The Plasma Environment of Comet 67P/Churyumov-Gerasimenko.

The environment of a comet is a fascinating and unique laboratory to study plasma processes and the formation of structures such as shocks and discontinuities from electron scales to ion scales and above. The European Space Agency's Rosetta mission collected data for more than two years, from the rendezvous with comet 67P/Churyumov-Gerasimenko in August 2014 until the final touch-down of the spacecraft end of September 2016. This escort phase spanned a large arc of the comet's orbit around the Sun, including its perihelion and corresponding to heliocentric distances between 3.

A 28-Day Toxicity Study of Tenofovir Alafenamide Hemifumarate by Subcutaneous Infusion in Rats and Dogs.

The toxicity of tenofovir alafenamide (TAF) hemifumarate (HF) was evaluated when administered by continuous subcutaneous (s.c.) infusion via an external infusion pump for 28 days to rats and dogs.

Tenofovir Alafenamide for HIV Prevention: Review of the Proceedings from the Gates Foundation Long-Acting TAF Product Development Meeting.

The ability to successfully develop a safe and effective vaccine for the prevention of HIV infection has proven challenging. Consequently, alternative approaches to HIV infection prevention have been pursued, and there have been a number of successes with differing levels of efficacy. At present, only two oral preexposure prophylaxis (PrEP) products are available, Truvada and Descovy.

Development and Regulatory Challenges for Peptide Therapeutics.

There has been an increased interest in and activity for the use of peptide therapeutics to treat a variety of human diseases. The number of peptide drugs entering clinical development and the market has increased significantly over the past decade despite inherent challenges of peptide therapeutic discovery, development, and patient-friendly delivery. Disparities in interpretation and application of existing regulatory guidances to innovative synthetic and conjugated peptide assets have resulted in challenges for both regulators and sponsors.

Insights into the Chemical Discovery of Remifentanil.

Design, Synthesis, and Pharmacological Evaluation of Ultrashort- to Long-acting Opioid Analgetics. By Feldman PL, James MK, Brackeen MF, Bilotta JM, Schuster SV, Lahey AP, Lutz MW, Johnson MR, Leighton HJ. J Med Chem 1991; 34:2202-8.

Quality guidelines for oral drug candidates: dose, solubility and lipophilicity.

In an attempt to seek increased understanding of compound attributes that influence successful drug pipeline progression, GlaxoSmithKline's portfolio of oral candidates was compared with reference sets of marketed oral drugs. The approach differs from other attrition studies by explicitly focusing on choosing 'the right compound' by applying relevant, experimentally derived properties. The analysis led to four proposed compound quality categories, created by combining specific criteria for three measures: dose, solubility and the property forecast index, a composite measure of lipophilicity using chromatographically determined LogD and aromaticity.

Clinicopathological features of acute kidney injury associated with immune checkpoint inhibitors.

Immune checkpoint inhibitors (CPIs), monoclonal antibodies that target inhibitory receptors expressed on T cells, represent an emerging class of immunotherapy used in treating solid organ and hematologic malignancies. We describe the clinical and histologic features of 13 patients with CPI-induced acute kidney injury (AKI) who underwent kidney biopsy. Median time from initiation of a CPI to AKI was 91 (range, 21 to 245) days.

Orbital apocenter is not a sufficient condition for HST/STIS detection of Europa's water vapor aurora.

We report far-ultraviolet observations of Jupiter's moon Europa taken by Space Telescope Imaging Spectrograph (STIS) of the Hubble Space Telescope (HST) in January and February 2014 to test the hypothesis that the discovery of a water vapor aurora in December 2012 by local hydrogen (H) and oxygen (O) emissions with the STIS originated from plume activity possibly correlated with Europa's distance from Jupiter through tidal stress variations. The 2014 observations were scheduled with Europa near the apocenter similar to the orbital position of its previous detection. Tensile stresses on south polar fractures are expected to be highest in this orbital phase, potentially maximizing the probability for plume activity.

Gut hormone pharmacology of a novel GPR119 agonist (GSK1292263), metformin, and sitagliptin in type 2 diabetes mellitus: results from two randomized studies.

Unlabelled: GPR119 receptor agonists improve glucose metabolism and alter gut hormone profiles in animal models and healthy subjects. We therefore investigated the pharmacology of GSK1292263 (GSK263), a selective GPR119 agonist, in two randomized, placebo-controlled studies that enrolled subjects with type 2 diabetes. Study 1 had drug-naive subjects or subjects who had stopped their diabetic medications, and Study 2 had subjects taking metformin.

Transient water vapor at Europa's south pole.

In November and December 2012, the Hubble Space Telescope (HST) imaged Europa's ultraviolet emissions in the search for vapor plume activity. We report statistically significant coincident surpluses of hydrogen Lyman-α and oxygen OI 130.4-nanometer emissions above the southern hemisphere in December 2012.

Discovery of a highly potent, nonabsorbable apical sodium-dependent bile acid transporter inhibitor (GSK2330672) for treatment of type 2 diabetes.

The apical sodium-dependent bile acid transporter (ASBT) transports bile salts from the lumen of the gastrointestinal (GI) tract to the liver via the portal vein. Multiple pharmaceutical companies have exploited the physiological link between ASBT and hepatic cholesterol metabolism, which led to the clinical investigation of ASBT inhibitors as lipid-lowering agents. While modest lipid effects were demonstrated, the potential utility of ASBT inhibitors for treatment of type 2 diabetes has been relatively unexplored.

LRO-LAMP observations of the LCROSS impact plume.

