Multi-object spectroscopy of the field surrounding PKS 2126-158: Discovery of a z=0.66 galaxy group

The high-redshift radio-loud quasar PKS 2126-158 is found to have a large number of red galaxies in close apparent proximity. We use the Gemini Multi-Object Spectrograph (GMOS) on Gemini South to obtain optical spectra for a large fraction of these sources. We show that there is a group of galaxies at $z\sim0.66$, coincident with a metal-line absorption system seen in the quasar's optical spectrum. The multiplexing capabilities of GMOS also allow us to measure redshifts of many foreground galaxies in the field surrounding the quasar. The galaxy group has five confirmed members, and a further four fainter galaxies are possibly associated. All confirmed members exhibit early-type galaxy spectra, a rare situation for a Mg II absorbing system. We discuss the relationship of this group to the absorbing gas, and the possibility of gravitational lensing of the quasar due to the intervening galaxies.Comment: Monthly Notices of the Royal Astronomical Society, in press. 10 pages, 8 figure

Estimating Waterfowl Densities in a Flooded Forest: a Comparison of Methods

During winter, aerial surveys are used to estimate densities of ducks that occupy open-water habitats. However, such surveys are ineffective for sampling forest-dwelling species, especially Aix sponsa (Wood Ducks), Anas platyrhynchos (Mallards), and Lophodytes cucullatus (Hooded Mergansers). We evaluated fixed-radius plot (FRP) and Reynolds and Goodrum variable-radius plot (VRP) methods for estimating waterfowl densities in a flooded hardwood bottomland. We constructed 15 elevated blinds on the Angelina River flood plain in eastern Texas and established a 1-ha FRP around each blind; color-coded markers were placed at fixed intervals from each blind. Observers surveyed waterfowl from blinds for 21 mornings during January–March, 1990. For FRPs, species, sex, and time a bird entered and exited the plot were recorded. For VRPs, similar data and estimated observer-to-bird distance were recorded. Data were arranged in a randomized block design and tested using 1-way analyses of variances. Wood Ducks, Mallards, and Hooded Mergansers comprised 68, 18, and 10% of the birds recorded, respectively. Wood Duck density estimates (per ha) for FRP, Reynolds VRP, and Goodrum VRP methods were 0.65, 0.49, and 1.00 (P \u3c 0.001), respectively; for Mallards, estimates were 0.27, 0.20, and 0.33 (P \u3c 0.001), respectively; and estimates were 0.09, 0.13, and 0.15 (P = 0.003) for Hooded Mergansers, respectively. Based on ease of implementation, complexity of data analyses, and precision of density estimates, the FRP and Goodrum VRP methods are recommended for sampling waterfowl in flooded forests

The Spectra of Red Quasars

We measure the spectral properties of a representative sub-sample of 187 quasars, drawn from the Parkes Half-Jansky, Flat-radio-spectrum Sample (PHFS). Quasars with a wide range of rest-frame optical/UV continuum slopes are included in the analysis: their colours range from 2 < B-K < 7. The median H-beta and [O III] emission-line equivalent widths of the red quasar sub-sample are a factor of ten weaker than those of the blue quasar sub-sample. Both the colours and the emission-line equivalent widths of the red quasars can be explained by the addition of a featureless red synchrotron continuum component to an otherwise normal blue quasar spectrum. The relative strengths of the blue and red components span two orders of magnitude at rest-frame 500nm. The blue component is weaker relative to the red component in low optical luminosity sources. This suggests that the fraction of accretion energy going into optical emission from the jet is greater in low luminosity quasars. This synchrotron model does not, however, fit around 10% of the quasars, which have both red colours and high equivalent width emission-lines. We hypothesise that these red, strong-lined quasars have intrinsically weak Big Blue Bumps. There is no discontinuity in spectral properties between the BL Lac objects in our sample and the other quasars. The synchrotron emission component only dominates the spectrum at longer wavelengths, so existing BL Lac surveys will be biassed against high redshift objects.Comment: 22 pages, 12 figures, accepted for publication in PASA. Data tables and composite spectra from the paper can be found at http://msowww.anu.edu.au/~pfrancis

Changing the Surgical Residency: A Mixed-Methods Study of Residents’ and Faculty Experiences One Year After Implementation

