Moiré synaptic transistor with room-temperature neuromorphic functionality.

Moiré quantum materials host exotic electronic phenomena through enhanced internal Coulomb interactions in twisted two-dimensional heterostructures1-4. When combined with the exceptionally high electrostatic control in atomically thin materials5-8, moiré heterostructures have the potential to enable next-generation electronic devices with unprecedented functionality. However, despite extensive exploration, moiré electronic phenomena have thus far been limited to impractically low cryogenic temperatures9-14, thus precluding real-world applications of moiré quantum materials. Here we report the experimental realization and room-temperature operation of a low-power (20 pW) moiré synaptic transistor based on an asymmetric bilayer graphene/hexagonal boron nitride moiré heterostructure. The asymmetric moiré potential gives rise to robust electronic ratchet states, which enable hysteretic, non-volatile injection of charge carriers that control the conductance of the device. The asymmetric gating in dual-gated moiré heterostructures realizes diverse biorealistic neuromorphic functionalities, such as reconfigurable synaptic responses, spatiotemporal-based tempotrons and Bienenstock-Cooper-Munro input-specific adaptation. In this manner, the moiré synaptic transistor enables efficient compute-in-memory designs and edge hardware accelerators for artificial intelligence and machine learning.

Dynamic Monitoring of Intracellular Tacrolimus and Mycophenolic Acid Therapy in Renal Transplant Recipients Using Magnetic Bead Extraction Combined with LC-MS/MS.

BACKGROUND: Tacrolimus (TAC) and mycophenolic acid (MPA) are commonly used immunosuppressive therapies after renal transplant. Our objective was to quantify TAC and MPA concentrations in peripheral blood mononuclear cells (PBMCs) using liquid chromatography tandem mass spectrometry (LC-MS/MS) and to evaluate and validate the performance of the methodology. A prospective follow-up cohort study was conducted to determine whether intracellular concentrations were associated with adverse outcomes in renal transplants. METHODS: PBMCs were prepared using the Ficoll separation technique and purified with erythrocyte lysis. The cells were counted using Sysmex XN-3100 and then packaged and frozen according to a 50 µL volume containing 1.0 × 106 cells. TAC and MPA were extracted using MagnaBeads and quantified using an LC-MS/MS platform. The chromatography was run on a reversed-phase Waters Acquity UPLC BEH C18 column (1.7 µm, 50 mm × 2.1 mm) for gradient elution separation with a total run time of 4.5 min and a flow rate of 0.3 mL/min. Mobile phases A and B were water and methanol, respectively, each containing 2 mM ammonium acetate and 0.1% formic acid. Renal transplant recipients receiving TAC and MPA in combination were selected for clinical validation and divided into two groups: a stable group and an adverse outcome group. The concentrations were dynamically monitored at 5, 7, 14, and 21 days (D5, D7, D14, and D21) and 1, 2, 3, and 6 months (M1, M2, M3, and M6) after operation. RESULTS: Method performance validation was performed according to Food and Drug Administration guidelines, showing high specificity and sensitivity. The TAC and MPA calibration curves were linear (r2 = 0.9988 and r2 = 0.9990, respectively). Both intra-day and inter-day imprecision and inaccuracy were less than 15%. Matrix effects and recoveries were satisfactory. The TAC and MPA concentrations in 304 "real" PBMC samples from 47 renal transplant recipients were within the calibration curve range (0.12 to 16.40 ng/mL and 0.20 to 4.72 ng/mL, respectively). There was a weak correlation between PBMC-C0TAC and WB-C0TAC (p < 0.05), but no correlation was found for MPA. The level of immunosuppressive intra-patient variation (IPV) was higher in PBMC at 77.47% (55.06, 97.76%) than in WB at 34.61% (21.90, 49.85%). During the dynamic change in C0TAC, PBMC-C0TAC was in a fluctuating state, and no stable period was found. PBMC-C0TAC did not show a significant difference between the stable and adverse outcome group, but the level of the adverse outcome group was generally higher than that of the stable group. CONCLUSIONS: Compared with conventional therapeutic drug monitoring, the proposed rapid and sensitive method can provide more clinically reliable information on drug concentration at an active site, which has the potential to be applied to the clinical monitoring of intracellular immunosuppressive concentration in organ transplantation. However, the application of PBMC-C0TAC in adverse outcomes of renal transplant should be studied further.

