Xenobiotic Nuclear Receptors Pregnane X Receptor and Constitutive Androstane Receptor Regulate Antiretroviral Drug Efflux Transporters at the Blood-Testis Barrier.

Poor antiretroviral drug (ARV) penetration in the testes could be due, in part, to the presence of ATP-binding cassette (ABC) membrane-associated drug efflux transporters such as P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance-associated proteins (MRPs) expressed at the blood-testis barrier (BTB). The functional expression of these transporters is known to be regulated by ligand-activated nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) in various tissues. This study aimed to investigate in vitro and ex vivo the role of PXR and CAR in the regulation of ABC transporters at the BTB.

Adverse Events of Atomoxetine in a Double-Blind Placebo-Controlled Study in Children with Autism.

Objective: Attention-deficit/hyperactivity disorder (ADHD) symptoms, including inattention and over activity, occur in approximately one-third of children with autism spectrum disorder (ASD). We describe the rate and duration of adverse events in a randomized controlled trial of atomoxetine (ATX) and parent training (PT) for ADHD symptoms and noncompliance in children with ASD.

Methods: We conducted a 10-week, double-blind, 2 × 2 trial of ATX and PT with 128 children (ages 5-14) randomized to ATX alone, ATX+PT, placebo+PT, or placebo alone.

Hypertension in Pregnancy and Offspring Cardiovascular Risk in Young Adulthood: Prospective and Sibling Studies in the HUNT Study (Nord-Trøndelag Health Study) in Norway.

Women with hypertensive disorders in pregnancy are at increased lifetime risk for cardiovascular disease. We examined the offspring's cardiovascular risk profile in young adulthood and their siblings' cardiovascular risk profile. From the HUNT study (Nord-Trøndelag Health Study) in Norway, 15 778 participants (mean age: 29 years), including 210 sibling groups, were linked to information from the Medical Birth Registry of Norway.

Exact Factorization-Based Density Functional Theory of Electrons and Nuclei.

The ground state energy of a system of electrons (r=r_{1},r_{2},…) and nuclei (R=R_{1},R_{2},…) is proven to be a variational functional of the electronic density n(r,R) and paramagnetic current density j_{p}(r,R) conditional on R, the nuclear wave function χ(R), an induced vector potential A_{μ}(R) and a quantum geometric tensor T_{μν}(R). n, j_{p}, A_{μ} and T_{μν} are defined in terms of the conditional electronic wave function Φ_{R}(r). The ground state (n,j_{p},χ,A_{μ},T_{μν}) can be calculated by solving self-consistently (i) conditional Kohn-Sham equations containing effective scalar and vector potentials v_{s}(r) and A_{xc}(r) that depend parametrically on R, (ii) the Schrödinger equation for χ(R), and (iii) Euler-Lagrange equations that determine T_{μν}.

On-target efficacy of a HIF-2α antagonist in preclinical kidney cancer models.

Clear cell renal cell carcinoma, the most common form of kidney cancer, is usually linked to inactivation of the pVHL tumour suppressor protein and consequent accumulation of the HIF-2α transcription factor (also known as EPAS1). Here we show that a small molecule (PT2399) that directly inhibits HIF-2α causes tumour regression in preclinical mouse models of primary and metastatic pVHL-defective clear cell renal cell carcinoma in an on-target fashion. pVHL-defective clear cell renal cell carcinoma cell lines display unexpectedly variable sensitivity to PT2399, however, suggesting the need for predictive biomarkers to be developed to use this approach optimally in the clinic.

Thyroid Function and Sudden Cardiac Death: A Prospective Population-Based Cohort Study.

Background: The association between thyroid function and cardiovascular disease is well established, but no study to date has assessed whether it is a risk factor for sudden cardiac death (SCD). Therefore, we studied the association of thyroid function with SCD in a prospective population-based cohort.

Methods: Participants from the Rotterdam Study ≥45 years with thyroid-stimulating hormone or free thyroxine (FT4) measurements and clinical follow-up were eligible.

Envelope K+/H+ Antiporters AtKEA1 and AtKEA2 Function in Plastid Development.

It is well established that thylakoid membranes of chloroplasts convert light energy into chemical energy, yet the development of chloroplast and thylakoid membranes is poorly understood. Loss of function of the two envelope K(+)/H(+) antiporters AtKEA1 and AtKEA2 was shown previously to have negative effects on the efficiency of photosynthesis and plant growth; however, the molecular basis remained unclear. Here, we tested whether the previously described phenotypes of double mutant kea1kea2 plants are due in part to defects during early chloroplast development in Arabidopsis (Arabidopsis thaliana).