Objective: To evaluate a reformed surgical residency curriculum aimed at addressing emerging practice models, enhancing residents’ educational experience, and improving the quality/continuity of patient care by reducing the service size and enhancing attending-resident interactions. Methods: A mixed-methods study of the surgical training program following curriculum reform including: 1) focus group and individual qualitative interviews with residents, attendings, nurses, and advanced practice providers to explore stakeholder perspectives on curriculum reform, 2) time study of surgical resident activities, and 3) quantitative assessment of surgical case logs. Results: Qualitative interviews demonstrated disparate knowledge and attitudes regarding the goals of the curriculum with emergence of several themes during transcript analysis including: Goals of the Change, Learning and Educational Value, Communication, Teamwork, Service, and Quality of Life. Both positive aspects of curriculum reform (e.g., improved focus on resident education and balance between educational and service activities, communication, and opportunity for direct feedback and observation) and negative ones (e.g., lack of role clarity, insufficient workforce) were identified. Despite limitations, the time study revealed variability in resident activities by post-graduate year with more time spent on indirect patient care activities in the early years and more time in the OR and one-on-one with attendings later. Quantitative analysis of surgical case logs, previously published, showed no significant decrease in number of cases for residents by either training level or role. Conclusions: This single-institution mixed methods study suggests that a reformed surgical residency curriculum improved residents’ educational experiences and the balance between educational and service activities without affecting operative volume. Multiple modalities of assessment are essential to identify the various positive and negative aspects of an educational intervention

Microglial Expression of the Wnt Signaling Modulator DKK2 Differs between Human Alzheimer's Disease Brains and Mouse Neurodegeneration Models

Wnt signaling is crucial for synapse and cognitive function. Indeed, deficient Wnt signaling is causally related to increased expression of DKK1, an endogenous negative Wnt regulator, and synapse loss, both of which likely contribute to cognitive decline in Alzheimer's disease (AD). Increasingly, AD research efforts have probed the neuroinflammatory role of microglia, the resident immune cells of the CNS, which have furthermore been shown to be modulated by Wnt signaling. The DKK1 homolog DKK2 has been previously identified as an activated response and/or disease-associated microglia (DAM/ARM) gene in a mouse model of AD. Here, we performed a detailed analysis of DKK2 in mouse models of neurodegeneration, and in human AD brain. In APP/PS1 and APPNL-G-F AD mouse model brains as well as in SOD1G93A ALS mouse model spinal cords, but not in control littermates, we demonstrated significant microgliosis and microglial Dkk2 mRNA upregulation in a disease-stage-dependent manner. In the AD models, these DAM/ARM Dkk2+ microglia preferentially accumulated close to βAmyloid plaques. Furthermore, recombinant DKK2 treatment of rat hippocampal primary neurons blocked WNT7a-induced dendritic spine and synapse formation, indicative of an anti-synaptic effect similar to that of DKK1. In stark contrast, no such microglial DKK2 upregulation was detected in the postmortem human frontal cortex from individuals diagnosed with AD or pathologic aging. In summary, the difference in microglial expression of the DAM/ARM gene DKK2 between mouse models and human AD brain highlights the increasingly recognized limitations of using mouse models to recapitulate facets of human neurodegenerative disease.Significance StatementThe endogenous negative Wnt regulator Dkk2 is significantly upregulated at the mRNA level in microglia of Alzheimer's disease (AD) mouse models, implying that microglia derived Dkk2 protein may detrimentally contribute to a reduced Wnt signaling tone in the AD brain, a known pathophysiological manifestation. Indeed, recombinant DKK2 prevented Wnt-dependent synapse formation in cultured neurons. However, DKK2 upregulation was not recapitulated in postmortem human AD brains. The success of neurodegeneration animal models has relied on pathophysiology that for the most part correctly modelled human disease. Increasingly, however, limitations to the validity of mouse models to recapitulate human neurodegenerative disease have become apparent, as evidenced by the present study by the difference in microglial DKK2 expression between AD mouse models and human AD brain

Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study

Abstract Aims/hypothesis Fenofibrate caused an acute, sustained plasma creatinine increase in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and Action to Control Cardiovascular Risk in Diabetes (ACCORD) studies. We assessed fenofibrate’s renal effects in a FIELD washout sub-study. Methods Type 2 diabetic patients (n=9795) aged 50 to 75 years were randomly assigned to fenofibrate (n=4895) or placebo (n=4900) for 5 years, after 6 weeks fenofibrate run-in. Albuminuria (urinary albumin:creatinine ratio) measured at baseline, year 2 and close-out) and estimated GFR, measured 4 to 6 monthly according to the Modification of Diet in Renal Disease study, were pre-specified endpoints. Plasma creatinine was re-measured 8 weeks after treatment cessation at close-out (washout sub-study, n=661). Analysis was by intention-to-treat. Results During fenofibrate run-in, plasma creatinine increased by 10.0 µmol/l (p<0.001), but quickly reversed on placebo assignment. It remained higher on fenofibrate than on placebo, but the chronic rise was slower (1.62 µmol/l vs 1.89 µmol/l annually, p=0.01), with less estimated GFR loss (1.19 vs 2.03 ml min−1 1.73 m−2 annually, p<0.001). After washout, estimated GFR had fallen less from baseline on fenofibrate (1.9 ml min−1 1.73 m−2, p=0.065) than on placebo (6.9 ml min−1 1.73 m−2, p<0.001), sparing 5.0 ml min−1 1.73 m−2 (95% CI 2.3-7.7, p<0.001). Greater preservation of estimated GFR with fenofibrate was observed during greater reduction over the active run-in period (pre-randomisation) of triacylglycerol (n=186 vs 170) and baseline hypertriacylglycerolaemia (n=89 vs 80) alone, or combined with low HDL-cholesterol (n=71 vs 60). Fenofibrate reduced urine albumin concentrations and hence albumin:creatinine ratio by 24% vs 12% (p<0.001; mean difference 14% [95% CI 9-18]; p<0.001), with 14% less progression and 18% more albuminuria regression (p<0.001) than in participants on placebo. End-stage renal event frequency was similar (n=21 vs 26, p=0.48). Conclusions/interpretation Fenofibrate reduced albuminuria and slowed estimated GFR loss over 5 years, despite initially and reversibly increasing plasma creatinine. Fenofibrate may delay albuminuria and GFR impairment in type 2 diabetes patients. Confirmatory studies are merited. Trial registration: ISRCTN64783481 Funding: The study was funded by grants from Laboratoires Fournier, Dijon, France (now part of Solvay and Abbott Pharmaceuticals) and the NHMRC of Australia.Laboratoires Fournier, Dijon, France (now part of Solvay and Abbott Pharmaceuticals

Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study

Abstract Aims/hypothesis Fenofibrate caused an acute, sustained plasma creatinine increase in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and Action to Control Cardiovascular Risk in Diabetes (ACCORD) studies. We assessed fenofibrate’s renal effects in a FIELD washout sub-study. Methods Type 2 diabetic patients (n=9795) aged 50 to 75 years were randomly assigned to fenofibrate (n=4895) or placebo (n=4900) for 5 years, after 6 weeks fenofibrate run-in. Albuminuria (urinary albumin:creatinine ratio) measured at baseline, year 2 and close-out) and estimated GFR, measured 4 to 6 monthly according to the Modification of Diet in Renal Disease study, were pre-specified endpoints. Plasma creatinine was re-measured 8 weeks after treatment cessation at close-out (washout sub-study, n=661). Analysis was by intention-to-treat. Results During fenofibrate run-in, plasma creatinine increased by 10.0 µmol/l (p<0.001), but quickly reversed on placebo assignment. It remained higher on fenofibrate than on placebo, but the chronic rise was slower (1.62 µmol/l vs 1.89 µmol/l annually, p=0.01), with less estimated GFR loss (1.19 vs 2.03 ml min−1 1.73 m−2 annually, p<0.001). After washout, estimated GFR had fallen less from baseline on fenofibrate (1.9 ml min−1 1.73 m−2, p=0.065) than on placebo (6.9 ml min−1 1.73 m−2, p<0.001), sparing 5.0 ml min−1 1.73 m−2 (95% CI 2.3-7.7, p<0.001). Greater preservation of estimated GFR with fenofibrate was observed during greater reduction over the active run-in period (pre-randomisation) of triacylglycerol (n=186 vs 170) and baseline hypertriacylglycerolaemia (n=89 vs 80) alone, or combined with low HDL-cholesterol (n=71 vs 60). Fenofibrate reduced urine albumin concentrations and hence albumin:creatinine ratio by 24% vs 12% (p<0.001; mean difference 14% [95% CI 9-18]; p<0.001), with 14% less progression and 18% more albuminuria regression (p<0.001) than in participants on placebo. End-stage renal event frequency was similar (n=21 vs 26, p=0.48). Conclusions/interpretation Fenofibrate reduced albuminuria and slowed estimated GFR loss over 5 years, despite initially and reversibly increasing plasma creatinine. Fenofibrate may delay albuminuria and GFR impairment in type 2 diabetes patients. Confirmatory studies are merited. Trial registration: ISRCTN64783481 Funding: The study was funded by grants from Laboratoires Fournier, Dijon, France (now part of Solvay and Abbott Pharmaceuticals) and the NHMRC of Australia.Laboratoires Fournier, Dijon, France (now part of Solvay and Abbott Pharmaceuticals

