Discovery of 5''-chloro-N-[(5,6-dimethoxypyridin-2-yl)methyl]-2,2':5',3''-terpyridine-3'-carboxamide (MK-1064): a selective orexin 2 receptor antagonist (2-SORA) for the treatment of insomnia.

The field of small-molecule orexin antagonist research has evolved rapidly in the last 15 years from the discovery of the orexin peptides to clinical proof-of-concept for the treatment of insomnia. Clinical programs have focused on the development of antagonists that reversibly block the action of endogenous peptides at both the orexin 1 and orexin 2 receptors (OX1 R and OX2 R), termed dual orexin receptor antagonists (DORAs), affording late-stage development candidates including Merck's suvorexant (new drug application filed 2012). Full characterization of the pharmacology associated with antagonism of either OX1 R or OX2 R alone has been hampered by the dearth of suitable subtype-selective, orally bioavailable ligands.

Age-associated stresses induce an anti-inflammatory senescent phenotype in endothelial cells.

Age is the greatest risk factor for cardiovascular disease. In addition, inflammation and age (senescence) have been linked at both the clinical and molecular levels. In general, senescent cells have been described as pro-inflammatory based on their senescence associated secretory phenotype (SASP).

Cubic topological Kondo insulators.

Current theories of Kondo insulators employ the interaction of conduction electrons with localized Kramers doublets originating from a tetragonal crystalline environment, yet all Kondo insulators are cubic. Here we develop a theory of cubic topological Kondo insulators involving the interaction of Γ(8) spin quartets with a conduction sea. The spin quartets greatly increase the potential for strong topological insulators, entirely eliminating the weak topological phases from the diagram.

Tetrahedral and orbital pairing: a fully gapped pairing scenario for the iron-based superconductors.

Motivated by the fully gapped superconductivity in iron-based superconductors with uncompensated electron pockets, we propose a spin singlet, but orbital triplet analogue of the superfluid phase of ^{3}He-B. We show that orbital triplets with a nominal d-wave symmetry at the iron sites can transform as s-wave pairs under rotations about the selenium sites. Linear combinations of such d(xy) and d(x2-y(2)) triplets form a fully gapped, topological superconductor.

Escherichia coli - Marauding masquerading microbe.

Background: Escherichia coli is a rare cause of monoarticular septic arthritis, but is an even rarer cause of polyarticular septic arthritis.

Case Description: We report an unusual case of polyarticular septic arthritis with an atypical presentation caused by E. coli, the source of which was a left pyelonephritis.

Discovery of 2,5-diarylnicotinamides as selective orexin-2 receptor antagonists (2-SORAs).

The orexin (or hypocretin) system has been identified as a novel target for the treatment of insomnia due to the wealth of biological and genetic data discovered over the past decade. Recently, clinical proof-of-concept was achieved for the treatment of primary insomnia using dual (OX1R/OX2R) orexin receptor antagonists. However, elucidation of the pharmacology associated with selective orexin-2 receptor antagonists (2-SORAs) has been hampered by the lack of orally bioavailable, highly selective small molecule probes.

Measuring the three-photon self-annihilation fraction of positronium in and above thin films: a tool for determining film morphology.

A technique is described for evaluating the fraction of positrons F incident on thin film samples which form ortho-positronium and subsequently decay into three gamma photons. The method involves the measurement of two linked phenomena: the decrease in the number of annihilation events involving the emission of two gamma photons with approximately 511 keV in the germanium detector photopeak, and the increase in the number of decays into three gamma photons with energies in the range 395-505 keV. After the application of a number of systematic corrections to the raw data, these measurements allow the determination of the absolute value of F without the need for calibration on a sample with known F values, thereby avoiding problems with changing samples of different geometries measured under different conditions.

The duration of sleep promoting efficacy by dual orexin receptor antagonists is dependent upon receptor occupancy threshold.

Background: Drugs targeting insomnia ideally promote sleep throughout the night, maintain normal sleep architecture, and are devoid of residual effects associated with morning sedation. These features of an ideal compound are not only dependent upon pharmacokinetics, receptor binding kinetics, potency and pharmacodynamic activity, but also upon a compound's mechanism of action.

Results: Dual orexin receptor antagonists (DORAs) block the arousal-promoting activity of orexin peptides and, as demonstrated in the current work, exhibit an efficacy signal window dependent upon oscillating levels of endogenous orexin neuropeptide.

Architecture, implementation, and testing of a multiple-shell gas injection system for high current implosions on the Z accelerator.

