The Utilization and Development of Viral Vectors in Vaccines as a Prophylactic Treatment Against Ebola Virus as an Emerging and Zoonotic Infectious Disease.

Alongside the prescription of commonly used antivirals, such as acyclovir, remdesivir, oseltamivir, and ciprofloxacin, the most efficient way to prevent or treat communicable diseases is by vaccination. Vaccines have been the most efficient way to prevent or treat highly transmissible infectious agents, such as Ebola, Anthrax, and Dengue Fever. Most epidemics of these highly transmissible infectious agents occur in places, such as South America, Central America, Tropical Asia, and Africa, where the availability of resources and access to adequate healthcare are limited. However, recent events in history have proven that even with access to resources and proper healthcare, those in firstworld countries are not invincible when it comes to infectious diseases and epidemics. The Ebola virus outbreak in West Africa highlighted the gaps in therapeutic advancement and readiness and led to the rapid development of novel vaccine approaches. Viral vectors, in the case of the Ebola vaccine the Vesicular Stomatitis Virus (VSV), can be safely used to activate or initiate the innate adaptive immune response to protect against viral infection. When developed properly and with extensive study, novel vaccine approaches allow physicians and health experts to control the rate at which viruses spread or prevent transmission. This review will discuss the advantages of viral vector vaccines, their chemistry and development, and the pathophysiology of the Ebola virus to develop advantageous and efficacious treatments.

Longitudinal, prospective study of head impacts in male high school football players.

INTRODUCTION: Repetitive, subconcussive events may adversely affect the brain and cognition during sensitive periods of development. Prevention of neurocognitive consequences of concussion in high school football is therefore an important public health priority. We aimed to identify the player positions and demographic, behavioral, cognitive, and impact characteristics that predict the frequency and acceleration of head impacts in high school football players. METHODS: In this prospective study, three cohorts of adolescent male athletes (N = 53, 28.3% Hispanic) were recruited over three successive seasons in a high school American football program. Demographic and cognitive functioning were assessed at baseline prior to participating in football. Helmet sensors recorded impact frequency and acceleration. Each head impact was captured on film from five different angles. Research staff verified and characterized on-field impacts. Player-level Poisson regressions and year-level and impact-level linear mixed-effect models were used to determine demographic, behavioral, cognitive, and impact characteristics as predictors of impact frequency and acceleration. RESULTS: 4,678 valid impacts were recorded. Impact frequency positively associated with baseline symptoms of hyperactivity-impulsivity [ß(SE) = 1.05 impacts per year per unit of symptom severity (1.00), p = 0.01] and inattentiveness [ß(SE) = 1.003 impacts per year per T-score unit (1.001), p = 0.01]. Compared to quarterbacks, the highest acceleration impacts were sustained by kickers/punters [ß(SE) = 21.5 g's higher (7.1), p = 0.002], kick/punt returners [ß(SE) = 9.3 g's higher (4.4), p = 0.03], and defensive backs [ß(SE) = 4.9 g's higher (2.5), p = 0.05]. Impacts were more frequent in the second [ß(SE) = 33.4 impacts (14.2), p = 0.02)] and third [ß(SE) = 50.9 impacts (20.1), p = 0.01] year of play. Acceleration was highest in top-of-the-head impacts [ß(SE) = 4.4 g's higher (0.8), p<0.001]. CONCLUSION: Including screening questions for Attention-Deficit/Hyperactivity Disorder in pre-participation evaluations can help identify a subset of prospective football players who may be at risk for increased head impacts. Position-specific strategies to modify kickoffs and correct tackling and blocking may also reduce impact burden.

Contamination by Antibiotic-Resistant Bacteria on Cell Phones of Vendors in a Peruvian Market.

