Short photoperiod-induced decrease of histamine H3 receptors facilitates activation of hypothalamic neurons in the Siberian Hamster

Nonhibernating seasonal mammals have adapted to temporal changes in food availability through behavioral and physiological mechanisms to store food and energy during times of predictable plenty and conserve energy during predicted shortage. Little is known, however, of the hypothalamic neuronal events that lead to a change in behavior or physiology. Here we show for the first time that a shift from long summer-like to short inter-like photoperiod, which induces physiological adaptation to winter in the Siberian hamster, including a body weight decrease of up to 30%, increases neuronal activity in the dorsomedial region of the arcuate nucleus (dmpARC) assessed by electro physiological patch-clamping recording. Increased neuronal activity in short days is dependent on a photoperiod-driven down-regulation of H3 receptor expression and can be mimicked in long-day dmpARC neurons by the application of the H3 receptor antagonist, clobenproprit. Short-day activation of dmpARC neurons results in increased c-Fos expression. Tract tracing with the trans-synaptic retrograde tracer, pseudorabies virus, delivered into adipose tissue reveals a multisynaptic neuronal sympathetic outflow from dmpARC to white adipose tissue. These data strongly suggest that increased activity of dmpARC neurons, as a consequence of down-regulation of the histamine H3 receptor, contributes to the physiological adaptation of body weight regulation in seasonal photoperiod

Effects of D-amino acid oxidase inhibition on memory performance and long-term potentiation in vivo

N-methyl-d-aspartate receptor (NMDAR) activation can initiate changes in synaptic strength, evident as long-term potentiation (LTP), and is a key molecular correlate of memory formation. Inhibition of d-amino acid oxidase (DAAO) may increase NMDAR activity by regulating d-serine concentrations, but which neuronal and behavioral effects are influenced by DAAO inhibition remain elusive. In anesthetized rats, extracellular field excitatory postsynaptic potentials (fEPSPs) were recorded before and after a theta frequency burst stimulation (TBS) of the Schaffer collateral pathway of the CA1 region in the hippocampus. Memory performance was assessed after training with tests of contextual fear conditioning (FC, mice) and novel object recognition (NOR, rats). Oral administration of 3, 10, and 30 mg/kg 4H-furo[3,2-b]pyrrole-5-carboxylic acid (SUN) produced dose-related and steady increases of cerebellum d-serine in rats and mice, indicative of lasting inhibition of central DAAO. SUN administered 2 h prior to training improved contextual fear conditioning in mice and novel object recognition memory in rats when tested 24 h after training. In anesthetized rats, LTP was established proportional to the number of TBS trains. d-cycloserine (DCS) was used to identify a submaximal level of LTP (5× TBS) that responded to NMDA receptor activation; SUN administered at 10 mg/kg 3–4 h prior to testing similarly increased in vivo LTP levels compared to vehicle control animals. Interestingly, in vivo administration of DCS also increased brain d-serine concentrations. These results indicate that DAAO inhibition increased NMDAR-related synaptic plasticity during phases of post training memory consolidation to improve memory performance in hippocampal-dependent behavioral tests

Activity of the DNA minor groove cross-linking agent SG2000 (SJG-136) against canine tumours