Tests are ongoing to conduct ~20 MA z-pinch implosions on the Z accelerator at Sandia National Laboratory using Ar, Kr, and D2 gas puffs as the imploding loads. The relatively high cost of operations on a machine of this scale imposes stringent requirements on the functionality, reliability, and safety of gas puff hardware. Here we describe the development of a prototype gas puff system including the multiple-shell nozzles, electromagnetic drivers for each nozzle's valve, a UV pre-ionizer, and an inductive isolator to isolate the ~2.

Quantitative electroencephalography within sleep/wake states differentiates GABAA modulators eszopiclone and zolpidem from dual orexin receptor antagonists in rats.

Dual orexin receptor antagonists (DORAs) induce sleep by blocking orexin 1 and orexin 2 receptor-mediated activities responsible for regulating wakefulness. DORAs represent a potential alternative mechanism to the current standard of care that includes the γ-aminobutyric acid (GABA)A receptor-positive allosteric modulators, eszopiclone and zolpidem. This work uses an innovative method to analyze electroencephalogram (EEG) spectral frequencies within sleep/wake states to differentiate the effects of GABAA modulators from DORA-22, an analog of the DORA MK-6096, in Sprague-Dawley rats.

Twenty years of measurement of polycyclic aromatic hydrocarbons (PAHs) in UK ambient air by nationwide air quality networks.

The impact of human activities on the health of the population and of the wider environment has prompted action to monitor the presence of toxic compounds in the atmosphere. Toxic organic micropollutants (TOMPs) are some of the most insidious and persistent of these pollutants. Since 1991 the United Kingdom has operated nationwide air quality networks to assess the presence of TOMPs, including polycyclic aromatic hydrocarbons (PAHs), in ambient air.

Consistent decrease in global DNA methylation and hydroxymethylation in the hippocampus of Alzheimer's disease patients.

Epigenetic dysregulation of gene expression is thought to be critically involved in the pathophysiology of Alzheimer's disease (AD). Recent studies indicate that DNA methylation and DNA hydroxymethylation are 2 important epigenetic mechanisms that regulate gene expression in the aging brain. However, very little is known about the levels of markers of DNA methylation and hydroxymethylation in the brains of patients with AD, the cell-type specificity of putative AD-related alterations in these markers, as well as the link between epigenetic alterations and the gross pathology of AD.

Direct observation of electron capture and reemission by the divacancy via charge transient positron spectroscopy.

Electron capture during forward bias and reemission at zero bias by divacancies in the depletion region of a silicon diode structure at room temperature have been studied for the first time using monoenergetic positrons. The positron response increases essentially linearly with electron current, as a result of increased positron trapping by negatively charged divacancies. The measurements indicate that ≤1% of the divacancies become negatively charged in the steady state at a forward bias of 1 V.

Orexin receptor antagonists differ from standard sleep drugs by promoting sleep at doses that do not disrupt cognition.

Current treatments for insomnia, such as zolpidem (Ambien) and eszopiclone (Lunesta), are γ-aminobutyric acid type A (GABAA)-positive allosteric modulators that carry a number of side effects including the potential to disrupt cognition. In an effort to develop better tolerated medicines, we have identified dual orexin 1 and 2 receptor antagonists (DORAs), which promote sleep in preclinical animal models and humans. We compare the effects of orally administered eszopiclone, zolpidem, and diazepam to the dual orexin receptor antagonist DORA-22 on sleep and the novel object recognition test in rat, and on sleep and two cognition tests (delayed match to sample and serial choice reaction time) in the rhesus monkey.

Pilot study of human recombinant hyaluronidase-enhanced subcutaneous hydration and opioid administration for sickle cell disease acute pain episodes.

The objective of this study was to determine the feasibility of protocol-driven human recombinant hyaluronidase (rHuPH20)-enhanced subcutaneous (SC) hydration and opioid administration in adults presenting to the emergency department (ED) with sickle cell disease acute pain episodes (SCDAPE). Adults with SCDAPE were given 150 U of rHuPH20 and normal saline subcutaneously. Opioids were administered SC every 15 minutes for 4 hours until numerical rating scale (NRS) pain intensity scores fell to <5, or Ramsay Sedation Scores were >4.

The "final" 5-year follow-up from the ENDEAVOR IV trial comparing a zotarolimus-eluting stent with a paclitaxel-eluting stent.

