Novel 1-hydroxypyridin-2-one metal chelators prevent and res-cue ubiquitin proteasomal-related neuronal injury in an in vitro model of Parkinson’s disease

Ubiquitin proteasome system (UPS) impairment, excessive cellular oxidative stress and iron dyshomeostasis are key to substantia nigra dopaminergic neuronal de-generation in Parkinson's disease (PD); however, a link between these features remains unconfirmed. By using the proteasome inhibitor lactacystin we confirm that nigral injury via UPS impairment disrupts iron homeostasis, in turn increasing oxi-dative stress and promoting protein aggregation. We demonstrate the neuroprotec-tive potential of two novel 1-hydroxy-2(1H)-pyridinone (1,2-HOPO) iron chelators, compounds C6 and C9, against lactacystin-induced cell death. We demonstrate that this cellular preservation relates to the compounds’ iron chelating capabilities and subsequent reduced capacity of iron to form reactive oxygen species (ROS), where we also show that the ligands act as antioxidant agents. Our results also de-monstrate the ability of C6 and C9 to reduce intracellular lactacystin-induced α-synuclein burden. Stability constant measurements confirmed a high affinity of C6 and C9 for Fe3+ and display a 3:1 HOPO:Fe3+ complex formation at physiological pH. Reducing iron reactivity could prevent the demise of nigral dopaminergic neurons. We provide evidence that the lactacystin model presents with several neuropatho-logical hallmarks of PD related to iron dyshomeostasis and that the novel chelating compounds C6 and C9 can protect against lactacystin-related neurotoxicity

Movement of pulsed resource subsidies from kelp forests to deep fjords

Resource subsidies in the form of allochthonous primary production drive secondary production in many ecosystems, often sustaining diversity and overall productivity. Despite their importance in structuring marine communities, there is little understanding of how subsidies move through juxtaposed habitats and into recipient communities. We investigated the transport of detritus from kelp forests to a deep Arctic fjord (northern Norway). We quantified the seasonal abundance and size structure of kelp detritus in shallow subtidal (0‒12 m), deep subtidal (12‒85 m), and deep fjord (400‒450 m) habitats using a combination of camera surveys, dive observations, and detritus collections over 1 year. Detritus formed dense accumulations in habitats adjacent to kelp forests, and the timing of depositions coincided with the discrete loss of whole kelp blades during spring. We tracked these blades through the deep subtidal and into the deep fjord, and showed they act as a short-term resource pulse transported over several weeks. In deep subtidal regions, detritus consisted mostly of fragments and its depth distribution was similar across seasons (50% of total observations). Tagged pieces of detritus moved slowly out of kelp forests (displaced 4‒50 m (mean 11.8 m ± 8.5 SD) in 11‒17 days, based on minimum estimates from recovered pieces), and most (75%) variability in the rate of export was related to wave exposure and substrate. Tight resource coupling between kelp forests and deep fjords indicate that changes in kelp abundance would propagate through to deep fjord ecosystems, with likely consequences for the ecosystem functioning and services they provide.acceptedVersio

A Description of Quasar Variability Measured Using Repeated SDSS and POSS Imaging

We provide a quantitative description and statistical interpretation of the optical continuum variability of quasars. The Sloan Digital Sky Survey (SDSS) has obtained repeated imaging in five UV-to-IR photometric bands for 33,881 spectroscopically confirmed quasars. About 10,000 quasars have an average of 60 observations in each band obtained over a decade along Stripe 82 (S82), whereas the remaining ~25,000 have 2-3 observations due to scan overlaps. The observed time lags span the range from a day to almost 10 years, and constrain quasar variability at rest-frame time lags of up to 4 years, and at rest-frame wavelengths from 1000A to 6000A. We publicly release a user-friendly catalog of quasars from the SDSS Data Release 7 that have been observed at least twice in SDSS or once in both SDSS and the Palomar Observatory Sky Survey, and we use it to analyze the ensemble properties of quasar variability. Based on a damped random walk (DRW) model defined by a characteristic time scale and an asymptotic variability amplitude that scale with the luminosity, black hole mass, and rest wavelength for individual quasars calibrated in S82, we can fully explain the ensemble variability statistics of the non-S82 quasars such as the exponential distribution of large magnitude changes. All available data are consistent with the DRW model as a viable description of the optical continuum variability of quasars on time scales of ~5-2000 days in the rest frame. We use these models to predict the incidence of quasar contamination in transient surveys such as those from PTF and LSST.Comment: 33 pages, 19 figures, replaced with accepted version. Catalog is available at http://www.astro.washington.edu/users/ivezic/macleod/qso_dr7

Room temperature triplet state spectroscopy of organic semiconductors

Organic light-emitting devices and solar cells are devices that create, manipulate, and convert excited states in organic semiconductors. It is crucial to characterize these excited states, or excitons, to optimize device performance in applications like displays and solar energy harvesting. This is complicated if the excited state is a triplet because the electronic transition is ‘dark’ with a vanishing oscillator strength. As a consequence, triplet state spectroscopy must usually be performed at cryogenic temperatures to reduce competition from non-radiative rates. Here, we control non-radiative rates by engineering a solid-state host matrix containing the target molecule, allowing the observation of phosphorescence at room temperature and alleviating constraints of cryogenic experiments. We test these techniques on a wide range of materials with functionalities spanning multi-exciton generation (singlet exciton fission), organic light emitting device host materials, and thermally activated delayed fluorescence type emitters. Control of non-radiative modes in the matrix surrounding a target molecule may also have broader applications in light-emitting and photovoltaic devices.United States. Dept. of Energy. Center for Excitonics (Award DE-SC0001088

