Clathrin mediates membrane fission and budding by constricting membrane pores.

Membrane budding, which underlies fundamental processes like endocytosis, intracellular trafficking, and viral infection, is thought to involve membrane coat-forming proteins, including the most observed clathrin, to form Ω-shape profiles and helix-forming proteins like dynamin to constrict Ω-profiles' pores and thus mediate fission. Challenging this fundamental concept, we report that polymerized clathrin is required for Ω-profiles' pore closure and that clathrin around Ω-profiles' base/pore region mediates pore constriction/closure in neuroendocrine chromaffin cells. Mathematical modeling suggests that clathrin polymerization at Ω-profiles' base/pore region generates forces from its intrinsically curved shape to constrict/close the pore.

Construction of stable photo-Fenton system with efficient removal capability of ciprofloxacin by accelerating photoreduction of Fe in MIL-100(Fe).

Well-dispersed MIL-100(Fe) nanoparticles were synthesized under mild conditions and used to construct a photo-Fenton system (VMH system) with the assistance of visible-light irradiation and hydrogen peroxide. In such a VMH system, the MIL-100(Fe) has a high specific surface area and provides numerous Fe active sites, thus accelerating the reaction of Fe with photo-generated electrons under visible-light irradiation and generates Fe, and then the acquired Fe can activate HO to generate OH, accompanying with the oxidation of Fe to Fe. Hence, the recycling of Fe/Fe promotes the generation of ·OH, thus making the VMH system exhibits promising photocatalytic activity.

Experimental factors that impact CaV1.2 channel pharmacology-Effects of recording temperature, charge carrier, and quantification of drug effects on the step and ramp currents elicited by the "step-step-ramp" voltage protocol.

Background And Purpose: CaV1.2 channels contribute to action potential upstroke in pacemaker cells, plateau potential in working myocytes, and initiate excitation-contraction coupling. Understanding drug action on CaV1.

Bisphenol S and Bisphenol F Are Less Disruptive to Cardiac Electrophysiology, as Compared With Bisphenol A.

Bisphenol A (BPA) is a high-production volume chemical used to manufacture consumer and medical-grade plastic products. Due to its ubiquity, the general population can incur daily environmental exposure to BPA, whereas heightened exposure has been reported in intensive care patients and industrial workers. Due to health concerns, structural analogs are being explored as replacements for BPA.

Estradiol analogs attenuate autophagy, cell migration and invasion by direct and selective inhibition of TRPML1, independent of estrogen receptors.

The cation channel TRPML1 is an important regulator of lysosomal function and autophagy. Loss of TRPML1 is associated with neurodegeneration and lysosomal storage disease, while temporary inhibition of this ion channel has been proposed to be beneficial in cancer therapy. Currently available TRPML1 channel inhibitors are not TRPML isoform selective and block at least two of the three human isoforms.

Enhanced Dielectric and Hydrophobic Properties of Poly(vinylidene fluoride-trifluoroethylene)/TiO Nanowire Arrays Composite Film Surface Modified by Electrospinning.

In this research, we designed a feasible method to prepare composite films with high permittivity and significantly enhanced hydrophobic performance, which showed huge potential in the electrowetting field. TiO nanowire arrays were prepared by a one-step hydrothermal process, and poly(vinylidene fluoride-trifluoroethylene) (P(VDF-TrFE)) was spin-coated on the nanowire arrays to form composite, the surface of which was modified by electrospinning. Due to the great orientation of TiO nanowires, dipoles and space charges are in ordered arrangement along the electric field, and this strongly reinforced the Maxwell-Wagner-Sillars (MWS) polarization, thus the permittivity of the composite (TiO nanowire length/film thickness is 0.

Synthesis of Janus Au@BCP nanoparticles UV light-initiated RAFT polymerization-induced self-assembly.

It is a great challenge to fabricate Janus inorganic/polymeric hybrid nanoparticles with both precisely controlled nanostructures and high yields. Herein, we report a new method to synthesize Janus Au@BCPs UV light-initiated RAFT polymerization-induced self-assembly at a high solid content. This strategy provides a promising alternative for achieving asymmetric hybrid nanoparticles with a controllable size, tunable morphology and convenient operation.

