Lidocaine, an anesthetic drug, protects Neuro2A cells against cadmium toxicity

Purpose: To investigate the neuroprotective effect of lidocaine in Neuro2A cells Methods: Differentiated N2a cells were used in this study. Cell viability and neuroprotection were assessed using dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and trypan blue assays, while Bax/Bcl-2 expression was assayed by western blotting. Mitochondrial membrane potential, reactive oxygen species and calcium levels were measured using flow cytometry. Results: Lidocaine protected differentiated N2a cells against cadmium-induced toxicity, and also attenuated cadmium toxicity-induced changes in mitochondrial membrane potential (MMP), reactive oxygen species (ROS) and calcium (Ca2+) levels. Furthermore, Bax/Bcl-2 ratio, which was disrupted by cadmium, and cadmium-induced apoptosis, were reversed by lidocaine. Conclusion: Lidocaine protects differentiated N2a cells against cadmium-induced toxicity by reversing apoptosis. Thus, lidocaine is a potential neuroprotective agent

Genetic heterogeneity in primary and relapsed mantle cell lymphomas : impact of recurrent CARD11 mutations

The genetic mechanisms underlying disease progression, relapse and therapy resistance in mantle cell lymphoma (MCL) remain largely unknown. Whole-exome sequencing was performed in 27 MCL samples from 13 patients, representing the largest analyzed series of consecutive biopsies obtained at diagnosis and/or relapse for this type of lymphoma. Eighteen genes were found to be recurrently mutated in these samples, including known (ATM, MEF2B and MLL2) and novel mutation targets (S1PR1 and CARD11). CARD11, a scaffold protein required for B-cell receptor (BCR)-induced NF-κB activation, was subsequently screened in an additional 173 MCL samples and mutations were observed in 5.5% of cases. Based on in vitro cell line-based experiments, overexpression of CARD11 mutants were demonstrated to confer resistance to the BCR-inhibitor ibrutinib and NF-κB-inhibitor lenalidomide. Genetic alterations acquired in the relapse samples were found to be largely non-recurrent, in line with the branched evolutionary pattern of clonal evolution observed in most cases. In summary, this study highlights the genetic heterogeneity in MCL, in particular at relapse, and provides for the first time genetic evidence of BCR/NF-κB activation in a subset of MCL

DNA repair genes are selectively mutated in diffuse large B cell lymphomas

DNA repair mechanisms are fundamental for B cell development, which relies on the somatic diversification of the immunoglobulin genes by V(D)J recombination, somatic hypermutation, and class switch recombination. Their failure is postulated to promote genomic instability and malignant transformation in B cells. By performing targeted sequencing of 73 key DNA repair genes in 29 B cell lymphoma samples, somatic and germline mutations were identified in various DNA repair pathways, mainly in diffuse large B cell lymphomas (DLBCLs). Mutations in mismatch repair genes (EXO1, MSH2, and MSH6) were associated with microsatellite instability, increased number of somatic insertions/deletions, and altered mutation signatures in tumors. Somatic mutations in nonhomologous end-joining (NHEJ) genes (DCLRE1C/ARTEMIS, PRKDC/DNA-PKcs, XRCC5/KU80, and XRCC6/KU70) were identified in four DLBCL tumors and cytogenetic analyses revealed that translocations involving the immunoglobulin-heavy chain locus occurred exclusively in NHEJ-mutated samples. The novel mutation targets, CHEK2 and PARP1, were further screened in expanded DLBCL cohorts, and somatic as well as novel and rare germline mutations were identified in 8 and 5% of analyzed tumors, respectively. By correlating defects in a subset of DNA damage response and repair genes with genomic instability events in tumors, we propose that these genes play a role in DLBCL lymphomagenesis

A Switch-Reduced Multicell-to-Multicell Battery Equalizer Based on Full-Bridge Bipolar-Resonant LC Converter