Decreased expression of ADAM10 on monocytes is associated with chronic allograft dysfunction in kidney transplant recipients.

BACKGROUND: Chronic allograft dysfunction (CAD) is a common cause of allograft loss in kidney transplant recipients (KTRs). Our previous study found that elevated serum soluble T cell immunoglobulin mucin-3 (sTim-3) was positively associated with the severity of CAD in KTRs. sTim-3 was reported to be generated from ADAM10/ADAM17-mediated ectodomain shedding of membrane Tim-3 (mTim-3) in humans. However, whether mTim-3 shedding-related molecules participate in the progression of CAD remains unknown. Here, we explored the relationships between different forms of Tim-3, including mTim-3 on different peripheral blood cell subsets, serum and urine sTim-3, and ADAM10/17 expression and active status to investigate their roles in CAD. METHODS: 63 KTRs with stable grafts, 91 KTRs with CAD and 42 healthy controls (HCs) were enrolled. Total Tim-3, pADAM10/17 and mADAM10/17 proteins were semiquantified by western blot. Serum and urine sTim-3 concentrations were determined by ELISA. mTim-3 and ADAM10/17 expression on leukocyte subpopulations was determined by flow cytometry. RESULTS: The KTR groups displayed significantly higher levels of urine sTim-3 pg/µmol creatinine than the HC group, while no difference was found between the two KTR groups. KTRs with CAD presented reduced nonactive pADAM10 protein but unaltered active mADAM10 when compared to the Stable group; no difference was found between the KTR groups regarding total Tim-3 and p/m ADAM17 protein levels. In addition, the CAD group showed lower mTim-3 expression on BDCA3+ DC than the Stable group; no other difference was observed in its expression on B, T, NK, NKT, monocyte subsets and other DC subsets among groups. With the deterioration of allograft function, ADAM10 expression densities on classical, intermediate, and non-classical monocytes were significantly decreased. Correlation analyses revealed that eGFR and serum sTim-3 exhibited weak to modest correlations with ADAM10 on monocyte and DC subsets. CONCLUSIONS: Our data indicated that ADAM10, especially its decreased expression on monocytes, may play an important role in the progression of CAD in KTRs. However, whether there is an interaction between ADAM10 and mTim-3 in the pathogenesis of CAD in KTRs needs to be further studied.

A Volumetric Absorptive Microsampling UPLC-MS/MS Method for Simultaneous Quantification of Tacrolimus, Mycophenolic Acid and Creatinine in Whole Blood of Renal Transplant Recipients.

(1) Background: Continuous monitoring of tacrolimus (TAC), mycophenolic acid (MPA), and creatinine (Cre) after renal transplantation is vitally important. In this study, we developed a new method based on volumetric absorptive microsampling (VAMS) combined with Ultra Performance Liquid Chromatography−Tandem Mass Spectrometry (UPLC-MS/MS) to simultaneously quantify three analytes including TAC, MPA, and Cre in whole blood. (2) Methods: The VAMS-based UPLC-MS/MS assay used a shared extraction and a single injection to simultaneously quantify the included TAC, MPA, and Cre. Development and validation were carried out following the Food and Drug Administration and European Medicines Agency guidelines for the validation of bioanalytical methods. Moreover, clinical validation for the three analytes was performed in both dried blood spot (DBS) and VAMS. Furthermore, a willingness survey was conducted using the system usability scale (SUS) for renal transplant recipients. (3) Results: The assay was successfully validated for all analytes. No interference, carryover, or matrix effects were observed, and extraction recoveries and process efficiencies were >90.00%. Analysis was unaffected by hematocrit (0.20~0.60, L/L) and anticoagulants (EDTA-2K). Dried VAMS samples were stable for 7 days at ambient temperature and stable for at least 1 month at −20 °C. During clinical validation, the measured TAC, corrected MPA, and Cre concentrations of VAMS samples met the analytical standards (95.00%, 88.57%, and 92.50%). When more stringent clinical acceptance criteria were set, the results obtained by VAMS (90.00%, 71.43%, and 85.00%) better than DBS (77.50%, 62.86%, and 70.00%). Compared with DBS, the survey found that renal transplant recipients are more inclined to use VAMS. (4) Conclusions: A robust extraction and UPLC-MS/MS analysis method in VAMS tips was developed and fully validated for the simultaneous quantification of TAC, MPA, and Cre concentrations. This method provides analytical support for the one-sample remote monitoring of both immunosuppressive drug concentrations and renal function in allo-renal recipients. Based on the good consistency between this method and the routine detection of venous blood samples and higher patient satisfaction than DBS, we believe that VAMS sampling can be a better alternative to venous whole-blood sampling.