Mechanisms of QT prolongation by buprenorphine cannot be explained by direct hERG channel block.

Buprenorphine is a μ-opioid receptor (MOR) partial agonist used to manage pain and addiction. QTC prolongation that crosses the 10 msec threshold of regulatory concern was observed at a supratherapeutic dose in two thorough QT studies for the transdermal buprenorphine product BUTRANS®. Because QTC prolongation can be associated with Torsades de Pointes (TdP), a rare but potentially fatal ventricular arrhythmia, these results have led to further investigation of the electrophysiological effects of buprenorphine.

A general procedure to select calibration drugs for lab-specific validation and calibration of proarrhythmia risk prediction models: An illustrative example using the CiPA model.

Introduction: In response to the ongoing shift of the regulatory cardiac safety paradigm, a recent White Paper proposed general principles for developing and implementing proarrhythmia risk prediction models. These principles included development strategies to validate models, and implementation strategies to ensure a model developed by one lab can be used by other labs in a consistent manner in the presence of lab-to-lab experimental variability. While the development strategies were illustrated through the validation of the model under the Comprehensive In vitro Proarrhythmia Assay (CiPA), the implementation strategies have not been adopted yet.

Influences and Mechanisms of Nano-C-S-H Gel Addition on Fresh Properties of the Cement-Based Materials with Sucrose as Retarder.

Influences and mechanisms of chemically synthesized nano-C-S-H gel addition on fresh properties of the cement-based materials with sucrose as a retarder were investigated in this study. The results showed that the flow value of the fresh cement paste was gradually but slightly reduced with increasing nano-C-S-H gel addition due to its fibrous but well-dispersed characteristic in both water and cement paste. The semi-adiabatic calorimetry testing results verified that incorporation of nano-C-S-H gel could greatly mitigate the retarding effect of sucrose on cement hydration.

A systematic strategy for estimating hERG block potency and its implications in a new cardiac safety paradigm.

Introduction: hERG block potency is widely used to calculate a drug's safety margin against its torsadogenic potential. Previous studies are confounded by use of different patch clamp electrophysiology protocols and a lack of statistical quantification of experimental variability. Since the new cardiac safety paradigm being discussed by the International Council for Harmonisation promotes a tighter integration of nonclinical and clinical data for torsadogenic risk assessment, a more systematic approach to estimate the hERG block potency and safety margin is needed.

Drug potency on inhibiting late Na current is sensitive to gating modifier and current region where drug effects were measured.

Introduction: Cardiac late Na current (I) contributes to ventricular action potential duration. Pathological increase in I is arrhythmogenic, and inhibition of I offers protection against ventricular repolarization disturbance. Recently, two I datasets generated by different laboratories that assessed current inhibition by a panel of clinical drugs as a part of the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative were published.

Plasticizer Interaction With the Heart: Chemicals Used in Plastic Medical Devices Can Interfere With Cardiac Electrophysiology.

Background: Phthalates are used as plasticizers in the manufacturing of flexible, plastic medical products. Patients can be subjected to high phthalate exposure through contact with plastic medical devices. We aimed to investigate the cardiac safety and biocompatibility of mono-2-ethylhexyl phthalate (MEHP), a phthalate with documented exposure in intensive care patients.

Assessment of an In Silico Mechanistic Model for Proarrhythmia Risk Prediction Under the CiPA Initiative.

The International Council on Harmonization (ICH) S7B and E14 regulatory guidelines are sensitive but not specific for predicting which drugs are pro-arrhythmic. In response, the Comprehensive In Vitro Proarrhythmia Assay (CiPA) was proposed that integrates multi-ion channel pharmacology data in vitro into a human cardiomyocyte model in silico for proarrhythmia risk assessment. Previously, we reported the model optimization and proarrhythmia metric selection based on CiPA training drugs.

Corrigendum: Optimization of an Cardiac Cell Model for Proarrhythmia Risk Assessment.

[This corrects the article on p. 616 in vol. 8, PMID: 28878692.

Uncertainty Quantification Reveals the Importance of Data Variability and Experimental Design Considerations for Proarrhythmia Risk Assessment.