Many battery equalizers have been proposed to achieve voltage consistency between series connected battery cells. Among them, the multicell-to-multicell (MC2MC) equalizers, which can directly transfer energy from consecutive more-charged cells to less-charged cells, can enable fast balancing and a high efficiency. However, due to the limitations of the equalizers, it is not possible to achieve fast equalization and reduce the size of the circuit at the same time. Therefore, a MC2MC equalizer based on a full-bridge bipolar-resonant LC Converter (FBBRLCC) is proposed in this paper, which not only implements MC2MC equalization, but also greatly reduces the circuit size by reducing the number of switches by nearly half. A mathematical model and simulation comparison with conventional equalizers are used to illustrate the high-speed equalization performance of the proposed equalizer and excellent balancing efficiency. An experimental prototype for eight cells is built to verify the performance of the proposed FBBRLCC equalizer and the balancing efficiencies in different operating modes are from 85.19% to 88.77% with the average power from 1.888 W to 14.227 W

Phosphorylation of CaMK and CREB-Mediated Cardiac Aldosterone Synthesis Induced by Arginine Vasopressin in Rats with Myocardial Infarction

Both aldosterone and arginine vasopressin (AVP) are produced in the heart and may participate in cardiac fibrosis. However, their relationship remains unknown. This study aims to demonstrate the regulation and role of AVP in aldosterone synthesis in the heart. Rats were subjected to a sham operation or myocardial infarction (MI) by ligating the coronary artery. Cardiac function and fibrosis were assessed using echocardiography and immunohistochemical staining, respectively. In addition, the effects of AVP stimulation on cardiac microvascular endothelial cells (CMECs) were studied using ELISA, real-time PCR, and Western blotting. Compared with the rats having undergone a sham operation, the MI rats had an increased LVMI, type I collagen composition, and concentrations of aldosterone and AVP in the heart but decreased cardiac function. As the MI rats aged, the LVMI, type I collagen, aldosterone, and AVP increased, while the LVMI decreased. Furthermore, AVP time-dependently induced aldosterone secretion and CYP11B2 mRNA expression in CMECs. The p-CREB levels were significantly increased by AVP. Nevertheless, these effects were completely blocked by SR49059 or partially inhibited by KN93. This study demonstrated that AVP could induce the secretion of local cardiac aldosterone, which may involve CaMK and CREB phosphorylation and CYP11B2 upregulation through V1 receptor activation

I Ks Protects from Ventricular Arrhythmia during Cardiac Ischemia and Reperfusion in Rabbits by Preserving the Repolarization Reserve

Introduction: The function of the repolarization reserve in the prevention of ventricular arrhythmias during cardiac ischemia/reperfusion and the impact of ischemia on slowly activated delayed rectifier potassium current (IKs) channel subunit expression are not well understood. Methods and Results: The responses of monophasic action potential duration (MAPD) prolongation and triangulation were investigated following an L-768,673-induced blockade of I Ks with or without ischemia/reperfusion in a rabbit model of lef

Effect of Intensive Lifestyle Intervention on Cardiovascular Risk Factors: Analysis From the Perspective of Long‐Term Variability

Background An association between variability of cardiovascular risk factors and cardiovascular events has been reported. We examined whether intensive lifestyle intervention (ILI) for weight loss decreased variability of cardiovascular risk factors with a view to additional cardiometabolic benefits. Methods and Results This study was a post hoc secondary analysis of the Look AHEAD (Action for Health in Diabetes) study. Cardiovascular risk factors were measured at 1‐year intervals for 4 years in 4249 adults with overweight or obesity and type 2 diabetes who were randomly assigned to ILI or diabetes support and education. Long‐term variability was defined as the SD of cardiovascular risk factors during 4‐year follow‐up. At multiple linear regression analysis, compared with the diabetes support and education group, the ILI group was associated with reduced variability of fasting blood glucose (β=−1.49 [95% CI, −2.39 to −0.59]), total cholesterol (β=−1.12 [95% CI, −1.75 to −0.48]), and low‐density lipoprotein cholesterol (β=−1.04 [95% CI, −1.59 to −0.49]), as well as increased variability of systolic blood pressure (β=0.27 [95% CI, 0.00–0.54]). No significant effect of ILI was found on the variability of diastolic blood pressure (β=−0.08 [95% CI, −0.22 to 0.05]). Conclusions Among adults with overweight or obesity and type 2 diabetes, ILI may reduce long‐term variability of fasting blood glucose, total cholesterol, and low‐density lipoprotein cholesterol. Our results support that ILI should be recommended to individuals with diabetes as part of management of long‐term glycemic and blood lipid control