Background and Objectives. Multiple studies have evaluated the presence of bacterial contamination on cell phones in clinical settings; however, the presence and transmission of antibiotic-resistant bacteria on cell phones in the community have not been adequately elucidated. Material and Methods. A cross-sectional study was carried out to determine the presence of bacteria resistant to antibiotics on the cell phones of vendors in a Peruvian market and the associated factors. A sample of 127 vendors was obtained through stratified probabilistic sampling using a data collection form validated by experts. Cell phone samples were cultured using a standard technique, and antibiotic sensitivity was determined using the Kirby-Bauer technique. Chi-squared and Mann-Whitney U tests were used to determine factors associated with resistance in cell phone cultures. Results. Among the cell phones, 92.1% showed bacterial growth, predominantly Gram-positive bacteria (coagulase-negative staphylococci and Staphylococcus aureus), and 17% of the cultures showed resistance to at least three antibiotics evaluated. Two strains fell into the category of methicillin-resistant S. aureus, and three strains of E. coli had resistance to carbapenems. Conclusions. A short distance between customers and vendors, lack of a cell phone case, and having a cell phone with touchscreen are factors associated with antibiotic-resistant bacteria on cell phones.

Bringing Plant Immunity to Light: A Genetically Encoded, Bioluminescent Reporter of Pattern-Triggered Immunity in Nicotiana benthamiana.

Plants rely on innate immune systems to defend against a wide variety of biotic attackers. Key components of innate immunity include cell-surface pattern-recognition receptors (PRRs), which recognize pest- and pathogen-associated molecular patterns (PAMPs). Unlike other classes of receptors that often have visible cell-death immune outputs upon activation, PRRs generally lack rapid methods for assessing function. Here, we describe a genetically encoded bioluminescent reporter of immune activation by heterologously expressed PRRs in the model organism Nicotiana benthamiana. We characterized N. benthamiana transcriptome changes in response to Agrobacterium tumefaciens and subsequent PAMP treatment to identify pattern-triggered immunity (PTI)-associated marker genes, which were then used to generate promoter-luciferase fusion fungal bioluminescence pathway (FBP) constructs. A reporter construct termed pFBP_2xNbLYS1::LUZ allows for robust detection of PTI activation by heterologously expressed PRRs. Consistent with known PTI signaling pathways, reporter activation by receptor-like protein (RLP) PRRs is dependent on the known adaptor of RLP PRRs, i.e., SOBIR1. The FBP reporter minimizes the amount of labor, reagents, and time needed to assay function of PRRs and displays robust sensitivity at biologically relevant PAMP concentrations, making it ideal for high throughput screens. The tools described in this paper will be powerful for investigations of PRR function and characterization of the structure-function of plant cell-surface receptors. [Formula: see text] The author(s) have dedicated the work to the public domain under the Creative Commons CC0 "No Rights Reserved" license by waiving all of his or her rights to the work worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law, 2023.

Evolutionary gain and loss of a plant pattern-recognition receptor for HAMP recognition.

As a first step in innate immunity, pattern recognition receptors (PRRs) recognize the distinct pathogen and herbivore-associated molecular patterns and mediate activation of immune responses, but specific steps in the evolution of new PRR sensing functions are not well understood. We employed comparative genomic and functional analyses to define evolutionary events leading to the sensing of the herbivore-associated peptide inceptin (In11) by the PRR inceptin receptor (INR) in legume plant species. Existing and de novo genome assemblies revealed that the presence of a functional INR gene corresponded with ability to respond to In11 across ~53 million years (my) of evolution. In11 recognition is unique to the clade of Phaseoloid legumes, and only a single clade of INR homologs from Phaseoloids was functional in a heterologous model. The syntenic loci of several non-Phaseoloid outgroup species nonetheless contain non-functional INR-like homologs, suggesting that an ancestral gene insertion event and diversification preceded the evolution of a specific INR receptor function ~28 my ago. Chimeric and ancestrally reconstructed receptors indicated that 16 amino acid differences in the C1 leucine-rich repeat domain and C2 intervening motif mediate gain of In11 recognition. Thus, high PRR diversity was likely followed by a small number of mutations to expand innate immune recognition to a novel peptide elicitor. Analysis of INR evolution provides a model for functional diversification of other germline-encoded PRRs.