Loss of Myostatin Alters Mitochondrial Oxidative Phosphorylation, TCA Cycle Activity, and ATP Production in Skeletal Muscle.

Myostatin (MSTN) is an important negative regulator of skeletal muscle growth in animals. A lack of MSTN promotes lipolysis and glucose metabolism but inhibits oxidative phosphorylation (OXPHOS). Here, we aimed to investigate the possible mechanism of MSTN regulating the mitochondrial energy homeostasis of skeletal muscle. To this end, MSTN knockout mice were generated by the CRISPR/Cas9 technique. Expectedly, the MSTN null (Mstn-/-) mouse has a hypermuscular phenotype. The muscle metabolism of the Mstn-/- mice was detected by an enzyme-linked immunosorbent assay, indirect calorimetry, ChIP-qPCR, and RT-qPCR. The resting metabolic rate and body temperature of the Mstn-/- mice were significantly reduced. The loss of MSTN not only significantly inhibited the production of ATP by OXPHOS and decreased the activity of respiratory chain complexes, but also inhibited key rate-limiting enzymes related to the TCA cycle and significantly reduced the ratio of NADH/NAD+ in the Mstn-/- mice, which then greatly reduced the total amount of ATP. Further ChIP-qPCR results confirmed that the lack of MSTN inhibited both the TCA cycle and OXPHOS, resulting in decreased ATP production. The reason may be that Smad2/3 is not sufficiently bound to the promoter region of the rate-limiting enzymes Idh2 and Idh3a of the TCA cycle, thus affecting their transcription.

Myostatin Knockout Affects Mitochondrial Function by Inhibiting the AMPK/SIRT1/PGC1α Pathway in Skeletal Muscle.

Myostatin (Mstn) is a major negative regulator of skeletal muscle mass and initiates multiple metabolic changes. The deletion of the Mstn gene in mice leads to reduced mitochondrial functions. However, the underlying regulatory mechanisms remain unclear. In this study, we used CRISPR/Cas9 to generate myostatin-knockout (Mstn-KO) mice via pronuclear microinjection. Mstn-KO mice exhibited significantly larger skeletal muscles. Meanwhile, Mstn knockout regulated the organ weights of mice. Moreover, we found that Mstn knockout reduced the basal metabolic rate, muscle adenosine triphosphate (ATP) synthesis, activities of mitochondrial respiration chain complexes, tricarboxylic acid cycle (TCA) cycle, and thermogenesis. Mechanistically, expressions of silent information regulator 1 (SIRT1) and phosphorylated adenosine monophosphate-activated protein kinase (pAMPK) were down-regulated, while peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) acetylation modification increased in the Mstn-KO mice. Skeletal muscle cells from Mstn-KO and WT were treated with AMPK activator 5-aminoimidazole-4-carboxamide riboside (AICAR), and the AMPK inhibitor Compound C, respectively. Compared with the wild-type (WT) group, Compound C treatment further down-regulated the expression or activity of pAMPK, SIRT1, citrate synthase (CS), isocitrate dehydrogenase (ICDHm), and α-ketoglutarate acid dehydrogenase (α-KGDH) in Mstn-KO mice, while Mstn knockout inhibited the AICAR activation effect. Therefore, Mstn knockout affects mitochondrial function by inhibiting the AMPK/SIRT1/PGC1α signaling pathway. The present study reveals a new mechanism for Mstn knockout in regulating energy homeostasis.

