Drosophila tan Encodes a Novel Hydrolase Required in Pigmentation and Vision

Many proteins are used repeatedly in development, but usually the function of the protein is similar in the different contexts. Here we report that the classical Drosophila melanogaster locus tan encodes a novel enzyme required for two very different cellular functions: hydrolysis of N-β-alanyl dopamine (NBAD) to dopamine during cuticular melanization, and hydrolysis of carcinine to histamine in the metabolism of photoreceptor neurotransmitter. We characterized two tan-like P-element insertions that failed to complement classical tan mutations. Both are inserted in the 5′ untranslated region of the previously uncharacterized gene CG12120, a putative homolog of fungal isopenicillin-N N-acyltransferase (EC 2.3.1.164). Both P insertions showed abnormally low transcription of the CG12120 mRNA. Ectopic CG12120 expression rescued tan mutant pigmentation phenotypes and caused the production of striking black melanin patterns. Electroretinogram and head histamine assays indicated that CG12120 is required for hydrolysis of carcinine to histamine, which is required for histaminergic neurotransmission. Recombinant CG12120 protein efficiently hydrolyzed both NBAD to dopamine and carcinine to histamine. We conclude that D. melanogaster CG12120 corresponds to tan. This is, to our knowledge, the first molecular genetic characterization of NBAD hydrolase and carcinine hydrolase activity in any organism and is central to the understanding of pigmentation and photoreceptor function

The Murchison Widefield Array Transients Survey (MWATS). A search for low frequency variability in a bright Southern hemisphere sample

We report on a search for low-frequency radio variability in 944 bright (> 4Jy at 154 MHz) unresolved, extragalactic radio sources monitored monthly for several years with the Murchison Widefield Array. In the majority of sources we find very low levels of variability with typical modulation indices < 5%. We detect 15 candidate low frequency variables that show significant long term variability (>2.8 years) with time-averaged modulation indices M = 3.1 - 7.1%. With 7/15 of these variable sources having peaked spectral energy distributions, and only 5.7% of the overall sample having peaked spectra, we find an increase in the prevalence of variability in this spectral class. We conclude that the variability seen in this survey is most probably a consequence of refractive interstellar scintillation and that these objects must have the majority of their flux density contained within angular diameters less than 50 milli-arcsec (which we support with multi-wavelength data). At 154 MHz we demonstrate that interstellar scintillation time-scales become long (~decades) and have low modulation indices, whilst synchrotron driven variability can only produce dynamic changes on time-scales of hundreds of years, with flux density changes less than one milli-jansky (without relativistic boosting). From this work we infer that the low frequency extra-galactic southern sky, as seen by SKA-Low, will be non-variable on time-scales shorter than one year.Comment: 19 pages, 11 figure

Size-dependent microwave heating and catalytic activity of fine iron particles in the deep dehydrogenation of hexadecane

Knowledge of the electromagnetic microwave radiation–solid matter interaction and ensuing mechanisms at active catalytic sites will enable a deeper understanding of microwave-initiated chemical interactions and processes, and will lead to further optimization of this class of heterogeneous catalysis. Here, we study the fundamental mechanism of the interaction between microwave radiation and solid Fe catalysts and the deep dehydrogenation of a model hydrocarbon, hexadecane. We find that the size-dependent electronic transition of particulate Fe metal from a microwave “reflector” to a microwave “absorber” lies at the heart of efficient metal catalysis in these heterogeneous processes. In this regard, the optimal particle size of a Fe metal catalyst for highly effective microwave-initiated dehydrogenation reactions is approximately 80–120 nm, and the catalytic performance is strongly dependent on the ratio of the mean radius of Fe particles to the microwave skin depth (r/δ) at the operating frequency. Importantly, the particle size of selected Fe catalysts will ultimately affect the basic heating properties of the catalysts and decisively influence their catalytic performance under microwave initiation. In addition, we have found that when two or more materials─present as a mechanical mixture─are simultaneously exposed to microwave irradiation, each constituent material will respond to the microwaves independently. Thus, the interaction between the two materials has been found to have synergistic effects, subsequently contributing to heating and improving the overall catalytic performance

