2,4‑Di‑tert‑butylphenol,a potential HDAC6 inhibitor,induces senescence and mitotic catastrophe in human gastric adenocarcinoma AGS cells

The natural product 2,4?di?tert?butylphenol (DTBP) has a wide spectrum of biological functions, including anticancer activities, although the underlying mechanisms are poorly understood. Here, we found that DTBP induces senescence in human gastric adenocarcinoma AGS cells as evidenced by upregulation of p21 and Rb and increased β?galactosidase activity. DTBP also induces mitotic catastrophe and generates multinucleated cells, which is accompanied by an increase in the proportion of polymerized tubulin, possibly caused by inhibition of HDAC6 enzyme activity. In silico docking analysis showed that DTBP docked at the entrance of the ligand-binding pocket of the HDAC6 enzyme. Accordingly, DTBP represents a promising lead structure for the development of HDAC6 inhibitors, with an improvement in specificity conferred by modification of the cap group. We propose for the first time that the underlying mechanism of the anticancer activity of DTBP is attributed to inhibition of HDAC6 activity.     

Universal Optimality of Nearest Neighbour Balanced Block Designs using Second Order Correlated Models

Block designs for observations correlated in one dimension are investigated. Santharam and Ponnusamy (1995) investigated the universal optimality of Nearest Neighbour balanced block designs (NNBD) using first order correlated models (AR(1), MA(1) and ARMA(1,1)). In this article we have investigated the universal optimality of NNBD using second order correlated models (ar(2), and MA (2)).     

2021 PACES expert consensus statement on the indications and management of cardiovascular implantable electronic devices in pediatric patients: Executive summary

Guidelines for the implantation of cardiac implantable electronic devices (CIEDs) have evolved since publication of the initial ACC/AHA pacemaker guidelines in 1984 [1]. CIEDs have evolved to include novel forms of cardiac pacing, the development of implantable cardioverter defibrillators (ICDs) and the introduction of devices for long term monitoring of heart rhythm and other physiologic parameters. In view of the increasing complexity of both devices and patients, practice guidelines, by necessity, have become increasingly specific. In 2018, the ACC/AHA/HRS published Guidelines on the Evaluation and Management of Patients with Bradycardia and Cardiac Conduction Delay [2], which were specific recommendations for patients >18 years of age. This age-specific threshold was established in view of the differing indications for CIEDs in young patients as well as size-specific technology factors. Therefore, the following document was developed to update and further delineate indications for the use and management of CIEDs in pediatric patients, defined as ≤21 years of age, with recognition that there is often overlap in the care of patents between 18 and 21 years of age.This document is an abbreviated expert consensus statement (ECS) intended to focus primarily on the indications for CIEDs in the setting of specific disease/diagnostic categories. This document will also provide guidance regarding the management of lead systems and follow-up evaluation for pediatric patients with CIEDs. The recommendations are presented in an abbreviated modular format, with each section including the complete table of recommendations along with a brief synopsis of supportive text and select references to provide some context for the recommendations. This document is not intended to provide an exhaustive discussion of the basis for each of the recommendations, which are further addressed in the comprehensive PACES-CIED document [3], with further data easily accessible in electronic searches or textbooks.     

Effect of several uncouplers of cell-to-cell communication on gap junction morphology in mammalian heart

Summary Electrical conduction in sheep Purkinje fibers has been blocked by three different procedures: (I) 1mm 2–4-dinitrophenol, (II) 3.5mm n-Heptan-1-ol (heptanol), and (III) treatment by a hypotonic (120 mOsmoles) Ca²⁺-free solution for half an hour, followed by return to normal conditions. The gap junction morphology was analyzed quantitatively in freezefracture replicas and compared in electrically conducting and nonconducting fibers. It is found that the three uncouplers of cell-to-cell conduction induce consistent and statistically significant alterations of the gap junction structure. The investigated morphological criteria: (a) P-face junctional particle diameter, control value 8.18±0.70 nm (mean±sd), (b) P-face junctional particles center-to-center spacing, control value 10.23±1.57 nm, and (c) E-face pits spacing, control value 9.45±0.98 nm, are, respectively, decreased to 7.46±0.62 nm, 9.25±1.34 nm and 8.67±1.13 nm in Purkinje fibers with complete conduction blocks. All three gap junctional dimensions are seen to decline progressively with time from the onset of an uncoupling treatment towards stable minima reached in half an hour. The observed morphological transitions appear related to the electrical uncoupling for the following reasons: partial electrical uncoupling results in values of the gap junctional dimensions that are intermediate between those measured in electrically coupled and uncoupled preparations, and the three morphological indices are seen to increase again towards control values very soon after electrical conduction has been re-established. It is concluded that the junctional channels closure on electrical uncoupling correlates with a measurable (−0.72±0.01 nm, difference of the means±se) decrease of the junctional particle diameters.     