Myostatin Deficiency Enhances Antioxidant Capacity of Bovine Muscle via the SMAD-AMPK-G6PD Pathway.

During exercise, the body's organs and skeletal muscles produce reactive oxygen species (ROS). Excessive ROS can destroy cellular lipids, sugars, proteins, and nucleotides and lead to cancer. The production of nicotinamide adenine dinucleotide phosphate (NADPH) by the pentose phosphate pathway (PPP) is an auxiliary process of the cellular antioxidant system that supplements the reducing power of glutathione (GSH) to eliminate ROS in the cell. Myostatin (MSTN) is mainly expressed in skeletal muscle and participates in the regulation of skeletal muscle growth and development. Loss of MSTN leads to muscular hypertrophy, and MSTN deficiency upregulates glycolysis. However, the effect of MSTN on the PPP has not been reported. This study investigated the effect of MSTN on muscle antioxidant capacity from a metabolic perspective. We found that reducing MSTN modulates AMP-activated protein kinase (AMPK), a key molecule in cellular energy metabolism that directly regulates glucose metabolism through phosphorylation. Downregulation of MSTN promotes tyrosine modification of glucose-6-phosphate-dehydrogenase (G6PD) by AMPK and is regulated by the Smad signaling pathway. The Smad2/3 complex acts as a transcription factor to inhibit the AMPK expression. These results suggest that reduced MSTN expression inhibits the Smad signaling pathway, promotes AMPK expression, enhances the activity of G6PD enzyme, and enhances the antioxidant capacity of nonenzymatic GSH.

N-3 Polyunsaturated Fatty Acid Dehydrogenase Fat-1 Regulates Mitochondrial Energy Metabolism by Altering DNA Methylation in Isolated Cells of Transgenic Cattle.

The fatty acid dehydrogenase fat-1 gene, derived from Caenorhabditis elegans, encodes n-3 polyunsaturated fatty acid dehydrogenase (Δ15 desaturase) and catalyzes the 18-20-carbon n-6 polyunsaturated fatty acids (n-6 PUFA) to generate corresponding n-3 polyunsaturated fatty acids (n-3 PUFA). Subsequently, fat-1 can influence the n-6: n-3 PUFA ratio in fat-1 transgenic cells. This study aimed to explore which processes of energy metabolism are affected exogenous fat-1 transgene and the relationship between these effects and DNA methylation. Compared with the wild-type group, the n-3 PUFA content in fat-1 transgenic bovine fetal fibroblasts was significantly increased, and the n-6 PUFA content and the n-6: n-3 PUFA ratio decreased. In the context of energy metabolism, the increase of exogenous fat-1 transgene decreased ATP synthesis by 39% and reduced the activity and expression of key rate-limiting enzymes in glycolysis, the tricarboxylic acid cycle, and oxidative phosphorylation, thus weakening the cells' capacity for ATP production. DNA methylation sequencing indicated that this inhibition of gene expression may be due to altered DNA methylation that regulates cell energy metabolism. Exogenous fat-1 transgenic cells showed changes in the degree of methylation in the promoter region of genes related to energy metabolism rate-limiting enzymes. We suggest that alters the balance of n-6/n-3 PUFA could regulate altered DNA methylation that affect mitochondrial energy metabolism.

Comparison of Microbial Community and Metabolites in Four Stomach Compartments of Myostatin-Gene-Edited and Non-edited Cattle.

