Development of a glucose sensor based on competitive binding and laser-excited fluorescence

An optical glucose sensor has been developed using competitive binding in conjunction with energy transfer. Sensor response is based on competition between glucose and dextran for a limited number of binding sites on the protein concanavalin A (conA). The system is optically monitored using fluorescent donor-acceptor dye pairs labeled to concanavalin A and dextran. When the dyes are sufficiently close, on the order of 50 A, energy is transferred from the donor emission band to the overlapping excitation band of the acceptor. This nonradiative, singlet-singlet transfer of energy enhances the acceptor emission at the expense of donor emission. In absence of glucose, the conA and dextran are bound together and energy transfer takes place. Upon addition of glucose, the dextran is displaced, and energy transfer is disrupted. The ratio of the two emission intensities can be related to glucose concentration. Donor-acceptor systems investigated included energy transfer from fluorescein (FITC) to three different types of rhodamine, TRITC, XRITC, and Texas Red, and both coumarin and fluorescamine donating energy to FITC. The system that gave the largest change in intensity involved FITC labeled conA as the donor and TRITC labeled dextran as the donor. Fluorescence was measured with both conventional fluorescence instrumentation and a computer controlled, laser excited spectrometer. The laser instrument was developed specifically for the optical glucose sensor, but was designed to support a wide range of fiber optic sensors. Instrument components include a nitrogen pumped dye laser, fiber optic beam splitters, photomultiplier tubes fitted with interference filters for wavelength selection, and boxcar averagers. Instrument development included calibration of the dye laser, evaluation of different fiber optic beam splitter arrangements, reduction of stray light, and evaluation of the boxcar averagers. The spectrometer was interfaced to an Apple IIc computer which was programmed to collect the data, perform baseline corrections, ratio the two channels, and trigger the laser to initiate the next data point. The instrument\u27s detection level, using Rhodamine 6G standards, is 1.0 $\times$ 10\sp{-9}molar and is limited by stray light. Precision of the instrument is approximately 3% and is limited by drift of the boxcar averagers

Mobility of the SecA 2-helix-finger is not essential for polypeptide translocation via the SecYEG complex

The bacterial ATPase SecA and protein channel complex SecYEG form the core of an essential protein translocation machinery. The nature of the conformational changes induced by each stage of the hydrolytic cycle of ATP and how they are coupled to protein translocation are not well understood. The structure of the SecA–SecYEG complex revealed a 2-helix-finger (2HF) of SecA in an ideal position to contact the substrate protein and push it through the membrane. Surprisingly, immobilization of this finger at the edge of the protein channel had no effect on translocation, whereas its imposition inside the channel blocked transport. This analysis resolves the stoichiometry of the active complex, demonstrating that after the initiation process translocation requires only one copy each of SecA and SecYEG. The results also have important implications on the mechanism of energy transduction and the power stroke driving transport. Evidently, the 2HF is not a highly mobile transducing element of polypeptide translocation

Deep Underground Science and Engineering Laboratory - Preliminary Design Report

The DUSEL Project has produced the Preliminary Design of the Deep Underground Science and Engineering Laboratory (DUSEL) at the rehabilitated former Homestake mine in South Dakota. The Facility design calls for, on the surface, two new buildings - one a visitor and education center, the other an experiment assembly hall - and multiple repurposed existing buildings. To support underground research activities, the design includes two laboratory modules and additional spaces at a level 4,850 feet underground for physics, biology, engineering, and Earth science experiments. On the same level, the design includes a Department of Energy-shepherded Large Cavity supporting the Long Baseline Neutrino Experiment. At the 7,400-feet level, the design incorporates one laboratory module and additional spaces for physics and Earth science efforts. With input from some 25 science and engineering collaborations, the Project has designed critical experimental space and infrastructure needs, including space for a suite of multidisciplinary experiments in a laboratory whose projected life span is at least 30 years. From these experiments, a critical suite of experiments is outlined, whose construction will be funded along with the facility. The Facility design permits expansion and evolution, as may be driven by future science requirements, and enables participation by other agencies. The design leverages South Dakota's substantial investment in facility infrastructure, risk retirement, and operation of its Sanford Laboratory at Homestake. The Project is planning education and outreach programs, and has initiated efforts to establish regional partnerships with underserved populations - regional American Indian and rural populations

The effect of elevated carbon dioxide on a Sierra-Nevadan dominant species: Pinus ponderosa