On 9 October 2009, the Lunar Crater Observation and Sensing Satellite (LCROSS) sent a kinetic impactor to strike Cabeus crater, on a mission to search for water ice and other volatiles expected to be trapped in lunar polar soils. The Lyman Alpha Mapping Project (LAMP) ultraviolet spectrograph onboard the Lunar Reconnaissance Orbiter (LRO) observed the plume generated by the LCROSS impact as far-ultraviolet emissions from the fluorescence of sunlight by molecular hydrogen and carbon monoxide, plus resonantly scattered sunlight from atomic mercury, with contributions from calcium and magnesium. The observed light curve is well simulated by the expansion of a vapor cloud at a temperature of ~1000 kelvin, containing ~570 kilograms (kg) of carbon monoxide, ~140 kg of molecular hydrogen, ~160 kg of calcium, ~120 kg of mercury, and ~40 kg of magnesium.

Crohn's disease complicated by primary gastrointestinal Hodgkin's lymphoma presenting with small bowel perforation.

An increased incidence of non-Hodgkin's lymphoma has been reported in patients with inflammatory bowel disease, particularly in those receiving immunosuppressive therapy. Rare cases of Hodgkin;s lymphoma have been reported in a setting of inflammatory bowel disease. The mechanism underlying the apparent association is unclear, but alterations in immune surveillance could play a role.

Medical management of Crohn's disease.

The clinical course of Crohn's disease (CD) is characterized by unpredictable phases of disease activity and quiescence. The majority of CD patients experience mild to moderate disease or are in clinical remission over significant periods during the course of their disease. These patients can be treated conservatively with 5-aminosalicylates or budesonide depending on the disease location.

CNS 7056: a novel ultra-short-acting Benzodiazepine.

Background: A new benzodiazepine derivative, CNS 7056, has been developed to permit a superior sedative profile to current agents, i.e., more predictable fast onset, short duration of sedative action, and rapid recovery profile.

6-(4-chlorophenyl)-3-substituted-thieno[3,2-d]pyrimidin-4(3H)-one-based melanin-concentrating hormone receptor 1 antagonist.

Genetic manipulation studies in mice at both the MCH receptor 1 (MCHR1) as well as the MCH peptide levels have implicated MCHR1 as a key player in energy homeostasis. The phenotype exhibited by these studies, that is, increased metabolic rate, resistance to high fat diet, and subsequent weight loss, has spurred considerable efforts to develop antagonists of MCHR1. In continuation of efforts directed toward this goal, the present work capitalizes on the putative binding mode of an MCH antagonist, resulting in the identification of several novel chemotypes that are potent and selective MCHR1 antagonists.

Potent, selective, and orally efficacious antagonists of melanin-concentrating hormone receptor 1.

The high expression of MCH in the hypothalamus with the lean hypophagic phenotype coupled with increased resting metabolic rate and resistance to high fat diet-induced obesity of MCH KO mice has spurred considerable efforts to develop small molecule MCHR1 antagonists. Starting from a lead thienopyrimidinone series, structure-activity studies at the 3- and 6-positions of the thienopyrimidinone core afforded potent and selective MCHR1 antagonists with representative examples having suitable pharmacokinetic properties. Based on structure-activity relationships, a structural model for MCHR1 was constructed to explain the binding mode of these antagonists.

Povidone-iodine sclerotherapy is ineffective in the treatment of symptomatic renal cysts.

Purpose: To evaluate the efficacy of povidone-iodine sclerotherapy after percutaneous drainage of simple renal cysts in the treatment of symptomatic patients.

Patients And Methods: Sixteen patients with symptomatic renal cysts were treated by percutaneous drainage and injection of povidone-iodine solution. The cysts were drained by a nephrostomy tube catheter, and povidone- iodine injections were repeated every 24 hours for 3 days.

Stabilization of the disk around beta Pictoris by extremely carbon-rich gas.

The edge-on disk surrounding the nearby young star beta Pictoris is the archetype of 'debris disks', which are composed of dust and gas produced by collisions between--and evaporation of--planetesimals, analogues of Solar System comets and asteroids. These disks may provide insight into the formation and early evolution of terrestrial planets. Previous work on beta Pic concluded that the disk gas has roughly solar abundances of elements, but this poses a problem because such gas should rapidly be blown away from the star, contrary to observations showing a stable gas disk in keplerian rotation.

Candida albicans colonization of dental plaque in elderly dysphagic patients.

Background: Dysphagia is a common disorder among the elderly population. As many as 50% of nursing home residents suffer from dysphagia. It is important to identify patients at increased risk for colonization of dental and denture plaque by pathogenic organisms in order to prevent associated disease.

Preclinical pharmacology of GW280430A (AV430A) in the rhesus monkey and in the cat: a comparison with mivacurium.

Background: No replacement for succinylcholine is yet available. GW280430A (AV430A) is a representative of a new class of nondepolarizing neuromuscular blocking drugs called asymmetric mixed-onium chlorofumarates. It undergoes rapid degradation in plasma by chemical hydrolysis and inactivation by cysteine adduction, resulting in a very short duration of effect.

A large population of 'Lyman-break' galaxies in a protocluster at redshift z approximately 4.1.

The most massive galaxies and the richest clusters are believed to have emerged from regions with the largest enhancements of mass density relative to the surrounding space. Distant radio galaxies may pinpoint the locations of the ancestors of rich clusters, because they are massive systems associated with 'overdensities' of galaxies that are bright in the Lyman-alpha line of hydrogen. A powerful technique for detecting high-redshift galaxies is to search for the characteristic 'Lyman break' feature in the galaxy colour, at wavelengths just shortwards of Lyalpha, which is due to absorption of radiation from the galaxy by the intervening intergalactic medium.