Rapid Diagnosis of Tuberculosis from Analysis of Urine Volatile Organic Compounds.

The World Health Organization has called for simple, sensitive, and non-sputum diagnostics for tuberculosis. We report development of a urine tuberculosis test using a colorimetric sensor array (CSA). The sensor comprised of 73 different indicators captures high-dimensional, spatiotemporal signatures of volatile chemicals emitted by human urine samples.

A Leadless Intracardiac Transcatheter Pacing System.

Background: A leadless intracardiac transcatheter pacing system has been designed to avoid the need for a pacemaker pocket and transvenous lead.

Methods: In a prospective multicenter study without controls, a transcatheter pacemaker was implanted in patients who had guideline-based indications for ventricular pacing. The analysis of the primary end points began when 300 patients reached 6 months of follow-up.

Phosphido- and Amidozirconocene Cation-Based Frustrated Lewis Pair Chemistry.

Methyl abstraction from neutral [Cp2ZrMe(ERR')] complexes 1 (E = N, P; R, R' = alkyl, aryl) with either B(C6F5)3 or [Ph3C][B(C6F5)4] results in the formation of [Cp2Zr(ERR')][X] complexes 2 (X(-) = MeB(C6F5)3(-), B(C6F5)4(-)). The X-ray structure of amido complexes [Cp2Zr(NPh2)][MeB(C6F5)3] (2d) and [Cp2Zr(N(t)BuAr)][B(C6F5)4] (2e', Ar = 3,5-C6H3(CH3)2) is reported, showing a sterically dependent Zr/N-π interaction. Complexes 2 catalyze the hydrogenation of electron-rich olefins and alkynes under mild conditions (room temperature, 1.

Effects of red-cell storage duration on patients undergoing cardiac surgery.

Background: Some observational studies have reported that transfusion of red-cell units that have been stored for more than 2 to 3 weeks is associated with serious, even fatal, adverse events. Patients undergoing cardiac surgery may be especially vulnerable to the adverse effects of transfusion.

Methods: We conducted a randomized trial at multiple sites from 2010 to 2014.

Mechanistic understanding for the greater sensitivity of monkeys to antisense oligonucleotide-mediated complement activation compared with humans.

Differences in sensitivity of monkeys and humans to antisense oligonucleotide (ASO)-induced complement alternative pathway (AP) activation were evaluated in monkeys, humans, and in serum using biochemical assays. Transient AP activation was evident in monkeys at higher doses of two 2'-O-methoxyethyl (2'-MOE) ASOs (ISIS 426115 and ISIS 183750). No evidence of AP activation was observed in humans for either ASO, even with plasma ASO concentrations that reached the threshold for activation in monkeys.

Pi3kcb links Hippo-YAP and PI3K-AKT signaling pathways to promote cardiomyocyte proliferation and survival.

Rationale: Yes-associated protein (YAP), the nuclear effector of Hippo signaling, regulates cellular growth and survival in multiple organs, including the heart, by interacting with TEA (transcriptional enhancer activator)-domain sequence-specific DNA-binding proteins. Recent studies showed that YAP stimulates cardiomyocyte proliferation and survival. However, the direct transcriptional targets through which YAP exerts its effects are poorly defined.

Is nuclear factor erythroid 2-related factor 2 responsible for sex differences in susceptibility to acetaminophen-induced hepatotoxicity in mice?

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that positively regulates the expression and activity of cytoprotective genes during periods of oxidative stress. It has previously been shown that some Nrf2 genes are more highly expressed in livers of female than male mice. This could explain previously reported sex-related differences in susceptibility to acetaminophen (APAP) hepatotoxicity in mice, where females show greater resistance to APAP hepatotoxicity.

Langevin and fOkker-Planck analyses of inhibited molecular passing processes controlling transport and reactivity in nanoporous materials.

Inhibited passing of reactant and product molecules within the linear pores of nanoporous catalytic materials strongly reduces reactivity. The dependence of the passing propensity P on pore radius R is analyzed utilizing Langevin dynamics to account for solvent effects. We find that P ∼ (R-R(c))(σ), where passing is sterically blocked for R≤R(c), with σ below the transition state theory value.

Cardiac-specific YAP activation improves cardiac function and survival in an experimental murine MI model.

Rationale: Yes-associated protein (YAP), the terminal effector of the Hippo signaling pathway, is crucial for regulating embryonic cardiomyocyte proliferation.