(un)Doing standards in education with actor-network theory

Recent critiques have drawn important attention to the depoliticized consensus and empty promises embedded in network discourses of educational policy. While acceding this critique, this discussion argues that some forms of network analysis – specifically those adopting actor-network theory (ANT) approaches - actually offer useful theoretical resources for policy studies. Drawing from ANT-inspired studies of policy processes associated with educational standards, the article shows the ambivalences and contradictions as well as the possibilities that can be illuminated by ANT analysis of standards as networks. The discussion outlines the diverse network conceptions, considerations and sensibilities afforded by ANT approaches. Then it shows four phenomena that have been highlighted by ANT studies of educational standards: ordering (and rupturing) practice through ‘immutable mobiles’, local universality, tensions among networks of prescription and networks of negotiation, and different co-existing ontological forms of the same standards. The conclusion suggests starting points, drawing from these ANT-inspired network analyses, for examining policy processes associated with educational standards

Using tunable infrared laser direct absorption spectroscopy for ambient hydrogen chloride detection : HCl-TILDAS

The largest inorganic, gas-phase reservoir of chlorine atoms in the atmosphere is hydrogen chloride (HCl), but challenges in quantitative sampling of this compound cause difficulties for obtaining high-quality, high-frequency measurements. In this work, tunable infrared laser direct absorption spectroscopy (TILDAS) was demonstrated to be a superior optical method for sensitive, in situ detection of HCl at the 2925.89645 cm-1 absorption line using a 3 μm inter-band cascade laser. The instrument has an effective path length of 204 m, 1 Hz precision of 7-8 pptv, and 3σ limit of detection ranging from 21 to 24 pptv. For longer averaging times, the highest precision obtained was 0.5 pptv with a 3σ limit of detection of 1.6 pptv at 2.4 min. HCl-TILDAS was also shown to have high accuracy when compared with a certified gas cylinder, yielding a linear slope within the expected 5 % tolerance of the reported cylinder concentration (slope = 0.964 ± 0.008). The use of heated inlet lines and active chemical passivation greatly improve the instrument response times to changes in HCl mixing ratios, with minimum 90 % response times ranging from 1.2 to 4.4 s depending on inlet flow rate. However, these response times lengthened at relative humidities >50 %, conditions under which HCl concentration standards were found to elicit a significantly lower response (-5.8 %). The addition of high concentrations of gas-phase nitric acid (>3.0 ppbv) were found to increase HCl signal (<10 %), likely due to acid displacement with HCl or particulate chloride adsorbed to inlet surfaces. The equilibrium model ISORROPIA suggested a potential of particulate chloride partitioning into HCl gas within the heated inlet system if allowed to thermally equilibrate, but field results did not demonstrate a clear relationship between particulate chloride and HCl signal obtained with a denuder installed on the inlet

Preclinical and clinical biomarker studies of CT1812:A novel approach to Alzheimer's disease modification

INTRODUCTION: Amyloid beta (Aβ) oligomers are one of the most toxic structural forms of the Aβ protein and are hypothesized to cause synaptotoxicity and memory failure as they build up in Alzheimer’s disease (AD) patients’ brain tissue. We previously demonstrated that antagonists of the sigma-2 receptor complex effectively block Aβ oligomer toxicity. CT1812 is an orally bioavailable, brain penetrant small molecule antagonist of the sigma-2 receptor complex that appears safe and well tolerated in healthy elderly volunteers. We tested CT1812’s effect on Aβ oligomer pathobiology in preclinical AD models and evaluated CT1812’s impact on cerebrospinal fluid (CSF) protein biomarkers in mild to moderate AD patients in a clinical trial (ClinicalTrials.gov NCT02907567). METHODS: Experiments were performed to measure the impact of CT1812 versus vehicle on Aβ oligomer binding to synapses in vitro, to human AD patient post mortem brain tissue ex vivo, and in living APP(Swe)/PS1dE9 transgenic mice in vivo. Additional experiments were performed to measure the impact of CT1812 versus vehicle on Aβ oligomer-induced deficits in membrane trafficking rate, synapse number, and protein expression in mature hippocampal/cortical neurons in vitro. The impact of CT1812 on cognitive function was measured in transgenic Thy1 huAPP(Swe/Lnd+) and wild-type littermates. A multicenter, double-blind, placebo-controlled parallel group trial was performed to evaluate the safety, tolerability, and impact on protein biomarker expression of CT1812 or placebo given once daily for 28 days to AD patients (Mini-Mental State Examination 18–26). CSF protein expression was measured by liquid chromatography with tandem mass spectrometry or enzyme-linked immunosorbent assay in samples drawn prior to dosing (Day 0) and at end of dosing (Day 28) and compared within each patient and between pooled treated versus placebo-treated dosing groups. RESULTS: CT1812 significantly and dose-dependently displaced Aβ oligomers bound to synaptic receptors in three independent preclinical models of AD, facilitated oligomer clearance into the CSF, increased synaptic number and protein expression in neurons, and improved cognitive performance in transgenic mice. CT1812 significantly increased CSF concentrations of Aβ oligomers in AD patient CSF, reduced concentrations of synaptic proteins and phosphorylated tau fragments, and reversed expression of many AD-related proteins dysregulated in CSF. DISCUSSION: These preclinical studies demonstrate the novel disease-modifying mechanism of action of CT1812 against AD and Aβ oligomers. The clinical results are consistent with preclinical data and provide evidence of target engagement and impact on fundamental disease-related signaling pathways in AD patients, supporting further development of CT1812