Myostatin (MSTN), a major negative regulator of skeletal muscle mass and an endocrine factor, can regulate the metabolism of various organisms. Inhibition of the MSTN gene can improve meat production from livestock. Rumen microorganisms are associated with production and health traits of cattle, but changes in the microbial composition and metabolome in the four stomach compartments of MSTN gene-edited cattle have not previously been studied. Our results indicated that microbial diversity and dominant bacteria in the four stomach compartments were very similar between MSTN gene-edited and wild-type (WT) cattle. The microbiota composition was significantly different between MSTN gene-edited and WT cattle. Our results show that the relative abundance of the phylum Proteobacteria in the reticulum of MSTN gene-edited cattle was lower than that of WT cattle, whereas the relative abundance of the genus Prevotella in the omasum of MSTN gene-edited cattle was significantly higher than that of WT cattle. Metabolomics analysis revealed that the intensity of L-proline and acetic acid was significantly different in the rumen, reticulum, and abomasum between the two types of cattle. Meanwhile, pathway topology analysis indicated that the differential metabolites were predominantly involved in arginine biosynthesis and glutamate metabolism in the rumen, reticulum, and omasum but were mainly involved in pyruvate metabolism and glycolysis/gluconeogenesis in the abomasum. Spearman correlation network analysis further demonstrated that there was a significant correlation between microflora composition and metabolic pathways. These findings provide clues for studying nutrient digestion and absorption ability of MSTN gene-edited cattle.

Myostatin Knockout Limits Exercise-Induced Reduction in Bovine Erythrocyte Oxidative Stress by Enhancing the Efficiency of the Pentose Phosphate Pathway.

Moderate exercise can strengthen the body, however, exhaustive exercise generates large amounts of reactive oxygen species (ROS). Although erythrocytes have antioxidant systems that quickly eliminate ROS, erythrocytes become overwhelmed by ROS when the body is under oxidative stress, such as during exhaustive exercise. Myostatin (MSTN) has important effects on muscle hair development. Individuals lacking myostatin (MSTN) exhibit increased muscle mass. The purpose of this study was to investigate the mechanism by which MSTN affects erythrocyte antioxidant changes after exhaustive exercise in cattle. Antioxidant and metabolite detection analysis, western blotting, immunofluorescence, and fatty acid methyl ester analysis were used to assess exercise-associated antioxidant changes in erythrocytes with or without MSTN. Knockdown of MSTN enhances Glucose-6-phosphate dehydrogenase (G6PD) activity after exhaustive exercise. MSTN and its receptors were present on the erythrocyte membrane, but their levels, especially that of TGF-ß RI, were significantly reduced in the absence of MSTN and following exhaustive exercise. Our results suggest that knockout of MSTN accelerates the pentose phosphate pathway (PPP), thereby enhancing the antioxidant capacity of erythrocytes. These results provide important insights into the role of MSTN in erythrocyte antioxidant regulation after exhaustive exercise.

The diagnostic role of PD-1+ CXCR5+ follicular helper CD8+ T cell in renal allograft dysfunction.

BACKGROUND: The roles of PD-1+ CXCR5+ follicular helper CD8+ T cell were reported in different disease conditions, but their roles in transplantation are unclear. In this study, the association between PD-1+ CXCR5+ follicular helper CD8+ T cell and renal allograft dysfunction in kidney transplant recipients (KTRs) was investigated. METHODS: 82 KTRs were enrolled in this study. 45 KTRs were included in the chronic allograft dysfunction (CAD) group, and 37 KTRs were included in the stable recipients group. Among the CAD group, 12 cases of antibody-mediated rejection (ABMR) and 4 cases of T cell-mediated rejection (TCMR) were diagnosed by biopsy. The percentage of CXCR5+ CD8+ T cells and the co-expression of signal transducers and activators of transcription 4 (STAT4), STAT5, and PD-1 in peripheral blood were determined by flow cytometry. RESULTS: The expression of CXCR5 on CD3+ CD8+ T cells and the percentage of STAT5+ CXCR5+ cells in the CD3+ CD8+ T-cell population were significantly lower in the CAD group (p < 0.05), while the expression of PD-1+ CXCR5+ CD8+ T cells was significantly higher (p < 0.05). Through logistic regression analysis, we concluded that the percentage of PD-1+ CXCR5+ CD8+ T cells was an independent risk factor for renal dysfunction. Grouping by pathological type, PD-1+ CXCR5+ CD8+ T cells showed relatively good diagnostic efficacy for ABMR by ROC analysis. CONCLUSIONS: Our results suggested that PD-1+ CXCR5+ CD8+ T cells were a promising biomarker for distinguishing renal allograft dysfunction and different allograft pathological types. Also, our findings may provide new ways of identifying and treating allograft rejection.

