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The United States government has operated Dobson ozone spectrophotometers at various sites, starting during the International Geophysical Year (1 July 1957 to 31 December 1958). A network of stations for long-term monitoring of the total column content (thickness of the ozone layer) of the atmosphere was established in the early 1960s and eventually grew to 16 stations, 14 of which are still operational and submit data to the United States of America's National Oceanic and Atmospheric Administration (NOAA). Seven of these sites are also part of the Network for the Detection of Atmospheric Composition Change (NDACC), an organization that maintains its own data archive. Due to recent changes in data processing software the entire dataset was re-evaluated for possible changes. To evaluate and minimize potential changes caused by the new processing software, the reprocessed data record was compared to the original data record archived in the World Ozone and UV Data Center (WOUDC) in Toronto, Canada. The history of the observations at the individual stations, the instruments used for the NOAA network monitoring at the station, the method for reducing zenith-sky observations to total ozone, and calibration procedures were re-evaluated using data quality control tools built into the new software. At the completion of the evaluation, the new datasets are to be published as an update to the WOUDC and NDACC archives, and the entire dataset is to be made available to the scientific community. The procedure for reprocessing Dobson data and the results of the reanalysis on the archived record are presented in this paper. A summary of historical changes to 14 station records is also provided.

Remote sounding methods are used to derive ozone profile and column information from various ground-based and satellite measurements. Vertical ozone profiles measured in Dobson units (DU) are currently retrieved based on laboratory measurements of the ozone absorption cross-section spectrum between 270 and 400 nm published in 1985 by Bass and Paur (BP). Recently, the US National Aeronautics and Space Administration (NASA) and the European Space Agency (ESA) proposed using the set of ozone cross-section measurements made at the Daumont laboratory in 1992 (BDM) for revising the Aura Ozone Monitoring Instrument (OMI) and Global Ozone Monitoring Experiment (GOME) satellite ozone profiles and total ozone column retrievals. Dobson Umkehr zenith sky data have been collected by NOAA ground-based stations at Boulder, CO (BDR) and Mauna Loa Observatory, HI (MLO) since the 1980s. The UMK04 algorithm is based on the BP ozone cross-section data. It is currently used for all Dobson Umkehr data processing submitted to the World Ozone and Ultraviolet radiation Data Centre (WOUDC) under the Global Atmosphere Watch (GAW) program of the World Meteorological Organization (WMO). Ozone profiles are also retrieved from measurements by the Mark IV Brewers operated by the NOAA-EPA Brewer Spectrophotometer UV and Ozone Network (NEUBrew) using a modified UMK04 algorithm (O3BUmkehr v.2.6, Martin Stanek). This paper describes the sensitivity of the Umkehr retrievals with respect to the proposed ozone cross-section changes. It is found that the ozone cross-section choice only minimally (within the retrieval accuracy) affects the Dobson and the Brewer Umkehr retrievals. On the other hand, significantly larger errors were found in the MLO and Boulder Umkehr ozone data (−8 and +5% bias in stratosphere and troposphere respectively) when the out-of-band (OOB) stray light contribution to the Umkehr measurement is not taken into account (correction is currently not included in the UMK04). The vertical distribution of OOB effect in the retrieved profile can be related to the local ozone climatology, instrument degradation, and optical characteristics of the instrument. Nonetheless, recurring OOB errors do not contribute to the long-term ozone trends.

The loss of synapses is a strong histological correlate of the cognitive decline in Alzheimer's disease (AD). Amyloid β-peptide (Aβ), a cleavage product of the amyloid precursor protein (APP), exerts detrimental effects on synapses, a process thought to be causally related to the cognitive deficits in AD. Here, we used in vivo two-photon microscopy to characterize the dynamics of axonal boutons and dendritic spines in APP/Presenilin 1 (APP(swe)/PS1(L166P))-green fluorescent protein (GFP) transgenic mice. Time-lapse imaging over 4 weeks revealed a pronounced, concerted instability of pre- and postsynaptic structures within the vicinity of amyloid plaques. Treatment with a novel sulfonamide-type γ-secretase inhibitor (GSI) attenuated the formation and growth of new plaques and, most importantly, led to a normalization of the enhanced dynamics of synaptic structures close to plaques. GSI treatment did neither affect spines and boutons distant from plaques in amyloid precursor protein/presenilin 1-GFP (APPPS1-GFP) nor those in GFP-control mice, suggesting no obvious neuropathological side effects of the drug.

Herein, we describe our strategy to design metabolically stable γ-secretase inhibitors which are selective for inhibition of Aβ generation over Notch. We highlight our synthetic strategy to incorporate diversity and chirality. Compounds 30 (ELND006) and 34 (ELND007) both entered human clinical trials. The in vitro and in vivo characteristics for these two compounds are described. A comparison of inhibition of Aβ generation in vivo between 30, 34, Semagacestat 41, Begacestat 42, and Avagacestat 43 in mice is made. 30 lowered Aβ in the CSF of healthy human volunteers.

The SAR of a series of brain penetrant, trisubstituted thiophene based JNK inhibitors with improved pharmacokinetic properties is described. These compounds were designed based on information derived from metabolite identification studies which led to compounds such as 42 with lower clearance, greater brain exposure and longer half life compared to earlier analogs., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Antibody microarrays have the potential to revolutionize protein expression profiling. The intensity of specific signal produced on a feature of such an array is related to the amount of analyte that is captured from the biological mixture by the immobilized antibody (the "capture agent"). This in turn is a function of the surface density and fractional activity of the capture agents. Here we investigate how these two factors are affected by the orientation of the capture agents on the surface. We compare randomly versus specifically oriented capture agents based on both full-sized antibodies and Fab' fragments. Each comparison was performed using three different antibodies and two types of streptavidin-coated monolayer surfaces. The specific orientation of capture agents consistently increases the analyte-binding capacity of the surfaces, with up to 10-fold improvements over surfaces with randomly oriented capture agents. Surface plasmon resonance revealed a dense monolayer of Fab' fragments that are on average 90% active when specifically oriented. Randomly attached Fab's could not be packed at such a high density and generally also had a lower specific activity. These results emphasize the importance of attaching proteins to surfaces such that their binding sites are oriented toward the solution phase.