The health status of a plant depends on the immune system it inherits from its parents. Plants have many receptor proteins that can recognize distinct molecules from insects and microbes, and trigger an immune response. Inheriting the right set of receptors allows plants to detect certain threats and to cope with diseases and pests. Soybeans, chickpeas and other closely-related crop plants belong to a family of plants known as the legumes. Previous studies have found that, unlike other plants, some legumes are able to respond to oral secretions from caterpillars. These plants have a receptor known as INR that binds to a molecule called inceptin in the secretions. However, it remained unclear how or when INR evolved. To address this gap, Snoeck et al. tested immune responses to inceptin in the leaves of 22 species of legume. The experiments revealed that only members of a subgroup of legumes called the Phaseoloids were able to recognize the molecule. Analyzing the genomes of several legume species revealed that the gene encoding INR first emerged around 28 million years ago. Among the descendants of the legumes that first evolved this receptor, only the crop plant soybean and a few other species were unable to respond to inceptin. The genomic data indicated that these species had in fact lost the gene encoding INR over evolutionary time. Snoeck et al. then combined data from genes encoding modern-day receptors to reconstruct the sequence of building blocks that make up the 28-million-year-old version of INR. This ancestral receptor was able to respond to inceptin in the caterpillar secretion, whereas an older version of the protein, which had a slightly different set of building blocks, could not. This suggests that INR evolved the ability to respond to inceptin as a result of small mutations in the gene encoding a more ancient receptor. The work of Snoeck et al. reveals how the Phaseoloids evolved to respond to caterpillars, and how this ability has been lost in soybeans and other members of the subgroup. In the future, these findings may aid plant breeding or genetic engineering approaches for enhancing soybeans and other crops resistance to caterpillar pests.

SUMO paralogue-specific functions revealed through systematic analysis of human knockout cell lines and gene expression data.

The small ubiquitin-related modifiers (SUMOs) regulate nearly every aspect of cellular function, from gene expression in the nucleus to ion transport at the plasma membrane. In humans, the SUMO pathway has five SUMO paralogues with sequence homologies that range from 45% to 97%. SUMO1 and SUMO2 are the most distantly related paralogues and also the best studied. To what extent SUMO1, SUMO2, and the other paralogues impart unique and nonredundant effects on cellular functions, however, has not been systematically examined and is therefore not fully understood. For instance, knockout studies in mice have revealed conflicting requirements for the paralogues during development and studies in cell culture have relied largely on transient paralogue overexpression or knockdown. To address the existing gap in understanding, we first analyzed SUMO paralogue gene expression levels in normal human tissues and found unique patterns of SUMO1-3 expression across 30 tissue types, suggesting paralogue-specific functions in adult human tissues. To systematically identify and characterize unique and nonredundant functions of the SUMO paralogues in human cells, we next used CRISPR-Cas9 to knock out SUMO1 and SUMO2 expression in osteosarcoma (U2OS) cells. Analysis of these knockout cell lines revealed essential functions for SUMO1 and SUMO2 in regulating cellular morphology, promyelocytic leukemia (PML) nuclear body structure, responses to proteotoxic and genotoxic stress, and control of gene expression. Collectively, our findings reveal nonredundant regulatory roles for SUMO1 and SUMO2 in controlling essential cellular processes and provide a basis for more precise SUMO-targeting therapies.

Deconstructing Noncovalent Kelch-like ECH-Associated Protein 1 (Keap1) Inhibitors into Fragments to Reconstruct New Potent Compounds.

Targeting the protein-protein interaction (PPI) between nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) is a potential therapeutic strategy to control diseases involving oxidative stress. Here, six classes of known small-molecule Keap1-Nrf2 PPI inhibitors were dissected into 77 fragments in a fragment-based deconstruction reconstruction (FBDR) study and tested in four orthogonal assays. This gave 17 fragment hits of which six were shown by X-ray crystallography to bind in the Keap1 Kelch binding pocket. Two hits were merged into compound 8 with a 220-380-fold stronger affinity (Ki = 16 µM) relative to the parent fragments. Systematic optimization resulted in several novel analogues with Ki values of 0.04-0.5 µM, binding modes determined by X-ray crystallography, and enhanced microsomal stability. This demonstrates how FBDR can be used to find new fragment hits, elucidate important ligand-protein interactions, and identify new potent inhibitors of the Keap1-Nrf2 PPI.