Three-Dimensional Printed MoS2/Graphene Aerogel Electrodes for Hydrogen Evolution Reactions.

In this work, we demonstrate the use of direct ink writing (DIW) technology to create 3D catalytic electrodes for electrochemical applications. Hybrid MoS2/graphene aerogels are made by mixing commercially available MoS2 and graphene oxide powders into a thixotropic, high concentration, viscous ink. A porous 3D structure of 2D graphene sheets and MoS2 particles was created after post treatment by freeze-drying and reducing graphene oxide through annealing. The composition and morphology of the samples were fully characterized through XPS, BET, and SEM/EDS. The resulting 3D printed MoS2/graphene aerogel electrodes had a remarkable electrochemically active surface area (>1700 cm2) and were able to achieve currents over 100 mA in acidic media. Notably, the catalytic activity of the MoS2/graphene aerogel electrodes was maintained with minimal loss in surface area compared to the non-3D printed electrodes, suggesting that DIW can be a viable method of producing durable electrodes with a high surface area for water splitting. This demonstrates that 3D printing a MoS2/graphene 3D porous network directly using our approach not only improves electrolyte dispersion and facilitates catalyst utilization but also provides multidimensional electron transport channels for improving electronic conductivity.

Iron deficiency exacerbates cisplatin- or rhabdomyolysis-induced acute kidney injury through promoting iron-catalyzed oxidative damage.

Iron deficiency is the most common micronutrient deficiency worldwide. While iron deficiency is known to suppress embryonic organogenesis, its effect on the adult organ in the context of clinically relevant damage has not been considered. Here we report that iron deficiency is a risk factor for nephrotoxic intrinsic acute kidney injury of the nephron (iAKI). Iron deficiency exacerbated cisplatin-induced iAKI by markedly increasing non-heme catalytic iron and Nox4 protein which together catalyze production of hydroxyl radicals followed by protein and DNA oxidation, apoptosis and ferroptosis. Crosstalk between non-heme catalytic iron/Nox4 and downstream oxidative damage generated a mutual amplification cycle that facilitated rapid progression of cisplatin-induced iAKI. Iron deficiency also exacerbated a second model of iAKI, rhabdomyolysis, via increasing catalytic heme-iron. Heme-iron induced lipid peroxidation and DNA oxidation by interacting with Nox4-independent mechanisms, promoting p53/p21 activity and cellular senescence. Our data suggests that correcting iron deficiency and/or targeting specific catalytic iron species are strategies to mitigate iAKI in a wide range of patients with diverse forms of kidney injury.

Proof-of-concept study investigating the role of S100P-RAGE in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is an epithelial carcinoma that arises from the lining of the nasopharyngeal mucosa. The efficacy of radiation therapy is limited due to radiation resistance, particularly in the advanced stages of NPC. The S100P protein is a small isoform of the S100 protein family, which is involved in the regulation of various intracellular and extracellular processes, including proliferation, differentiation and intracellular signaling. The aim of the current study was to investigate the significance of the S100P-RAGE axis in NPC progression. The expression levels of S100P and receptor for activated glycation end-products (RAGE) in NPC specimens were determined by western blotting. In addition, the effect of the S100P-RAGE axis on NPC was evaluated in vitro by proliferation and migration assays using C666-1 cells treated with S100P or the RAGE inhibitor FPS-ZM1. The underlying mechanism was also investigated by western blotting. The expression of S100P and RAGE was detected in clinical specimens from 15 patients with NPC and 15 patients with benign nasopharyngeal inflammation, and was observed to be higher in NPC tissues compared with inflamed tissues. Furthermore, the interaction of S100P with RAGE increased the proliferation and migration potential of C666-1 cells, and activated mitogen-activated protein kinase and NF-κB signaling. These results indicate that the S100P-RAGE axis exerts a promoting effect on the progression of NPC. Therefore therapeutic strategies targeting S100P-RAGE merit further exploration for the treatment of NPC.

