Delayed Ventricular Repolarization and Sodium Channel Current Modification in a Mouse Model of Rett Syndrome

Rett syndrome (RTT) is a severe developmental disorder that is strongly linked to mutations in the MECP2 gene. RTT has been associated with sudden unexplained death and ECG QT interval prolongation. There are mixed reports regarding QT prolongation in mouse models of RTT, with some evidence that loss of Mecp2 function enhances cardiac late Na current, I_Na,Late. The present study was undertaken in order to investigate both ECG and ventricular AP characteristics in the Mecp2^Null/Y male murine RTT model and to interrogate both fast I_Na and I_Na,Late in myocytes from the model. ECG recordings from 8–10-week-old Mecp2^Null/Y male mice revealed prolongation of the QT and rate corrected QT (QTc) intervals and QRS widening compared to wild-type (WT) controls. Action potentials (APs) from Mecp2^Null/Y myocytes exhibited longer APD₇₅ and APD₉₀ values, increased triangulation and instability. I_Na,Late was also significantly larger in Mecp2^Null/Y than WT myocytes and was insensitive to the Nav1.8 inhibitor A-803467. Selective recordings of fast I_Na revealed a decrease in peak current amplitude without significant voltage shifts in activation or inactivation V_0.5. Fast I_Na ‘window current’ was reduced in RTT myocytes; small but significant alterations of inactivation and reactivation time-courses were detected. Effects of two I_Na,Late inhibitors, ranolazine and GS-6615 (eleclazine), were investigated. Treatment with 30 µM ranolazine produced similar levels of inhibition of I_Na,Late in WT and Mecp2^Null/Y myocytes, but produced ventricular AP prolongation not abbreviation. In contrast, 10 µM GS-6615 both inhibited I_Na,Late and shortened ventricular AP duration. The observed changes in I_Na and I_Na,Late can account for the corresponding ECG changes in this RTT model. GS-6615 merits further investigation as a potential treatment for QT prolongation in RTT.     

High‐Throughput Miniaturized Screening of Nanoparticle Formation via Inkjet Printing

The self‐assembly of specific polymers into well‐defined nanoparticles (NPs) is of great interest to the pharmaceutical industry as the resultant materials can act as drug delivery vehicles. In this work, a high‐throughput method to screen the ability of polymers to self‐assemble into NPs using a picoliter inkjet printer is presented. By dispensing polymer solutions in dimethyl sulfoxide (DMSO) from the printer into the wells of a 96‐well plate, containing water as an antisolvent, 50 suspensions are screened for nanoparticle formation rapidly using only nanoliters to microliters. A variety of polymer classes are used and in situ characterization of the submicroliter nanosuspensions shows that the particle size distributions match those of nanoparticles made from bulk suspensions. Dispensing organic polymer solutions into well plates via the printer is thus shown to be a reproducible and fast method for screening nanoparticle formation which uses two to three orders of magnitude less material than conventional techniques. Finally, a pilot study for a high‐throughput pipeline of nanoparticle production, physical property characterization, and cytocompatibility demonstrates the feasibility of the printing approach for screening of nanodrug delivery formulations. Nanoparticles are produced in the well plates, characterized for size and evaluated for effects on metabolic activity of lung cancer cells.     

Nonstationary response of nonlinear systems using equivalent linearization with a compact analytical form of the excitation process

A new method based on equivalent linearization approaches is presented for estimating the nonstationary response of a class of nonlinear multi-degree-of-freedom systems subjected to nonstationary excitations. The highly efficient method is based on creating a compact analytical approximation of measured nonstationary excitation process data through use of a two-stage decomposition procedure. The analytic data condensation of the excitation process is performed in two stages; (1) by performing the Karhunen–Loeve spectral decomposition on the covariance matrix of the input random process to obtain the dominant eigenvectors, and (2) by fitting these eigenvectors with orthogonal polynomials to produce a truncated series of analytically approximated eigenvectors. The efficiency and accuracy of the method is demonstrated through simulation with synthetically generated excitation data as well as measured data from a real-world physical process. Although the decomposition procedure used can characterize very general input processes, because the equivalent linearization technique requires the Gaussian assumption of the response process, the constraint on applying this approach is similar to the constraints on all other equivalent linearization techniques. However, the additional freedom gained from being able to work with data-based nonstationary random processes is a significant addition to this area of research.     

The effectiveness of Light Rail transit in achieving regional CO<Subscript>2</Subscript> emissions targets is linked to building energy use: insights from system dynamics modeling