The Australia Telescope 20GHz Survey: Hardware, Observing Strategy, and Scanning Survey Catalog

The Australia Telescope 20GHz (AT20G) survey is a large area (2{\pi} sr), sensitive (40mJy), high frequency (20GHz) survey of the southern sky. The survey was conducted in two parts: an initial fast scanning survey, and a series of more accurate follow-up observations. The follow-up survey catalog has been presented by Murphy et al. 2010. In this paper we discuss the hardware setup and scanning survey strategy as well as the production of the scanning survey catalog.Comment: 32 pages, 20 figures, accepted for publication in experimental astronom

Ethics review as a component of institutional approval for a multicentre continuous quality improvement project: the investigator's perspective

BACKGROUND: For ethical approval of a multicentre study in Canada, investigators must apply separately to individual Research Ethics Boards (REBs). In principle, the protection of human research subjects is of utmost importance. However, in practice, the process of multicentre ethics review can be time consuming and costly, requiring duplication of effort for researchers and REBs. We used our experience with ethical review of The Canadian Perinatal Network (CPN), to gain insight into the Canadian system. METHODS: The applications forms of 16 different REBs were abstracted for a list of standardized items. The application process across sites was compared. Correspondence between the REB and the investigators was documented in order to construct a timeline to approval, identify the specific issues raised by each board, and describe how they were resolved. RESULTS: Each REB had a different application form. Most (n = 9) had a two or three step application process. Overall, it took a median of 31 days (range 2-174 days) to receive an initial response from the REB. Approval took a median of 42 days (range 4-443 days). Privacy and consent were the two major issues raised. Several additional minor or administrative issues were raised which delayed approval. CONCLUSIONS: For CPN, the Canadian REB process of ethical review proved challenging. REBs acted independently and without unified application forms or submission procedures. We call for a critical examination of the ethical, privacy and institutional review processes in Canada, to determine the best way to undertake multicentre review

Developing consensus measures for global programs: lessons from the Global Alliance for Chronic Diseases Hypertension research program.

BACKGROUND: The imperative to improve global health has prompted transnational research partnerships to investigate common health issues on a larger scale. The Global Alliance for Chronic Diseases (GACD) is an alliance of national research funding agencies. To enhance research funded by GACD members, this study aimed to standardise data collection methods across the 15 GACD hypertension research teams and evaluate the uptake of these standardised measurements. Furthermore we describe concerns and difficulties associated with the data harmonisation process highlighted and debated during annual meetings of the GACD funded investigators. With these concerns and issues in mind, a working group comprising representatives from the 15 studies iteratively identified and proposed a set of common measures for inclusion in each of the teams' data collection plans. One year later all teams were asked which consensus measures had been implemented. RESULTS: Important issues were identified during the data harmonisation process relating to data ownership, sharing methodologies and ethical concerns. Measures were assessed across eight domains; demographic; dietary; clinical and anthropometric; medical history; hypertension knowledge; physical activity; behavioural (smoking and alcohol); and biochemical domains. Identifying validated measures relevant across a variety of settings presented some difficulties. The resulting GACD hypertension data dictionary comprises 67 consensus measures. Of the 14 responding teams, only two teams were including more than 50 consensus variables, five teams were including between 25 and 50 consensus variables and four teams were including between 6 and 24 consensus variables, one team did not provide details of the variables collected and two teams did not include any of the consensus variables as the project had already commenced or the measures were not relevant to their study. CONCLUSIONS: Deriving consensus measures across diverse research projects and contexts was challenging. The major barrier to their implementation was related to the time taken to develop and present these measures. Inclusion of consensus measures into future funding announcements would facilitate researchers integrating these measures within application protocols. We suggest that adoption of consensus measures developed here, across the field of hypertension, would help advance the science in this area, allowing for more comparable data sets and generalizable inferences