Incretins play an important role in FFA4/GPR120 regulation of glucose metabolism by GW-9508

Aims: To assess the role of GPR120 in glucose metabolism and incretin regulation from enteroendocrine L- and K-cells with determination of the cellular localisation of GPR120 in intestinal tissue and clonal Glucagon-Like Peptide-1 (GLP-1)/Gastric Inhibitory Polypeptide (GIP) cell lines. Main methods: Anti-hyperglycaemic, insulinotropic and incretin secreting properties of the GPR120 agonist, GW-9508 were explored in combination with oral and intraperitoneal glucose tolerance tests (GTT) in lean, diabetic and incretin receptor knockout mice. Cellular localisation of GPR120 was assessed by double immunofluorescence. Key findings: Compared to intraperitoneal injection, oral administration of GW-9508 (0.1 μmol/kg body weight) together with glucose reduced the glycaemic excursion by 22–31 % (p &lt; 0.05-p &lt; 0.01) and enhanced glucose-induced insulin release by 30 % (p &lt; 0.01) in normal mice. In high fat fed diabetic mice, orally administered GW-9508 lowered plasma glucose by 17–27 % (p &lt; 0.05-p &lt; 0.01) and augmented insulin release by 22–39 % (p &lt; 0.05-p &lt; 0.001). GW-9508 had no effect on the responses of GLP-1 receptor knockout mice and GIP receptor knockout mice. Consistent with this, oral GW-9508 increased circulating total GLP-1 release by 39–44 % (p &lt; 0.01) and total GIP by 37–47 % (p &lt; 0.01-p &lt; 0.001) after 15 and 30 min in lean NIH Swiss mice. Immunocytochemistry demonstrated GPR120 expression on mouse enteroendocrine L- and K-cells, GLUTag cells and pGIP/Neo STC-1 cells. Significance: GPR120 is expressed on intestinal L- and K-cells and stimulates GLP-1/GIP secretory pathways involved in mediating enhanced insulin secretion and improved glucose tolerance, following oral GW-9508. These novel data strongly support the development of potent and selective GPR120 agonists as an effective therapeutic approach for diabetes.</p

Nonlinear optical signatures of ultraviolet light-induced ring opening in α -terpinene

Photoinduced electrocyclic ring opening reactions in conjugated cylcoalkenes are among the most elementary processes in organic chemistry. One prototypical ring opening reaction transforms cyclohexadiene into hexatriene. It is known that a sequence of sub-100 fs internal conversion transitions precedes bond breaking in cyclohexadiene and some of its derivatives. However, these excited state dynamics have never been directly monitored in solution because of insufficient time resolution. Here we aim to uncover the extraordinary photophysics behind related ultrafast internal conversion processes in a derivative of cyclohexadiene, α-terpinene (α-TP), solvated in cyclohexane. Transient absorption anisotropy experiments conducted with 20 fs laser pulses at 267 nm expose non-exponential depopulation kinetics for the ππ* electronic state of α-TP. Our data show that population transfer rapidly accelerates within the first 100 fs after photoexcitation. In addition, recurrences in two-dimensional photon echo (2DPE) line shapes reveal strong vibronic coupling in a normal mode near 523 cm−1, which involves torsions of the C=C bonds and hydrogen out-of-plane (HOOP) wagging on a vinyl group. With the support of several experiments, we hypothesize that the excited state wavepacket in α-TP undergoes several recurrences in the C=C stretching coordinate before displacement along the C=C torsion/vinyl HOOP coordinate finally sets it free from the Franck–Condon region of the potential energy surface. The unconfined wavepacket departs the ππ* electronic state by way of a conical intersection with a lower energy excited state. The present observations are made possible by recent improvements to both the time resolution and detection sensitivity of our experimental setup. This work demonstrates that it is now possible to acquire 2DPE signals in the deep ultraviolet, which are comparable with high-quality measurements in the visible spectral region. These technical developments open the door to studies of many beautiful models for elementary chemical dynamics

Polygenic overlap between schizophrenia risk and antipsychotic response: a genomic medicine approach

Therapeutic treatments for schizophrenia do not alleviate symptoms for all patients and efficacy is limited by common, often severe, side-effects. Genetic studies of disease can identify novel drug targets, and drugs for which the mechanism has direct genetic support have increased likelihood of clinical success. Large-scale genetic studies of schizophrenia have increased the number of genes and gene sets associated with risk. We aimed to examine the overlap between schizophrenia risk loci and gene targets of a comprehensive set of medications to potentially inform and improve treatment of schizophrenia

B 12 -Mediated, Long Wavelength Photopolymerization of Hydrogels

Medical hydrogel applications have expanded rapidly over the past decade. Implantation in patients by non-invasive injection is preferred, but this requires hydrogel solidification from a low viscosity solution to occur in vivo via an applied stimuli. Transdermal photo-crosslinking of acrylated biopolymers with photoinitiators and lights offers a mild, spatiotemporally controlled solidification trigger. However, the current short wavelength initiators limit curing depth and efficacy because they do not absorb within the optical window of tissue (600 - 900 nm). As a solution to the current wavelength limitations, we report the development of a red light responsive initiator capable of polymerizing a range of acrylated monomers. Photo-activation occurs within a range of skin type models containing high biochromophore concentrations

Vancomycin Cerebrospinal Fluid Pharmacokinetics in Children with Cerebral Ventricular Shunt Infections