Catalytic Mechanism of Interfacial Water in the Cycloaddition of Quadricyclane and Diethyl Azodicarboxylate.

"On-water" catalysis, the unusual activity of water molecules at the organic solvent-water interface, has been demonstrated in many organic reactions. However, the catalytic mechanism has remained unclear, largely because of the irreproducibility of the organic-water interface under the common stirring condition. Here, the interfacial area was controlled by employing adsorbed water on mesoporous silica nanoparticles as the catalyst. Reliable kinetics of the cycloaddition reaction of quadricyclane and diethyl azodicarboxylate (DEAD) at the toluene-water interface within the nanoparticle pores were measured. Data reveal an Eley-Rideal mechanism, wherein DEAD adsorbs at the toluene-water interface via hydrogen bonds formed with interfacial water, which lower the activation energy of the cycloaddition reaction. The mechanistic insights gained and preparation of surface water in silica pores described herein may facilitate the future design of improved "on-water" catalysts.

Fundamental understanding of millipede morphology and locomotion dynamics.

A detailed model for the locomotory mechanics used by millipedes is provided here through systematic experimentation on the animal and validation of observations through a biomimetic robotic platform. Millipedes possess a powerful gait that is necessary for generating large thrust force required for proficient burrowing. Millipedes implement a metachronal gait through movement of many legs that generates a traveling wave. This traveling wave is modulated by the animal to control the magnitude of thrust force in the direction of motion for burrowing, climbing, or walking. The quasi-static model presented for the millipede locomotion mechanism matches experimental observations on live millipedes and results obtained from a biomimetic robotic platform. The model addresses questions related to the unique morphology of millipedes with respect to their locomotory performance. A complete understanding of the physiology of millipedes and mechanisms that provide modulation of the traveling wave locomotion using a metachronal gait to increase their forward thrust is provided. Further, morphological features needed to optimize various locomotory and burrowing functions are discussed. Combined, these results open opportunity for development of biologically inspired locomotory methods for miniaturized robotic platforms traversing terrains and substrates that present large resistances.

Tuning Redox Potential of Gold Nanoparticle Photocatalysts by Light.

Metallic nanoparticle-based photocatalysts have gained a lot of interest in catalyzing oxidation-reduction reactions. In previous studies, the poor performance of these catalysts is partly due to their operation that relies on picosecond-lifetime hot carriers. In this work, electrons that accumulate at a photostationary state, generated by photocharging the catalysts, have a much longer lifetime for catalysis. This approach makes it possible to determine and tune the photoredox potentials of the catalysts. As demonstrated in a model reaction, the photostationary state of the photocatalyzed oxidative etching of colloidal gold nanoparticles using FeCl3 was established under continuous irradiation of different wavelengths. The photoredox potentials of the nanoparticles were then calculated using the Nernst equation. The potentials can be tuned to a range of 1.28 to 1.40 V (vs SHE) under irradiation of different wavelengths in the range of 450 to 517 nm. The effects of particle size or optical power on the photoredox potentials are small compared to the wavelength effect. Control over the photoredox potential of the particles using different excitation wavelengths can potentially be used to tune the activities and selectivities of metallic nanoparticle photocatalysts.

Anodic Oxidation of Dithiane Carboxylic Acids: A Rapid and Mild Way to Access Functionalized Orthoesters.

A new electrochemical methodology has been developed for the preparation of a wide variety of functionalized orthoesters under mild and green conditions from easily accessible dithiane derivatives. The new methodology also offers an unprecedented way to access tri(fluorinated) orthoesters, a class of compound that has never been studied before. This provides the community with a rapid and general method to prepare libraries of functionalized orthoesters from simple and readily available starting materials.

Economical, Green, and Safe Route Towards Substituted Lactones by Anodic Generation of Oxycarbonyl Radicals.