Associations of Renal Function Trajectories and Long‐Term Cardiovascular Risks Among a Population Without Chronic Kidney Disease

Background The longitudinal trajectories of renal function have been associated with cardiovascular events in patients with chronic kidney disease (CKD). However, the change pattern of renal function in those without CKD has not yet been reported. We aim to explore patterns of renal function change in a non‐CKD population and its associated risks with cardiovascular outcomes. Methods and Results The present study analyzed data from 4 prospective cohorts and was restricted to participants without baseline CKD. The primary outcome was major adverse cardiovascular events, defined as a composite of myocardial infarction, chronic heart failure, stroke, and cardiovascular deaths. We used a group‐based trajectory model to identify latent groups and analyzed the associated risk with Cox regression models. The complete dates of this study were June 1, 2020, through January 1, 2021. The final sample comprised 23 760 participants (mean age, 58.63 [9.12] years, 10 618 men, and 17 799 White participants). During 20.56 years follow‐up, 8328 (35.05%) first major adverse cardiovascular events happened. Four trajectories in estimated glomerular renal function and 3 patterns of CKD progression were identified. Compared with subjects assigned to class I trajectory (high to mildly decreased group), the adjusted hazard ratios of major adverse cardiovascular events for class II (normal to mildly decreased group), class III (normal to moderately decreased group), and class IV (mildly to severely decreased group) were 1.11 (95% CI, 1.01–1.23), 1.27 (95% CI, 1.14–1.40), and 1.56 (95% CI, 1.38–1.77), respectively. Likewise, participants assigned to the slow and rapid progression groups had elevated HRs for major adverse cardiovascular events (1.75 [95% CI, 1.39–2.21] and 2.19 [95% CI, 1.68–2.86], respectively) when compared with the stable group. Findings were generally consistent in stratification analysis, but significant interaction effects by age and smoking status were detected. Conclusions In this study, we identified unique trajectory groups for renal function. These findings may signal an underlying high‐risk population and inspire future studies on individualized risk management

A 13C isotope labeling method for the measurement of lignin metabolic flux in Arabidopsis stems

Abstract Background Metabolic fluxes represent the functional phenotypes of biochemical pathways and are essential to reveal the distribution of precursors among metabolic networks. Although analysis of metabolic fluxes, facilitated by stable isotope labeling and mass spectrometry detection, has been applied in the studies of plant metabolism, we lack experimental measurements for carbon flux towards lignin, one of the most abundant polymers in nature. Results We developed a feeding strategy of excised Arabidopsis stems with 13C labeled phenylalanine (Phe) for the analysis of lignin biosynthetic flux. We optimized the feeding methods and found the stems continued to grow and lignify. Consistent with lignification profiles along the stems, higher levels of phenylpropanoids and activities of lignin biosynthetic enzymes were detected in the base of the stem. In the feeding experiments, 13C labeled Phe was quickly accumulated and used for the synthesis of phenylpropanoid intermediates and lignin. The intermediates displayed two different patterns of labeling kinetics during the feeding period. Analysis of lignin showed rapid incorporation of label into all three subunits in the polymers. Conclusions Our feeding results demonstrate the effectiveness of the stem feeding system and suggest a potential application for the investigations of other aspects in plant metabolism. The supply of exogenous Phe leading to a higher lignin deposition rate indicates the availability of Phe is a determining factor for lignification rates

Details of PCR.

<p>Details of PCR.</p