing copper-mediated inhibition of the channel. Furthermore, we show that activated CD4+ T cells deficient in intracellular copper exhibit increased KCa3.1 histidine phosphorylation and channel activity, leading to increased calcium flux and cytokine production. These findings reveal a novel regulatory mechanism for a mammalian potassium channel and for T-cell activation, and highlight a unique feature of histidine versus serine/threonine and tyrosine as a regulatory phosphorylation site.

The motor drive system represents a key technology for development of the electrical vehicles, and the permanent magnet synchronous motor becomes the mainstream of the new energy vehicle drive motor for the superior performances in power density, low-speed torque density, efficiency and reliability. The paper studies the field weakening control strategy for the interior permanent magnet synchronous motor (IPMSM) and provides a field weakening control strategy for the IPMSM at the full-speed range. By studying the mathematical IPMSM model and the methods of conventional vector control and analyzing the operating conditions of the IPMSM at the full-speed range, the paper divides the operating conditions into constant torque operation region I, constant torque operation region II, constant power field weakening operation region and high-speed field weakening operation region to confirm the control strategy algorithm in each region and the transition conditions between regions and provide the current control strategy that the d-axis current and q-axis current are confirmed by the reference torque and the feedback speed. Modeling of the field weakening control strategies in each region is made through the Matlab/Simulink, and simulation of the operating conditions with a steady-state load and a dynamic load is done to verify that the field weakening control strategy in each region is feasible. A co-simulation is made by combining the Matlab/Simulink-based control model, the RecurDyn-based virtual prototype and the RT-LAB to verify the feasible field weakening control strategy.