Objective: We hypothesized that YAP activation after myocardial infarction (MI) would preserve cardiac function and improve survival.

Methods And Results: We used a cardiac-specific, inducible expression system to activate YAP in adult mouse heart.

Genome sequencing of disease and carriage isolates of nontypeable Haemophilus influenzae identifies discrete population structure.

One of the main hurdles for the development of an effective and broadly protective vaccine against nonencapsulated isolates of Haemophilus influenzae (NTHi) lies in the genetic diversity of the species, which renders extremely difficult the identification of cross-protective candidate antigens. To assess whether a population structure of NTHi could be defined, we performed genome sequencing of a collection of diverse clinical isolates representative of both carriage and disease and of the diversity of the natural population. Analysis of the distribution of polymorphic sites in the core genome and of the composition of the accessory genome defined distinct evolutionary clades and supported a predominantly clonal evolution of NTHi, with the majority of genetic information transmitted vertically within lineages.

Pharmacologic suppression of inflammation by a diphenyldifluoroketone, EF24, in a rat model of fixed-volume hemorrhage improves survival.

An exaggerated release of proinflammatory cytokines and accompanying inflammation contributes to the development of multiple organ failure after hemorrhagic shock. Here, we tested the nuclear factor (NF) κ-light-chain-enhancer of activated B cell (NF-κB)-mediated transcriptional control of inflammatory pathways as a target in the management of hemorrhage-induced inflammation. We performed a study in a rat model of fixed-volume hemorrhage to investigate the anti-inflammatory effects of the diphenyldifluoroketone EF24 [3,5-bis(2-fluorobenzylidene)piperidin-4-one], an NF-κB inhibitor, in lung tissue.

Electron interference in molecular photoionization by attosecond laser pulses.

Molecular photoionization by intense attosecond linearly and circularly polarized X-ray laser pulses is investigated from numerical solutions of time-dependent Schrödinger equations for the one-electron systems H2(+) and H3(++). Both momentum stripes and rings in photoelectron angular distributions are observed. The first with momentum intervals Δp(s)=2 π/R, where R is the molecular internuclear distance, results from interference of the coherent continuum scattering electron wave packets, which is shown to be insensitive to the laser polarization and wavelength.

Diffusion, annihilation, and chemical reactions in complex networks with spatial constraints.

We consider Erdö]s-Rényi-type networks embedded in one-dimensional (de=1) and two-dimensional (de=2) Euclidean space with the link-length distribution p(r)∼r-δ. The dimension d of these networks, as a function of δ, has been studied earlier and has been shown to depend on δ. Here we consider diffusion, annihilation, and chemical reaction processes on these spatially constrained networks and show that their dynamics is controlled by the dimension d of the system.

High-frequency auditory filter shape for the Atlantic bottlenose dolphin.

High-frequency auditory filter shapes of an Atlantic bottlenose dolphin (Tursiops truncatus) were measured using a notched noise masking source centered on pure tone signals at frequencies of 40, 60, 80 and 100 kHz. A dolphin was trained to swim into a hoop station facing the noise/signal transducer located at a distance of 2 m. The dolphin's masked threshold was determined using an up-down staircase method as the width of the notched noise was randomly varied from 0, 0.

Incidence of adverse drug reactions in human immune deficiency virus-positive patients using highly active antiretroviral therapy.

To estimate the incidence of adverse drug reactions (ADRs) in Human immune deficiency virus (HIV) patients on highly active antiretroviral therapy (HAART). To identify the risk factors associated with ADRs in HIV patients. To analyze reported ADRs based on various parameters like causality, severity, predictability, and preventability.

Synthesis and reactivity of molybdenum and tungsten bis(dinitrogen) complexes supported by diphosphine chelates containing pendant amines.

Molybdenum and tungsten bis(dinitrogen) complexes of the formula M(N(2))(2)(PNP)(2) (M = Mo and W) and W(N(2))(2)(dppe)(PNP), supported by diphosphine ligands containing a pendant amine of the formula (CH(2)PR(2))(2)NR' = P(R)N(R')P(R) (R = Et, Ph; R' = Me, Bn), have been prepared by Mg reduction of metal halides under an N(2) atmosphere. The complexes have been characterized by NMR and IR spectroscopy, X-ray crystallography, and cyclic voltammetry. Reactivity of the target Mo and W bis(dinitrogen) compounds with CO results in the formation of dicarbonyl complexes.