Objectives: This study sought to report the final 5-year outcomes of the ENDEAVOR IV (A Randomized, Controlled Trial of the Medtronic Endeavor Drug [ABT-578] Eluting Coronary Stent System Versus the Taxus Paclitaxel-Eluting Coronary Stent System in De Novo Native Coronary Artery Lesions) trial comparing the Endeavor zotarolimus-eluting stent (E-ZES) (Medtronic, Santa Rosa, California) with the Taxus paclitaxel-eluting stent (PES) (Boston Scientific, Natick, Massachusetts) in patients with single de novo coronary lesions.

Background: Primary results of the ENDEAVOR IV trial demonstrated similar clinical outcomes with E-ZES and PES. Concerns with regard to late adverse clinical events with drug-eluting stents highlight the need for long-term follow-up with these devices.

Scrotal mass and unilateral lung masses with pleural effusion mimicking metastatic testicular malignancy: an unusual presentation of sarcoidosis.

Involvement of the genitourinary tract by sarcoidosis may present with a scrotal mass, mimicking infection or malignancy. Sarcoidosis is a systemic granulomatous disease that affects patients of both sexes worldwide. Sarcoidosis of the genitourinary tract is rare.

Emergent critical phase and Ricci flow in a 2D frustrated Heisenberg model.

We introduce a two-dimensional frustrated Heisenberg antiferromagnet on interpenetrating honeycomb and triangular lattices. Classically the two sublattices decouple, and "order from disorder" drives them into a coplanar state. Applying Friedan's geometric approach to nonlinear sigma models, we obtain the scaling of the spin stiffnesses governed by the Ricci flow of a four-dimensional metric tensor.

Hastatic order in the heavy-fermion compound URu2Si2.

The development of collective long-range order by means of phase transitions occurs by the spontaneous breaking of fundamental symmetries. Magnetism is a consequence of broken time-reversal symmetry, whereas superfluidity results from broken gauge invariance. The broken symmetry that develops below 17.

Reduced RAN expression and disrupted transport between cytoplasm and nucleus; a key event in Alzheimer's disease pathophysiology.

Transcription of DNA is essential for cell maintenance and survival; inappropriate localization of proteins that are involved in transcription would be catastrophic. In Alzheimer's disease brains, and in vitro studies, we have found qualitative and quantitative deficits in transport into the nucleus of DNA methyltransferase 1 (DNMT1) and RNA polymerase II (RNA pol II), accompanied by their abnormal sequestration in the cytoplasm. RAN (RAs-related Nuclear protein) knockdown, by siRNA and oligomeric Aβ42 treatment in neurons, replicate human data which indicate that transport disruption in AD may be mechanistically linked to reduced expression of RAN, a pivotal molecule in nucleocytoplasmic transport.

Differential processing of amyloid precursor protein in brain and in peripheral blood leukocytes.

Because amyloid precursor protein (APP) fragments exist in many tissues throughout the body, including the fluid compartments of blood, they have been the focus of numerous investigations into their potential as a biomarker of Alzheimer's disease. Using immunohistochemistry, immunoelectron microscopy, Western blot, and quantitative real-time-polymerase chain reaction (qRT-PCR) analysis we examined whether APP processing in leukocytes is analogous to APP processing in the brain. We show APP immunoreactivity at light and electron microscopic levels in the cytoplasm and nucleus of peripheral blood leukocytes (PBL) yet our Western blot analysis data demonstrated that brain and PBL contain different APP fragments and differentially expressed APP processing enzymes.

Synaptic genes are extensively downregulated across multiple brain regions in normal human aging and Alzheimer's disease.

Synapses are essential for transmitting, processing, and storing information, all of which decline in aging and Alzheimer's disease (AD). Because synapse loss only partially accounts for the cognitive declines seen in aging and AD, we hypothesized that existing synapses might undergo molecular changes that reduce their functional capacity. Microarrays were used to evaluate expression profiles of 340 synaptic genes in aging (20-99 years) and AD across 4 brain regions from 81 cases.

β-YbAlB4: a critical nodal metal.

We propose a model for the intrinsic quantum criticality of β-YbAlB(4), in which a vortex in momentum space gives rise to a new type of Fermi surface singularity. The unquenched angular momentum of the |J=7/2,m(J)=±5/2> Yb 4f states generates a momentum-space line defect in the hybridization between 4f and conduction electrons, leading to a quasi-two-dimensional Fermi surface with a k(⊥)(4) dispersion and a singular density of states proportional to E(-1/2). We discuss the implications of this line node in momentum space for our current understanding of quantum criticality and its interplay with topology.