The Comprehensive Proarrhythmia Assay (CiPA) is a global initiative intended to improve drug proarrhythmia risk assessment using a new paradigm of mechanistic assays. Under the CiPA paradigm, the relative risk of drug-induced Torsade de Pointes (TdP) is assessed using an model of the human ventricular action potential (AP) that integrates pharmacology data from multiple ion channels. Thus, modeling predictions of cardiac risk liability will depend critically on the variability in pharmacology data, and uncertainty quantification (UQ) must comprise an essential component of the assay.

Optimization of an Cardiac Cell Model for Proarrhythmia Risk Assessment.

Drug-induced Torsade-de-Pointes (TdP) has been responsible for the withdrawal of many drugs from the market and is therefore of major concern to global regulatory agencies and the pharmaceutical industry. The Comprehensive Proarrhythmia Assay (CiPA) was proposed to improve prediction of TdP risk, using models and multi-channel pharmacology data as integral parts of this initiative. Previously, we reported that combining dynamic interactions between drugs and the rapid delayed rectifier potassium current (IKr) with multi-channel pharmacology is important for TdP risk classification, and we modified the original O'Hara Rudy ventricular cell mathematical model to include a Markov model of IKr to represent dynamic drug-IKr interactions (IKr-dynamic ORd model).

Characterization of loperamide-mediated block of hERG channels at physiological temperature and its proarrhythmia propensity.

Background: Loperamide (Immodium®) is indicated for symptomatic control of diarrhea. It is a μ-opioid receptor agonist, and recently has been associated with misuse and abuse. At therapeutic doses loperamide has not been associated with cardiotoxicity.

Improving the In Silico Assessment of Proarrhythmia Risk by Combining hERG (Human Ether-à-go-go-Related Gene) Channel-Drug Binding Kinetics and Multichannel Pharmacology.

Background: The current proarrhythmia safety testing paradigm, although highly efficient in preventing new torsadogenic drugs from entering the market, has important limitations that can restrict the development and use of valuable new therapeutics. The CiPA (Comprehensive in vitro Proarrhythmia Assay) proposes to overcome these limitations by evaluating drug effects on multiple cardiac ion channels in vitro and using these data in a predictive in silico model of the adult human ventricular myocyte. A set of drugs with known clinical torsade de pointes risk was selected to develop and calibrate the in silico model.

Actin Is Crucial for All Kinetically Distinguishable Forms of Endocytosis at Synapses.

Mechanical force is needed to mediate endocytosis. Whether actin, the most abundant force-generating molecule, is essential for endocytosis is highly controversial in mammalian cells, particularly synapses, likely due to the use of actin blockers, the efficiency and specificity of which are often unclear in the studied cell. Here we addressed this issue using a knockout approach combined with measurements of membrane capacitance and fission pore conductance, imaging of vesicular protein endocytosis, and electron microscopy.

A temperature-dependent in silico model of the human ether-à-go-go-related (hERG) gene channel.

Introduction: Current regulatory guidelines for assessing the risk of QT prolongation include in vitro assays assessing drug effects on the human ether-à-go-go-related (hERG; also known as Kv11.1) channel expressed in cell lines. These assays are typically conducted at room temperature to promote the ease and stability of recording hERG currents.

α-Synuclein Mutation Inhibits Endocytosis at Mammalian Central Nerve Terminals.

Unlabelled: α-Synuclein (α-syn) missense and multiplication mutations have been suggested to cause neurodegenerative diseases, including Parkinson's disease (PD) and dementia with Lewy bodies. Before causing the progressive neuronal loss, α-syn mutations impair exocytosis, which may contribute to eventual neurodegeneration. To understand how α-syn mutations impair exocytosis, we developed a mouse model that selectively expressed PD-related human α-syn A53T (h-α-synA53T) mutation at the calyx of Held terminals, where release mechanisms can be dissected with a patch-clamping technique.

Post-fusion structural changes and their roles in exocytosis and endocytosis of dense-core vesicles.

Vesicle fusion with the plasma membrane generates an Ω-shaped membrane profile. Its pore is thought to dilate until flattening (full-collapse), followed by classical endocytosis to retrieve vesicles. Alternatively, the pore may close (kiss-and-run), but the triggering mechanisms and its endocytic roles remain poorly understood.