The impact of increasing atmospheric C0{sub 2} has not been fully evaluated on western coniferous forest species. Two year old seedlings of Pinusponderosa were grown in environmentally controlled chambers under increased C0{sub 2} conditions for 6 months. These trees exhibit morphological, physiological, and biochemical alterations when compared to our controls. Analysis of whole plant biomass distribution has shown no significant effect to the root to shoot ratios, however needles subjected to elevated C0{sub 2} exhibited an increased overall specific needle mass and a decreased total needle area. Morphological changes at the needle level included decreased mesophyll to vascular tissue 91 ratio and variations in starch storage in chloroplasts. The elevated CO{sub 2} increased internal CO{sub 2} concentrations and assimilation of carbon. Biochemical assays revealed that ribulose-bisphosphate carboxylase specific activities increased on per unit area basis with C0{sub 2} treatment levels. Sucrose phosphate synthase (SPS) activities exhibited an increase of 55% in the 700 uL L{sup {minus}1} treatment. These results indicate that the sink-source relationships of these trees have shifted carbon allocation toward above ground growth, possibly due to transport limitations

Sublobar resection is equivalent to lobectomy for clinical stage 1A lung cancer in solid nodules

ObjectivesA single randomized trial established lobectomy as the standard of care for the surgical treatment of early-stage non–small cell lung cancer. Recent advances in imaging/staging modalities and detection of smaller tumors have once again rekindled interest in sublobar resection for early-stage disease. The objective of this study was to compare lung cancer survival in patients with non–small cell lung cancer with a diameter of 30 mm or less with clinical stage 1 disease who underwent lobectomy or sublobar resection.MethodsWe identified 347 patients diagnosed with lung cancer who underwent lobectomy (n = 294) or sublobar resection (n = 53) for non–small cell lung cancer manifesting as a solid nodule in the International Early Lung Cancer Action Program from 1993 to 2011. Differences in the distribution of the presurgical covariates between sublobar resection and lobectomy were assessed using unadjusted P values determined by logistic regression analysis. Propensity scoring was performed using the same covariates. Differences in the distribution of the same covariates between sublobar resection and lobectomy were assessed using adjusted P values determined by logistic regression analysis with adjustment for the propensity scores. Lung cancer–specific survival was determined by the Kaplan–Meier method. Cox survival regression analysis was used to compare sublobar resection with lobectomy, adjusted for the propensity scores, surgical, and pathology findings, when adjusted and stratified by propensity quintiles.ResultsAmong 347 patients, 10-year Kaplan–Meier for 53 patients treated by sublobar resection compared with 294 patients treated by lobectomy was 85% (95% confidence interval, 80-91) versus 86% (confidence interval, 75-96) (P = .86). Cox survival analysis showed no significant difference between sublobar resection and lobectomy when adjusted for propensity scores or when using propensity quintiles (P = .62 and P = .79, respectively). For those with cancers 20 mm or less in diameter, the 10-year rates were 88% (95% confidence interval, 82-93) versus 84% (95% confidence interval, 73-96) (P = .45), and Cox survival analysis showed no significant difference between sublobar resection and lobectomy using either approach (P = .42 and P = .52, respectively).ConclusionsSublobar resection and lobectomy have equivalent survival for patients with clinical stage IA non–small cell lung cancer in the context of computed tomography screening for lung cancer

Observational and Dynamical Characterization of Main-Belt Comet P/2010 R2 (La Sagra)

We present observations of comet-like main-belt object P/2010 R2 (La Sagra) obtained by Pan-STARRS 1 and the Faulkes Telescope-North on Haleakala in Hawaii, the University of Hawaii 2.2 m, Gemini-North, and Keck I telescopes on Mauna Kea, the Danish 1.54 m telescope at La Silla, and the Isaac Newton Telescope on La Palma. An antisolar dust tail is observed from August 2010 through February 2011, while a dust trail aligned with the object's orbit plane is also observed from December 2010 through August 2011. Assuming typical phase darkening behavior, P/La Sagra is seen to increase in brightness by >1 mag between August 2010 and December 2010, suggesting that dust production is ongoing over this period. These results strongly suggest that the observed activity is cometary in nature (i.e., driven by the sublimation of volatile material), and that P/La Sagra is therefore the most recent main-belt comet to be discovered. We find an approximate absolute magnitude for the nucleus of H_R=17.9+/-0.2 mag, corresponding to a nucleus radius of ~0.7 km, assuming an albedo of p=0.05. Using optical spectroscopy, we find no evidence of sublimation products (i.e., gas emission), finding an upper limit CN production rate of Q_CN<6x10^23 mol/s, from which we infer an H2O production rate of Q_H2O<10^26 mol/s. Numerical simulations indicate that P/La Sagra is dynamically stable for >100 Myr, suggesting that it is likely native to its current location and that its composition is likely representative of other objects in the same region of the main belt, though the relatively close proximity of the 13:6 mean-motion resonance with Jupiter and the (3,-2,-1) three-body mean-motion resonance with Jupiter and Saturn mean that dynamical instability on larger timescales cannot be ruled out.Comment: 23 pages, 13 figures, accepted for publication in A