BACKGROUND: Cancer is the leading cause of death in older dogs and its prevalence is increasing. There is clearly a need to develop more effective anti-cancer drugs in dogs. SG2000 (SJG-136) is a sequence selective DNA minor groove cross-linking agent. Based on its in vitro potency, the spectrum of in vivo and clinical activity against human tumours, and its tolerability in human patients, SG2000 has potential as a novel therapeutic against spontaneously occurring canine malignancies. RESULTS: In vitro cytotoxicity was assessed using SRB and MTT assays, and in vivo activity was assessed using canine tumour xenografts. DNA interstrand cross-linking (ICL) was determined using a modification of the single cell gel electrophoresis (comet) assay. Effects on cell cycle distribution were assessed by flow cytometry and measurement of γ-H2AX by immunofluorescence and immunohistochemistry. SG2000 had a multi-log differential cytotoxic profile against a panel of 12 canine tumour cell lines representing a range of common tumour types in dogs. In the CMeC-1 melanoma cell line, DNA ICLs increased linearly with dose following a 1 h treatment. Peak ICL was achieved within 1 h and no removal was observed over 48 h. A relationship between DNA ICL formation and cytotoxicity was observed across cell lines. The formation of γ-H2AX foci was slow, becoming evident after 4 h and reaching a peak at 24 h. SG2000 exhibited significant anti-tumour activity against two canine melanoma tumour models in vivo. Anti-tumour activity was observed at 0.15 and 0.3 mg/kg given i.v. either once, or weekly x 3. Dose-dependent DNA ICL was observed in tumours (and to a lower level in peripheral blood mononuclear cells) at 2 h and persisted at 24 h. ICL increased following the second and third doses in a repeated dose schedule. At 24 h, dose dependent γ-H2AX foci were more numerous than at 2 h, and greater in tumours than in peripheral blood mononuclear cells. SG2000-induced H2AX phosphorylation measured by immunohistochemistry showed good correspondence, but less sensitivity, than measurement of foci. CONCLUSIONS: SG2000 displayed potent activity in vitro against canine cancer cell lines as a result of the formation and persistence of DNA ICLs. SG2000 also had significant in vivo antitumour activity against canine melanoma xenografts, and the comet and γ-H2AX foci methods were relevant pharmacodynamic assays. The clinical testing of SG2000 against spontaneous canine cancer is warranted. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12917-015-0534-2) contains supplementary material, which is available to authorized users

GPS phase scintillation and proxy index at high latitudes during a moderate geomagnetic storm

The amplitude and phase scintillation indices are customarily obtained by specialised GPS Ionospheric Scintillation and TEC Monitors (GISTMs) from L1 signal recorded at the rate of 50 Hz. The scintillation indices S[subscript 4] and σ[subscript Φ] are stored in real time from an array of high-rate scintillation receivers of the Canadian High Arctic Ionospheric Network (CHAIN). Ionospheric phase scintillation was observed at high latitudes during a moderate geomagnetic storm (Dst = −61 nT) that was caused by a moderate solar wind plasma stream compounded with the impact of two coronal mass ejections. The most intense phase scintillation (σ[subscript Φ] ~ 1 rad) occurred in the cusp and the polar cap where it was co-located with a strong ionospheric convection, an extended tongue of ionisation and dense polar cap patches that were observed with ionosondes and HF radars. At sub-auroral latitudes, a sub-auroral polarisation stream that was observed by mid-latitude radars was associated with weak scintillation (defined arbitrarily as σ[subscript Φ] 0.1 rad and DPR > 2 mm s[superscript −1], both mapped as a function of magnetic latitude and magnetic local time, are very similar.National Science Foundation (U.S.) (Grant ATM-0856093

SMILE: A joint ESA/CAS mission to investigate the interaction between the solar wind and Earth's magnetosphere

The Solar wind Magnetosphere Ionosphere Link Explorer (SMILE) is a collaborative science mission between ESA and the Chinese Academy of Sciences (CAS). SMILE is a novel self-standing mission to observe the coupling of the solar wind and Earth's magnetosphere via X-Ray imaging of the solar wind -- magnetosphere interaction zones, UV imaging of global auroral distributions and simultaneous in-situ solar wind, magnetosheath plasma and magnetic field measurements. The SMILE mission proposal was submitted by a consortium of European, Chinese and Canadian scientists following a joint call for mission by ESA and CAS. It was formally selected by ESA's Science Programme Committee (SPC) as an element of the ESA Science Program in November 2015, with the goal of a launch at the end of 2021. In order to achieve its scientific objectives, the SMILE payload will comprise four instruments: the Soft X-ray Imager (SXI), which will spectrally map the Earth's magnetopause, magnetosheath and magnetospheric cusps; the UltraViolet Imager (UVI), dedicated to imaging the auroral regions; the Light Ion Analyser (LIA) and the MAGnetometer (MAG), which will establish the solar wind properties simultaneously with the imaging instruments. We report on the status of the mission and payload developments and the findings of a design study carried out in parallel at the concurrent design facilities (CDF) of ESA and CAS in October/November 2015. © (2016) COPYRIGHT Society of Photo-Optical Instrumentation Engineers (SPIE). Downloading of the abstract is permitted for personal use only

Interhemispheric comparison of GPS phase scintillation at high latitudes during the magnetic-cloud-induced geomagnetic storm of 5–7 April 2010