A pilot survey for transients and variables with the Australian Square Kilometre Array Pathfinder

We present a pilot search for variable and transient sources at 1.4 GHz with the Australian Square Kilometre Array Pathfinder (ASKAP). The search was performed in a 30 deg2 area centred on the NGC 7232 galaxy group over eight epochs and observed with a near-daily cadence. The search yielded nine potential variable sources, rejecting the null hypothesis that the flux densities of these sources do not change with 99.9 per cent confidence. These nine sources displayed flux density variations with modulation indices m = 0.1 above our flux density limit of ~1.5mJy. They are identified to be compact active galactic nucleus (AGN)/quasars or galaxies hosting an AGN, whose variability is consistent with refractive interstellar scintillation.We also detect a highly variable source with modulation index m &gt; 0.5 over a time interval of a decade between the SydneyUniversity Molonglo Sky Survey (SUMSS) and our latest ASKAP observations. We find the source to be consistent with the properties of long-term variability of a quasar. No transients were detected on time-scales of days and we place an upper limit ?t &lt; 0.01 deg-2 with 95 per cent confidence for non-detections on near-daily time-scales. The future VAST-Wide survey with 36-ASKAP dishes will probe the transient phase space with similar cadence to our pilot survey, but better sensitivity, and will detect and monitor rarer brighter events

Structural Analysis and Development of Notum Fragment Screening Hits

The Wnt signaling suppressor Notum is a promising target for osteoporosis, Alzheimer's disease, and colorectal cancers. To develop novel Notum inhibitors, we used an X-ray crystallographic fragment screen with the Diamond-SGC Poised Library (DSPL) and identified 59 fragment hits from the analysis of 768 data sets. Fifty-eight of the hits were found bound at the enzyme catalytic pocket with potencies ranging from 0.5 to >1000 μM. Analysis of the fragments' diverse binding modes, enzymatic inhibitory activities, and chemical properties led to the selection of six hits for optimization, and five of these resulted in improved Notum inhibitory potencies. One hit, 1-phenyl-1,2,3-triazole 7, and its related cluster members, have shown promising lead-like properties. These became the focus of our fragment development activities, resulting in compound 7d with IC50 0.0067 μM. The large number of Notum fragment structures and their initial optimization provided an important basis for further Notum inhibitor development

Design of a Potent, Selective, and Brain-Penetrant Inhibitor of Wnt-Deactivating Enzyme Notum by Optimization of a Crystallographic Fragment Hit

Notum is a carboxylesterase that suppresses Wnt signaling through deacylation of an essential palmitoleate group on Wnt proteins. There is a growing understanding of the role Notum plays in human diseases such as colorectal cancer and Alzheimer's disease, supporting the need to discover improved inhibitors, especially for use in models of neurodegeneration. Here, we have described the discovery and profile of 8l (ARUK3001185) as a potent, selective, and brain-penetrant inhibitor of Notum activity suitable for oral dosing in rodent models of disease. Crystallographic fragment screening of the Diamond-SGC Poised Library for binding to Notum, supported by a biochemical enzyme assay to rank inhibition activity, identified 6a and 6b as a pair of outstanding hits. Fragment development of 6 delivered 8l that restored Wnt signaling in the presence of Notum in a cell-based reporter assay. Assessment in pharmacology screens showed 8l to be selective against serine hydrolases, kinases, and drug targets