Cities worldwide face the challenges of accommodating a growing population, while reducing emissions to meet climate mitigation targets. Public transit investments are often proposed as a way to curb emissions while maintaining healthy urban economies. However, cities face a system-level challenge in that transportation systems have cascading effects on land use and economic development. Understanding how an improved public transit system could affect urban growth and emissions requires a system-level view of a city, to anticipate side effects that could run counter to policy goals. To address this knowledge gap, we conducted a case study on the rapidly growing Research Triangle, North Carolina (USA) region, which has proposed to build a Light Railway by 2026 along a heavily used transportation corridor between the cities of Durham and Chapel Hill. At the same time, Durham County has set a goal of lowering greenhouse gas emissions by 30% from a 2005 baseline by 2030. In collaboration with local stakeholders, we developed a system dynamics model to simulate how Light Rail transit and concurrent policies could help or hinder these sustainable growth goals. The Durham–Orange Light Rail Project (D–O LRP) model simulates urban–regional dynamics between 2000 and 2040, including feedbacks from energy spending on economic growth and from land scarcity on development. Counter to expectations, model scenarios that included Light Rail had as much as 5% higher regional energy use and CO₂ emissions than business-as-usual (BAU) by 2040 despite many residents choosing to use public transit instead of private vehicles. This was largely due to an assumption that Light Rail increases demand for commercial development in the station areas, creating new jobs and attracting new residents. If regional solar capacity grew to 640 MW, this would offset the emissions growth, mostly from new buildings, that is indirectly due to Light Rail. National trends in building and automobile energy efficiency, as well as federal emissions regulation under the Clean Power Plan, would also allow significant progress toward the 2030 Durham emissions reduction goal. By simulating the magnitude of technology and policy effects, the D–O LRP model can enable policy makers to make strategic choices about regional growth.     

Imposition of essential boundary conditions in the material point method

There is increasing interest in the material point method (MPM) as a means of modelling solid mechanics problems in which very large deformations occur, e.g. in the study of landslides and metal forming; however, some aspects vital to wider use of the method have to date been ignored, in particular methods for imposing essential boundary conditions in the case where the problem domain boundary does not coincide with the background grid element edges. In this paper, we develop a simple procedure originally devised for standard finite elements for the imposition of essential boundary conditions, for the MPM, expanding its capabilities to model boundaries of any inclination. To the authors' knowledge, this is the first time that a method has been proposed that allows arbitrary Dirichlet boundary conditions (zero and nonzero values at any inclination) to be imposed in the MPM. The method presented in this paper is different from other MPM boundary approximation approaches, in that (1) the boundaries are independent of the background mesh, (2) artificially stiff regions of material points are avoided, and (3) the method does not rely on mirroring of the problem domain to impose symmetry. The main contribution of this work is equally applicable to standard finite elements and the MPM.     

Biological/biomedical accelerator mass spectrometry targets. 2. Physical, morphological, and structural characteristics

The number of biological/biomedical applications that require AMS to achieve their goals is increasing, and so is the need for a better understanding of the physical, morphological, and structural traits of high quality of AMS targets. The metrics of quality included color, hardness/texture, and appearance (photo and SEM), along with FT-IR, Raman, and powder X-ray diffraction spectra that correlate positively with reliable and intense ion currents and accuracy, precision, and sensitivity of fraction modern ( F m). Our previous method produced AMS targets of gray-colored iron-carbon materials (ICM) 20% of the time and of graphite-coated iron (GCI) 80% of the time. The ICM was hard, its FT-IR spectra lacked the sp (2) bond, its Raman spectra had no detectable G' band at 2700 cm (-1), and it had more iron carbide (Fe 3C) crystal than nanocrystalline graphite or graphitizable carbon (g-C). ICM produced low and variable ion current whereas the opposite was true for the graphitic GCI. Our optimized method produced AMS targets of graphite-coated iron powder (GCIP) 100% of the time. The GCIP shared some of the same properties as GCI in that both were black in color, both produced robust ion current consistently, their FT-IR spectra had the sp (2) bond, their Raman spectra had matching D, G, G', D +G, and D ' bands, and their XRD spectra showed matching crystal size. GCIP was a powder that was easy to tamp into AMS target holders that also facilitated high throughput. We concluded that AMS targets of GCIP were a mix of graphitizable carbon and Fe 3C crystal, because none of their spectra, FT-IR, Raman, or XRD, matched exactly those of the graphite standard. Nevertheless, AMS targets of GCIP consistently produced the strong, reliable, and reproducible ion currents for high-throughput AMS analysis (270 targets per skilled analyst/day) along with accurate and precise F m values.     

Nanoparticle Drug Delivery Can Reduce the Hepatotoxicity of Therapeutic Cargo

Hepatotoxicity is a key concern in the clinical translation of nanotherapeutics because preclinical studies have consistently shown that nanotherapeutics accumulates extensively in the liver. However, clinical‐stage nanotherapeutics have not shown increased hepatotoxicity. Factors that can contribute to the hepatotoxicity of nanotherapeutics beyond the intrinsic hepatotoxicity of nanoparticles (NPs) are poorly understood. Because of this knowledge gap, clinical translation efforts have avoided hepatotoxic molecules. By examining the hepatotoxicity of nanoformulations of known hepatotoxic compounds, it is demonstrated that nanotherapeutics are associated with lower hepatotoxicity than their small‐molecule counterparts. It is also found that the reduced hepatotoxicity is related to the uptake of nanotherapeutics by macrophages in the liver. These findings can facilitate further development and clinical translation of nanotherapeutics.     

Surface molecular doping of all-inorganic perovskite using zethrenes molecules

Nano Research - We present an optical and photoelectron spectroscopic study to elucidate the interfacial electronic properties of organic-inorganic semiconductor heterojunctions formed in a...