Genome-wide association study identifies 30 loci associated with bipolar disorder.

Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P &lt; 1 × 10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P &lt; 5 × 10-8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder

Enhanced relapse prevention for bipolar disorder – ERP trial. A cluster randomised controlled trial to assess the feasibility of training care coordinators to offer enhanced relapse prevention for bipolar disorder

BACKGROUND: Bipolar Disorder (BD) is a common and severe form of mental illness characterised by repeated relapses of mania or depression. Pharmacotherapy is the main treatment currently offered, but this has only limited effectiveness. A recent Cochrane review has reported that adding psycho-social interventions that train people to recognise and manage the early warning signs of their relapses is effective in increasing time to recurrence, improving social functioning and in reducing hospitalisations. However, the review also highlights the difficulties in offering these interventions within standard mental health services due to the need for highly trained therapists and extensive input of time. There is a need to explore the potential for developing Early Warning Sign (EWS) interventions in ways that will enhance dissemination. METHODS AND DESIGN: This article describes a cluster-randomised trial to assess the feasibility of training care coordinators (CCs) in community mental health teams (CMHTs) to offer Enhanced Relapse Prevention (ERP) to people with Bipolar Disorder. CMHTs in the North West of England are randomised to either receive training in ERP and to offer this to their clients, or to continue to offer treatment as usual (TAU). The main aims of the study are (1) to determine the acceptability of the intervention, training and outcome measures (2) to assess the feasibility of the design as measured by rates of recruitment, retention, attendance and direct feedback from participants (3) to estimate the design effect of clustering for key outcome variables (4) to estimate the effect size of the impact of the intervention on outcome. In this paper we provide a rationale for the study design, briefly outline the ERP intervention, and describe in detail the study protocol. DISCUSSION: This information will be useful to researchers attempting to carry out similar feasibility assessments of clinical effectiveness trials and in particular cluster randomised controlled trials

LSST: from Science Drivers to Reference Design and Anticipated Data Products

(Abridged) We describe here the most ambitious survey currently planned in the optical, the Large Synoptic Survey Telescope (LSST). A vast array of science will be enabled by a single wide-deep-fast sky survey, and LSST will have unique survey capability in the faint time domain. The LSST design is driven by four main science themes: probing dark energy and dark matter, taking an inventory of the Solar System, exploring the transient optical sky, and mapping the Milky Way. LSST will be a wide-field ground-based system sited at Cerro Pach\'{o}n in northern Chile. The telescope will have an 8.4 m (6.5 m effective) primary mirror, a 9.6 deg$^2$ field of view, and a 3.2 Gigapixel camera. The standard observing sequence will consist of pairs of 15-second exposures in a given field, with two such visits in each pointing in a given night. With these repeats, the LSST system is capable of imaging about 10,000 square degrees of sky in a single filter in three nights. The typical 5$\sigma$ point-source depth in a single visit in $r$ will be $\sim 24.5$ (AB). The project is in the construction phase and will begin regular survey operations by 2022. The survey area will be contained within 30,000 deg$^2$ with $\delta<+34.5^\circ$, and will be imaged multiple times in six bands, $ugrizy$, covering the wavelength range 320--1050 nm. About 90\% of the observing time will be devoted to a deep-wide-fast survey mode which will uniformly observe a 18,000 deg$^2$ region about 800 times (summed over all six bands) during the anticipated 10 years of operations, and yield a coadded map to $r\sim27.5$. The remaining 10\% of the observing time will be allocated to projects such as a Very Deep and Fast time domain survey. The goal is to make LSST data products, including a relational database of about 32 trillion observations of 40 billion objects, available to the public and scientists around the world.Comment: 57 pages, 32 color figures, version with high-resolution figures available from https://www.lsst.org/overvie