A new electrochemical methodology has been developed for the generation of oxycarbonyl radicals under mild and green conditions from readily available hemioxalate salts. Mono- and multi-functionalised γ-butyrolactones were synthesised through exo-cyclisation of these oxycarbonyl radicals with an alkene, followed by the sp3 -sp3 capture of the newly formed carbon-centred radical. The synthesis of functionalised valerolactone derivatives was also achieved, demonstrating the versatility of the newly developed methodology. This represents a viable synthetic route towards pharmaceutically important fragments and further demonstrates the practicality of electrosynthesis as a green and economical method to activate small organic molecules.

A Comparative Assessment Study of Known Small-Molecule Keap1-Nrf2 Protein-Protein Interaction Inhibitors: Chemical Synthesis, Binding Properties, and Cellular Activity.

Inhibiting the protein-protein interaction (PPI) between the transcription factor Nrf2 and its repressor protein Keap1 has emerged as a promising strategy to target oxidative stress in diseases, including central nervous system (CNS) disorders. Numerous non-covalent small-molecule Keap1-Nrf2 PPI inhibitors have been reported to date, but many feature suboptimal physicochemical properties for permeating the blood-brain barrier, while others contain problematic structural moieties. Here, we present the first side-by-side assessment of all reported Keap1-Nrf2 PPI inhibitor classes using fluorescence polarization, thermal shift assay, and surface plasmon resonance-and further evaluate the compounds in an NQO1 induction cell assay and in counter tests for nonspecific activities. Surprisingly, half of the compounds were inactive or deviated substantially from reported activities, while we confirm the cross-assay activities for others. Through this study, we have identified the most promising Keap1-Nrf2 inhibitors that can serve as pharmacological probes or starting points for developing CNS-active Keap1 inhibitors.

Synthesis, Derivatization, and Structural Analysis of Phosphorylated Mono-, Di-, and Trifluorinated d-Gluco-heptuloses by Glucokinase: Tunable Phosphoglucomutase Inhibition.

Glucokinase phosphorylated a series of C-1 fluorinated α-d-gluco-heptuloses. These phosphorylated products were discovered to be inhibitors of α-phosphomannomutase/phosphoglucomutase (αPMM/PGM) and ß-phosphoglucomutase (ßPGM). Inhibition potency with both mutases inversely correlated to the degree of fluorination. Structural analysis with αPMM demonstrated the inhibitor binding to the active site, with the phosphate in the phosphate binding site and the anomeric hydroxyl directed to the catalytic site.

Comparing the Effects of Loving-Kindness Meditation (LKM), Music and LKM Plus Music on Psychological Well-Being.

Loving-kindness meditation (LKM), a meditative practice directing caring feelings toward self and others, is a popular, evidence-base approach to increasing well-being. Music listening is also a popular form of emotion regulation used to enhance well-being. This interdisciplinary study evaluated a novel intervention called Convergence-combining LKM with accompanying classical guitar music-and its effects on adults' well-being, mindfulness, compassion and self-compassion outcomes. Convergence was compared to active control groups LKM-only and Music-only regarding their relative effectiveness in improving these outcomes. Participants (N = 78; aged 18 to 69 years; 90% females; recruited from the general public) were assigned to either the Convergence, LKM-only, or Music-only condition. Each condition received a 2-hour workshop, involving psychoeducation, three prerecorded meditations, and group enquiry and discussion. Participants were assessed at pre-program, post-program, and 4-week follow-up. Findings revealed that Convergence, LKM-only and Music-only were equally effective interventions, producing improvements in dependent variables with small effect sizes. There was no additive effect of the components when delivered together as Convergence. Significant correlations were found between the amount of home practice, and mindfulness and self-compassion at follow-up. LKM, music listening and Convergence all provide brief, evidence-based alternatives for improving well-being. Practical and theoretical implications are provided, as well as recommendations for future research.

Interferon-γ ablation exacerbates myocardial hypertrophy in diastolic heart failure.