Arrays of GPS Ionospheric Scintillation and TEC Monitors (GISTMs) are used in a comparative scintillation study focusing on quasi-conjugate pairs of GPS receivers in the Arctic and Antarctic. Intense GPS phase scintillation and rapid variations in ionospheric total electron content (TEC) that can result in cycle slips were observed at high latitudes with dual-frequency GPS receivers during the first significant geomagnetic storm of solar cycle 24 on 5–7 April 2010. The impact of a bipolar magnetic cloud of north-south (NS) type embedded in high speed solar wind from a coronal hole caused a geomagnetic storm with maximum 3-hourly Kp = 8- and hourly ring current Dst =−73 nT. The interhemispheric comparison of phase scintillation reveals similarities but also asymmetries of the ionospheric response in the northern and southern auroral zones, cusps and polar caps. In the nightside auroral oval and in the cusp/cleft sectors the phase scintillation was observed in both hemispheres at about the same times and was correlated with geomagnetic activity. The scintillation level was very similar in approximately conjugate locations in Qiqiktarjuaq (75.4° N; 23.4° E CGM lat. and lon.) and South Pole (74.1° S; 18.9° E), in Longyearbyen (75.3° N; 111.2° E) and Zhongshan (74.7° S; 96.7° E), while it was significantly higher in Cambridge Bay (77.0° N; 310.1° E) than at Mario Zucchelli (80.0° S; 307.7° E). In the polar cap, when the interplanetary magnetic field (IMF) was strongly northward, the ionization due to energetic particle precipitation was a likely cause of scintillation that was stronger at Concordia (88.8° S; 54.4° E) in the dark ionosphere than in the sunlit ionosphere over Eureka (88.1° N; 333.4° E), due to a difference in ionospheric conductivity. When the IMF tilted southward, weak or no significant scintillation was detected in the northern polar cap, while in the southern polar cap rapidly varying TEC and strong phase scintillation persisted for many hours. This interhemispheric asymmetry is explained by the difference in the location of solar terminator relative to the cusps in the Northern and Southern Hemisphere. Solar terminator was in the immediate proximity of the cusp in the Southern Hemisphere where sunlit ionospheric plasma was readily convected into the central polar cap and a long series of patches was observed. In contrast, solar terminator was far poleward of the northern cusp thus reducing the entry of sunlit plasma and formation of dense patches. This is consistent with the observed and modeled seasonal variation in occurrence of polar cap patches. The GPS scintillation and TEC data analysis is supported by data from ground-based networks of magnetometers, riometers, ionosondes, HF radars and all-sky imagers, as well as particle flux measurements by DMSP satellites

PANTHER: AZD8931, inhibitor of EGFR, ERBB2 and ERBB3 signalling, combined with FOLFIRI: a Phase I/II study to determine the importance of schedule and activity in colorectal cancer

BACKGROUND: Epidermal growth factor receptor (EGFR) is a therapeutic target to which HER2/HER3 activation may contribute resistance. This Phase I/II study examined the toxicity and efficacy of high-dose pulsed AZD8931, an EGFR/HER2/HER3 inhibitor, combined with chemotherapy, in metastatic colorectal cancer (CRC). METHODS: Treatment-naive patients received 4-day pulses of AZD8931 with irinotecan/5-FU (FOLFIRI) in a Phase I/II single-arm trial. Primary endpoint for Phase I was dose limiting toxicity (DLT); for Phase II best overall response. Samples were analysed for pharmacokinetics, EGFR dimers in circulating exosomes and Comet assay quantitating DNA damage. RESULTS: Eighteen patients received FOLFIRI and AZD8931. At 160 mg bd, 1 patient experienced G3 DLT; 160 mg bd was used for cohort expansion. No grade 5 adverse events (AE) reported. Seven (39%) and 1 (6%) patients experienced grade 3 and grade 4 AEs, respectively. Of 12 patients receiving 160 mg bd, best overall response rate was 25%, median PFS and OS were 8.7 and 21.2 months, respectively. A reduction in circulating HER2/3 dimer in the two responding patients after 12 weeks treatment was observed. CONCLUSIONS: The combination of pulsed high-dose AZD8931 with FOLFIRI has acceptable toxicity. Further studies of TKI sequencing may establish a role for pulsed use of such agents rather than continuous exposure. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov number: NCT01862003