This study described the cerebrospinal fluid (CSF) exposure of vancomycin in 8 children prescribed intravenous vancomycin therapy for cerebral ventricular shunt infection. Vancomycin CSF concentrations ranged from 0.06 to 9.13 mg/L and the CSF: plasma ratio ranged from 0 to 0.66. Two children out of three with a staphylococcal CSF infection had CSF concentrations > minimal inhibitory concentration at the end of the dosing interval

Australia Day, flags on cars and Australian nationalism

This article reports the results of research into the recent popular phenomenon of flying Australian flags on one’s car for Australia Day. A survey was undertaken in Western Australia in 2011 to ascertain who flies the flag and why. Results indicate the phenomenon was widespread, with a quarter of those surveyed displaying car-flags. A clear relationship between car-flag-flying and exclusionary nationalism is demonstrated. Car-flag-flyers rate more highly on measures of patriotism and nationalism, and feel more negative towards Muslims and asylum seekers, and more positive about the White Australia Policy. They are also significantly more likely to feel their culture and values are in danger, and have a nativist vision of Australian identity. While both groups are positive about Australia’s diversity, car-flag-flyers are more likely to feel that migrants should assimilate. The results support other literature that suggests that in some contexts the Australian flag has come to be associated with exclusionary nationalism

Institutional Transplant as Political Opportunity: The Practice and Politics of Indian Electricity Regulation

India has a decade-long experience with independent regulatory agencies in public services as an institutional transplant from the industrialized world. Introduced at the behest of international donor agencies, regulators in India are intended, somewhat naively, to provide an apolitical space for decision making to assuage investor concerns over arbitrary administrative actions, and thereby stimulate private investment. In practice, regulators have had to negotiate a terrain over which the state has continued to exercise considerable control. Regulators have also been been shaped in their functioning by national and sub-national political traditions and by administrative and political practices. The result is a hybrid institutional form that combines politics as usual with intriguing new, and unanticipated, opportunities for political intervention. This paper will explore the origins of electricity regulation as a form of institutional isomorphism. It will then compare the regulatory experience in India\u27s electricity sector across two Indian states to understand the implications of transplanting regulatory agencies in the global south. An examination of the process through which regulatory decisions are reached illustrates how existing bureaucratic and technocratic networks, transplanted procedures, and administrative cultures combine to conservatively manage long-standing political tensions around electricity. In seeking to manage those tensions, regulators often take decisions - on tariff setting, for example - based on a political reading that belies the technocratic narrative on which institutional credibility rests. At the same time, civil society groups ranging from residential associations to professional associations to individuals are using newly created regulatory spaces to structure a more deliberative decision process

Observing Strategy for the SDSS-IV/MaNGA IFU Galaxy Survey

Mapping Nearby Galaxies at Apache Point Observatory (MaNGA) is an integral-field spectroscopic survey that is one of three core programs in the fourth-generation Sloan Digital Sky Survey (SDSS-IV). MaNGA's 17 pluggable optical fiber-bundle integral field units (IFUs) will observe a sample of 10,000 nearby galaxies distributed throughout the SDSS imaging footprint (focusing particularly on the North Galactic Cap). In each pointing these IFUs are deployed across a 3° field; they yield spectral coverage 3600−10300 Å at a typical resolution R ~ 2000, and sample the sky with 2'' diameter fiber apertures with a total bundle fill factor of 56%. Observing over such a large field and range of wavelengths is particularly challenging for obtaining uniform and integral spatial coverage and resolution at all wavelengths and across each entire fiber array. Data quality is affected by the IFU construction technique, chromatic and field differential refraction, the adopted dithering strategy, and many other effects. We use numerical simulations to constrain the hardware design and observing strategy for the survey with the aim of ensuring consistent data quality that meets the survey science requirements while permitting maximum observational flexibility. We find that MaNGA science goals are best achieved with IFUs composed of a regular hexagonal grid of optical fibers with rms displacement of 5 μm or less from their nominal packing position; this goal is met by the MaNGA hardware, which achieves 3 μm rms fiber placement. We further show that MaNGA observations are best obtained in sets of three 15 minute exposures dithered along the vertices of a 1.44 arcsec equilateral triangle; these sets form the minimum observational unit, and are repeated as needed to achieve a combined signal-to-noise ratio of 5 Å-1 per fiber in the r-band continuum at a surface brightness of 23 AB arcsec-2. In order to ensure uniform coverage and delivered image quality, we require that the exposures in a given set be obtained within a 60 minute interval of each other in hour angle, and that all exposures be obtained at airmass ≲ 1.2 (i.e., within 1–3 hr of transit depending on the declination of a given field)

The relationship between moral judgment and cooperation in children with high-functioning autism.

This study investigated moral judgment in children with high-functioning autism and their cooperation in prisoner's dilemma game with partners of different moralities. Thirty-eight 6- to 12-year-old high-functioning autistic (HFA) children and 31 typically developing (TD) children were recruited. Children were asked to judge story protagonists' morality. After making this moral judgment correctly, they were asked to play with the morally nice and the morally naughty child in a repeated prisoner's dilemma game. Results showed that both HFA and TD children made correct moral judgments, and that HFA children might even have more rigid criteria for what constitutes morally naughty acts. HFA children's cooperation did not differ depending on the morality of the interaction partner, while TD children showed higher cooperation when interacting with the morally nice than the morally naughty child did. Thus, partner's morality did influence TD children's but not HFA children's subsequent cooperation