Metabolic syndrome components and acute pancreatitis: a case-control study in China.

BACKGROUND: Acute pancreatitis (AP) is a common inflammatory disorder of the pancreas. Recent evidence has shown that metabolic syndrome is positively correlated with the severity of AP. However, only a few studies have revealed the relationship between metabolic syndrome and the occurrence of AP. We therefore elucidated the association between metabolic syndrome and the occurrence of AP. METHODS: A hospital-based case-control study was conducted. A total of 705 patients admitted to our hospital from January 2016 to December 2018 were included in the study. Subjects were divided into case and control groups according to their diagnosis: (1) According to the revised Atlanta classification from 2012, patients diagnosed with AP were enrolled in the case group. (2) Patients without a history of AP or any disease related to metabolic syndrome were allocated into the control group. Controls were matched to cases individually by sex and age (control/case ratio = 1). RESULTS: The incidence rate of metabolic syndrome in AP patients was 30.9%, which was more frequent than that in controls (13.2%) (OR 2.837; 95% CI 1.873-4.298, p < 0.001). In the multivariate regression analysis, a history of smoking or alcohol consumption and biliary stones were significantly associated with AP (OR 2.441; 95% CI 1.865-5.172, p < 0.001; OR 1.777; 95% CI 1.060-2.977, p = 0.029; OR 28.995; 95% CI 13.253-63.435, p < 0.001). In addition, the occurrence of AP was significantly associated with total cholesterol (TC) (OR 1.992; 95% CI 1.246-3.183, p = 0.004), triglyceride (TG) (OR 2.134; 95% CI 1.403-3.245, p < 0.001), hyperglycaemia (OR 2.261; 95% CI 1.367-3.742, p = 0.001), and apolipoprotein A (Apo A) (OR 0.270; 95% CI 0.163-0.447, p < 0.001). CONCLUSIONS: Metabolic syndrome and its components were associated with AP occurrence.

Flexible and electrically conductive composites based on 3D hierarchical silver dendrites.

Conductive polymer composites have gained increasing popularity as essential components for next-generation flexible electronics. Chemical tuning of the polymer matrix and shape engineering of conductive fillers are two promising routes for material development to improve the electromechanical characteristics. Here we describe highly conductive and flexible polyurethane (PU)-based composites using 3D hierarchical silver dendrite (SD) micro/nanostructures as conductive fillers. The highly crystalline SDs adopt a 6-fold symmetry with high aspect ratio branches, which can be interlocked to provide better electrical contact under strain and sintered at low temperature to reduce contact resistance. By selecting the appropriate chemistry, SD fillers lubricated with surfactants can be well dispersed into PU resin and the surfactants can be in situ removed during the curing process due to the presence of polyols in the formulation. The unique SD structures and modified polymer-filler interface are key elements in realizing excellent electrical and mechanical properties. Specifically, the SD-PU composites demonstrated an ultralow resistivity of 7.6 × 10-5 Ω cm, a low percolation threshold of 3 vol%, minimal resistance change under mechanical strains, and strong adhesion to substrates. The evolution of temperature-dependent resistivity has been correlated with polymer dynamics and sintering behavior to understand the conduction mechanism.

Correction: 3-deazaneplanocin A protects against cisplatin-induced renal tubular cell apoptosis and acute kidney injury by restoration of E-cadherin expression.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Mstn knockdown decreases the trans-differentiation from myocytes to adipocytes by reducing Jmjd3 expression via the SMAD2/SMAD3 complex.