On the Construction of Balanced and Partially Balanced Ternary Design

A method of constructing balanced and partially balanced ternary designs from balanced and partially balanced incomplete block designs, respectively, and two methods of constructing partially balanced ternary designs from association schemes are obtained. Two new and efficient balanced ternary designs having K < V and R ≦ 20 are obtained by the first method.     

Consistent estimation of the number of communities via regularized network embedding

The network analysis plays an important role in numerous application domains including biomedicine. Estimation of the number of communities is a fundamental and critical issue in network analysis. Most existing studies assume that the number of communities is known a priori, or lack of rigorous theoretical guarantee on the estimation consistency. In this paper, we propose a regularized network embedding model to simultaneously estimate the community structure and the number of communities in a unified formulation. The proposed model equips network embedding with a novel composite regularization term, which pushes the embedding vector toward its center and pushes similar community centers collapsed with each other. A rigorous theoretical analysis is conducted, establishing asymptotic consistency in terms of community detection and estimation of the number of communities. Extensive numerical experiments have also been conducted on both synthetic networks and brain functional connectivity network, which demonstrate the superior performance of the proposed method compared with existing alternatives.     

Hunting for connexin hemichannels

Connexin hemichannels (connexons) are building blocks of gap junctions but also function as free unapposed channels, which has become an active field of research. Defining functions of hemichannels and their involvement in any biological event requires ruling out possible participation of other channels that share biophysical and regulatory properties, for example pannexins, CALHM1 and P2X receptors. The lack of specific inhibitors for these channels has become an obstacle in elucidating the role of connexin hemichannels. Several experimental approaches are now available to identify hemichannels at the cell surface and to characterize their electrophysiological, permeability and regulatory properties. The use of connexin knockout/knockdown, and the development of peptides that target intracellular connexin domains and specific antibodies directed to extracellular domains have helped to dissect the role of hemichannels in endogenously expressing systems. Moreover, studies of connexin mutants in exogenous expression systems have provided convincing evidence on hemichannels in the pathogenesis of several human genetic diseases. We here present a brief overview of connexin hemichannels as functional channels and itemize a list of aspects to consider when concluding on their involvement.     

Interactions of amiloride and other blocking cations with the apical Na channel in the toad urinary bladder

Summary A simple model of the action of amiloride to block apical Na channels in the toad urinary bladder was tested. According to the model, the positively charged form of the drug binds to a site in the lumen of the channel within the electric field of the membrane. In agreement with the predictions of the model: (1) The voltage dependence of amiloride block was consistent with the assumption of a single amiloride binding site, at which about 15% of the transmembrane voltage is sensed, over a voltage range of ±160 mV. (2) The time course of the development of voltage dependence was consistent with that predicted from the rate constants for amiloride binding previously determined. (3) The ability of organic cations to mimic the action of amiloride showed a size dependence implying a restriction of access to the binding site, with an effective diameter of about 5 angstroms. In a fourth test, divalent cations (Ca, Mg, Ba and Sr) were found to block Na channels with a complex voltage dependence, suggesting that these ions interact with two or more sites. at least one of which may be within the lumen of the pore.     

Effects of exercise programs on neuroelectric dynamics in drug addiction

Exercise interventions have been considered to be an effective treatment for drug addiction. However, there is little dirct evidence that exercise affects brain activity in individuals afftected by drug addiction. Therefore, the aim of the present study was to investigate the effects of different exercise programs on detoxification. Cognitive recovery with 64-channel electroencephalography (EEG) recordings was obtained before and after three months of daily aerobic and anaerobic exercise. A total of 63 subjects with methamphetamine addiction were recruited and randomly divided into three groups for cognitive study in four behavioral states: an anaerobic resistance treatment group, an aerobic cycling treatment group and a control group. In addition, four behavioral states were examined: eyes-closed and eyes-open resting states, and exploratory behavior states following either drug- or neutral-cue exposure. Over a 12-week period,the alpha block ratio in the control group showed a slight decrease, while clear increases were observed in the resistance exercise and cycling treatment groups, particularly under the frontal and temporal regions in the eyes-open and drug-cue conditions. The major EEG activity frequency in the resistance treatment group during the drug-cue behavior task decreased compared with the frequencies of the cycling exercise and control groups. Meanwhile, the power of higher brain rhythms in the resistance treatment group was increased. Finally, the brain alpha wave left-lateralization index from EEG recording sites, F1–F2, in the resistance and cycling treatment groups under the eyes-closed condition positively decreased, while the control groups only showed slight decreases. Taken together, these results suggest that different types of exercise may induce distince and different positive therapeutic effects to facilitate detoxification.Electronic supplementary materialThe online version of this article (10.1007/s11571-020-09647-w) contains supplementary material, which is available to authorized users.