Diastolic heart failure (HF) accounts for up to 50% of all HF admissions, with hypertension being the major cause of diastolic HF. Hypertension is characterized by left ventricular (LV) hypertrophy (LVH). Proinflammatory cytokines are increased in LVH and hypertension, but it is unknown if they mediate the progression of hypertension-induced diastolic HF. We sought to determine if interferon-γ (IFNγ) plays a role in mediating the transition from hypertension-induced LVH to diastolic HF. Twelve-week old BALB/c (WT) and IFNγ-deficient (IFNγKO) mice underwent either saline (n = 12) or aldosterone (n = 16) infusion, uninephrectomy, and fed 1% salt water for 4 wk. Tail-cuff blood pressure, echocardiography, and gene/protein analyses were performed. Isolated adult rat ventricular myocytes were treated with IFNγ (250 U/ml) and/or aldosterone (1 µM). Hypertension was less marked in IFNγKO-aldosterone mice than in WT-aldosterone mice (127 ± 5 vs. 136 ± 4 mmHg; P < 0.01), despite more LVH (LV/body wt ratio: 4.9 ± 0.1 vs. 4.3 ± 0.1 mg/g) and worse diastolic dysfunction (peak early-to-late mitral inflow velocity ratio: 3.1 ± 0.1 vs. 2.8 ± 0.1). LV ejection fraction was no different between IFNγKO-aldosterone vs. WT-aldosterone mice. LV end systolic dimensions were decreased significantly in IFNγKO-aldosterone vs. WT-aldosterone hearts (1.12 ± 0.1 vs. 2.1 ± 0.3 mm). Myocardial fibrosis and collagen expression were increased in both IFNγKO-aldosterone and WT-aldosterone hearts. Myocardial autophagy was greater in IFNγKO-aldosterone than WT-aldosterone mice. Conversely, tumor necrosis factor-α and interleukin-10 expressions were increased only in WT-aldosterone hearts. Recombinant IFNγ attenuated cardiac hypertrophy in vivo and modulated aldosterone-induced hypertrophy and autophagy in cultured cardiomyocytes. Thus IFNγ is a regulator of cardiac hypertrophy in diastolic HF and modulates cardiomyocyte size possibly by regulating autophagy. These findings suggest that IFNγ may mediate adaptive downstream responses and challenge the concept that inflammatory cytokines mediate only adverse effects.

Effect of wall-molecule interactions on electrokinetic transport of charged molecules in nanofluidic channels during FET flow control.

The interactions between charged molecules and channel surfaces are expected to significantly influence the electrokinetic transport of molecules and their separations in nanochannels. This study reports the effect of wall-molecule interactions on flow control of negatively charged Alexa 488 and positively charged Rhodamine B dye molecules in an array of nanochannels (100 nm wx 500 nm dx 14 mm l) embedded in fluidic field effect transistors (FETs). For FET flow control, a third electrical potential, known as a gate bias, is applied to the channel walls to manipulate their zeta-potential. Electroosmotic flow of charged dye molecules is accelerated or reversed according to the polarity and magnitude of the gate bias. During FET flow control, we monitor how the electrostatic interaction between charged dye molecules and channel walls affects the apparent velocity of molecules, using laser-scanning confocal fluorescence microscopy. We observe that the changes in flow speed and direction of negatively charged Alexa 488 is much more pronounced than that of positively charged Rhodamine B in response to the gate bias that causes either repulsive or attractive electrostatic interactions. This observation is supported by calculations of concentration-weighted velocity profiles of the two dye molecules during FET flow control. The velocity profile of negatively charged Alexa 488 is much more pronounced at the center of each nanochannel than near its walls since Alexa 488 molecules are repelled from negatively charged channel walls. This pronounced center velocity further responds to the gate bias, increasing the average velocity by as much as 23% when -30 V is applied to the gate (zeta-potential = -80.6 mV). In contrast, the velocity profile of positively charged Rhodamine B is dispersed over the entire channel width due to dye-wall attraction and adsorption. Our experimental observations and calculations support the hypothesis that valence-charge-dependent electrostatic interaction and its manipulation by the gate bias would enhance molecular separations of differentially charged molecules in nanofluidic FETs.