Myostatin (Mstn) is an important growth/differentiation factor, and knockdown of Mstn reduces fat content. Here, we knocked down Mstn expression in C2C12 myoblasts and then induced adipogenic trans-differentiation in the cells. The effects of Mstn knockdown on lipid droplet contents and H3K27me3 marker expression on adipocyte-specific genes were detected. The results showed that Mstn knockdown reduced the formation of lipid droplets, downregulated the expression of adipocyte-specific genes, and increased H3K27me3 marker expression on adipocyte-specific genes. Chromatin immunoprecipitation analysis showed that the SMAD2/SMAD3 complex could combine with the Jumonji D3 (Jmjd3) promoter and that Mstn regulated Jmjd3 expression through this process. Jmjd3 overexpression removed the H3K27me3 marker and increased the expression of adipocyte-specific genes. Overall, our results showed that Mstn regulated Jmjd3 expression through SMAD2/SMAD3, thus affecting the H3K27me3 marker on adipocyte-specific genes and the trans-differentiation from myocytes to adipocytes.

3-deazaneplanocin A protects against cisplatin-induced renal tubular cell apoptosis and acute kidney injury by restoration of E-cadherin expression.

3-deazaneplanocin A (3-DZNeP) has been used as an inhibitor of enhancer of zeste homolog 2 (EZH2). Here, we explore the role and underlying mechanisms action of 3-DZNeP in abrogating cisplatin nephrotoxicity. Exposure of cultured mouse renal proximal tubular epithelial cells (mTECs) to cisplatin resulted in dose and time-dependent cleavage of caspase-3, decrease of cell viability, and increase of histone H3 lysine 27 trimethylation (H3K27me3), whereas expression levels of EZH2, a major methyltransferase of H3K27me3, were not affected. Treatment with 3-DZNeP significantly inhibited cisplatin-induced activation of caspase-3, apoptosis, loss of cell viability but did not alter levels of EZH2 and H3K27me3 in cultured mTECs. 3-DZNeP treatment did not affect activation of extracellular signal-regulated kinase (ERK) 1/2, p38 or c-Jun N-terminal kinases (JNK) 1/2, which contribute to renal epithelial cell death, but caused dose-dependent restoration of E-cadherin in mTECs exposed to cisplatin. Silencing of E-cadherin expression by siRNA abolished the cytoprotective effects of 3-DZNeP. In contrast, 3-DZNeP treatment potentiated the cytotoxic effect of cisplatin in H1299, a non-small cell lung cancer cell line that expresses lower E-cadherin levels. Finally, administration of 3-DZNeP attenuated renal dysfunction, morphological damage, and renal tubular cell death, which was accompanied by E-cadherin preservation, in a mouse model of cisplatin nephrotoxicity. Overall, these data indicate that 3-DZNeP suppresses cisplatin-induced tubular epithelial cell apoptosis and acute kidney injury via an E-cadherin-dependent mechanism, and suggest that combined application of 3-DZNeP with cisplatin would be a novel chemotherapeutic strategy that enhances the anti-tumor effect of cisplatin and reduces its nephrotoxicity.

Processing and characterization of silver-filled conductive polysulfide sealants for aerospace applications.

Polysulfide (PS) rubbers have been widely used as high performance sealants to line or seal aircraft fuel tanks. However, safety concerns arise when electrostatic charges are built up due to the motion of flammable fuels. In this report, electrically conductive sealants were designed in order to dissipate these hazardous charges. Silver fillers with various sizes and surface coatings were incorporated into a polysulfide matrix to make conductive sealants. The low electrical conductivity of the sealants led to the assumption that unique filler-resin interactions occurred at their interfaces. To verify this assumption, various characterization methods were employed to investigate the chemical, thermal, morphological, electrical, and mechanical properties of the sealants. In addition, carbon fillers and other room temperature-cured polymer resins were used for comparative study. The systematic analysis revealed that the formation of coordination compounds at silver/PS interfaces could block electron conduction pathways between fillers. Based on the chemical understanding, post cure thermal annealing was utilized to break the coordinated bonds and restore high conductivity (>106 S m-1) of the sealants. Conductivity change as a function of annealing temperature and time was also explored to optimize processing conditions.