Formation and dynamics of supported phospholipid membranes on a periodic nanotextured substrate.

We have studied and modeled the morphology and dynamics of fluid planar lipid bilayer membranes supported on a textured silicon substrate. The substrate is fabricated to have channels on its surface that are a few hundred nanometers across, with a channel depth of a few hundred nanometers perpendicular to the plane of observation. Using atomic force microscopy and quantitative fluorescence microscopy, we have shown that the bilayer assemblies conform to the underlying nanostructured substrate. As far as dynamics is concerned, when observed over length scales exceeding the dimensions of the nanostructured features, the macroscopic diffusion is anisotropic. However, the macroscopic anisotropy is well simulated using models of diffusion on the nanostructured surface that consider the lipids to diffuse homogeneously and isotropically on the supporting substrate. Consistent with previous observations on less well characterized or less periodic nanostructures, we find that the nanostructured substrate produces an effective anisotropy in macroscopic diffusion of the conformal membrane. More importantly, we demonstrate how quantitative analysis of dynamics probed by larger-scale fluorescence imaging can yield information on nanoscale thin-film morphology.

Fenofibrate inhibits aldosterone-induced apoptosis in adult rat ventricular myocytes via stress-activated kinase-dependent mechanisms.

Aldosterone induces extracellular signal-regulated kinase (ERK)-dependent cardiac remodeling. Fenofibrate improves cardiac remodeling in adult rat ventricular myocytes (ARVM) partly via inhibition of aldosterone-induced ERK1/2 phosphorylation and inhibition of matrix metalloproteinases. We sought to determine whether aldosterone caused apoptosis in cultured ARVM and whether fenofibrate ameliorated the apoptosis. Aldosterone (1 microM) induced apoptosis by increasing terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL)-positive nuclei in ARVM. Spironolactone (100 nM), an aldosterone receptor antagonist, but not RU-486, a glucocorticoid receptor, inhibited aldosterone-mediated apoptosis, indicating that the mineralocorticoid receptor (MR) plays a role. SP-600125 (3 microM)-a selective inhibitor of c-Jun NH(2)-terminal kinase (JNK)-inhibited aldosterone-induced apoptosis in ARVM. Although aldosterone increased the expression of both stress-activated protein kinases, pretreatment with fenofibrate (10 microM) decreased aldosterone-mediated apoptosis by inhibiting only JNK phosphorylation and the aldosterone-induced increases in Bax, p53, and cleaved caspase-3 and decreases in Bcl-2 protein expression in ARVM. In vivo studies demonstrated that chronic fenofibrate (100 mg*kg body wt(-1)*day(-1)) inhibited myocardial Bax and increased Bcl-2 expression in aldosterone-induced cardiac hypertrophy. Similarly, eplerenone, a selective MR inhibitor, used in chronic pressure-overload ascending aortic constriction inhibited myocardial Bax expression but had no effect on Bcl-2 expression. Therefore, involvement of JNK MAPK-dependent mitochondrial death pathway mediates ARVM aldosterone-induced apoptosis and is inhibited by fenofibrate, a peroxisome proliferator-activated receptor (PPAR)alpha ligand. Fenofibrate mediates beneficial effects in cardiac remodeling by inhibiting programmed cell death and the stress-activated kinases.

Electrokinetic transport and separations in fluidic nanochannels.

This article presents a summary of theory, experimental studies, and results for the electrokinetic transport in small fluidic nanochannels. The main focus is on the effect of the electric double layer on the EOF, electric current, and electrophoresis of charged analytes. The double layer thickness can be of the same order as the width of the nanochannels, which has an impact on the transport by shaping the fluid velocity profile, local distributions of the electrolytes, and charged analytes. Our theoretical consideration is limited to continuum analysis where the equations of classical hydrodynamics and electrodynamics still apply. We show that small channels may lead to qualitatively new effects like selective ionic transport based on charge number as well as different modes for molecular separation. These new possibilities together with the rapid development of nanofabrication capabilities lead to an extensive experimental effort to utilize nanochannels for a variety of applications, which are also discussed and analyzed in this review.