The effect of the stromal component of breast tumours on prediction of clinical outcome using gene expression microarray analysis

INTRODUCTION: The aim of this study was to examine the effect of the cellular composition of biopsies on the error rates of multigene predictors of response of breast tumours to neoadjuvant adriamycin and cyclophosphamide (AC) chemotherapy. MATERIALS AND METHODS: Core biopsies were taken from primary breast tumours of 43 patients prior to AC, and subsequent clinical response was recorded. Post-chemotherapy (day 21) samples were available for 16 of these samples. Frozen sections of each core were used to estimate the proportion of invasive cancer and other tissue components at three levels. Transcriptional profiling was performed using a cDNA array containing 4,600 elements. RESULTS: Twenty-three (53%) patients demonstrated a 'good' and 20 (47%) a 'poor' clinical response. The percentage invasive tumour in core biopsies collected from these patients varied markedly. Despite this, agglomerative clustering of sample expression profiles showed that almost all biopsies from the same tumour aggregated as nearest neighbours. SAM (significance analysis of microarrays) regression analysis identified 144 genes which distinguished high- and low-percentage invasive tumour biopsies at a false discovery rate of not more than 5%. The misclassification error of prediction of clinical response using microarray data from pre-treatment biopsies (on leave-one-out cross-validation) was 28%. When prediction was performed on subsets of samples which were more homogeneous in their proportions of malignant and stromal cells, the misclassification error was considerably lower (8%–13%, p < 0.05 on permutation). CONCLUSION: The non-tumour content of breast cancer samples has a significant effect on gene expression profiles. Consideration of this factor improves accuracy of response prediction by expression array profiling. Future gene expression array prediction studies should be planned taking this into account

Hydrogen-poor Superluminous Supernovae with Late-time H alpha Emission: Three Events From the Intermediate Palomar Transient Factory

We present observations of two new hydrogen-poor superluminous supernovae (SLSN-I), iPTF15esb and iPTF16bad, showing late-time Hα emission with line luminosities of (1\mbox{--}3)\times {10}^{41} erg s−1 and velocity widths of (4000–6000) km s−1. Including the previously published iPTF13ehe, this makes up a total of three such events to date. iPTF13ehe is one of the most luminous and the slowest evolving SLSNe-I, whereas the other two are less luminous and fast decliners. We interpret this as a result of the ejecta running into a neutral H-shell located at a radius of ~1016 cm. This implies that violent mass loss must have occurred several decades before the supernova explosion. Such a short time interval suggests that eruptive mass loss could be common shortly before core collapse, and more importantly helium is unlikely to be completely stripped off the progenitor and could be present in the ejecta. It is a mystery why helium features are not detected, even though nonthermal energy sources, capable of ionizing He, may exist as suggested by the O ii absorption series in the early-time spectra. Our late-time spectra (+240 days) appear to have intrinsically lower [O i] 6300 Å luminosities than that of SN2015bn and SN2007bi, which is possibly an indication of less oxygen (<10 M ⊙). The blueshifted Hα emission relative to the hosts for all three events may be in tension with the binary model proposed for iPTF13ehe. Finally, iPTF15esb has a peculiar light curve (LC) with three peaks separated from one another by ~22 days. The LC undulation is stronger in bluer bands. One possible explanation is ejecta-circumstellar medium interaction

DNA Barcoding for Community Ecology - How to Tackle a Hyperdiverse, Mostly Undescribed Melanesian Fauna

Trigonopterus weevils are widely distributed throughout Melanesia and hyperdiverse in New Guinea. They are a dominant feature in natural forests, with narrow altitudinal zonation. Their use in community ecology has been precluded by the "taxonomic impediment". We sampled >6,500 specimens from seven areas across New Guinea; 1,002 specimens assigned to 270 morphospecies were DNA sequenced. Objective clustering of a refined dataset (excluding nine cryptic species) at 3% threshold revealed 324 genetic clusters (DNA group count relative to number of morphospecies = 20.0% overestimation of species diversity, or 120.0% agreement) and 85.6% taxonomic accuracy (the proportion of DNA groups that "perfectly" agree with morphology-based species hypotheses). Agreement and accuracy were best at an 8% threshold. GMYC analysis revealed 328 entities (21.5% overestimation) with 227 perfect GMYC entities (84.1% taxonomic accuracy). Both methods outperform the parataxonomist (19% underestimation; 31.6% taxonomic accuracy). The number of species found in more than one sampling area was highest in the Eastern Highlands and Huon (Sørensen similarity index 0.07, 4 shared species); ⅓ of all areas had no species overlap. Success rates of DNA barcoding methods were lowest when species showed a pronounced geographical structure. In general, Trigonopterus show high α and β-diversity across New Guinea. DNA barcoding is an excellent tool for biodiversity surveys but success rates might drop when closer localities are included. Hyperdiverse Trigonopterus are a useful taxon for evaluating forest remnants in Melanesia, allowing finer-grained analyses than would be possible with vertebrate taxa commonly used to date. Our protocol should help establish other groups of hyperdiverse fauna as target taxa for community ecology. Sequencing delivers objective data on taxa of incredible diversity but mostly without a solid taxonomic foundation and should help pave the road for the eventual formal naming of new species

Post translational changes to α-synuclein control iron and dopamine trafficking : a concept for neuron vulnerability in Parkinson's disease

Parkinson's disease is a multifactorial neurodegenerative disorder, the aetiology of which remains elusive. The primary clinical feature of progressively impaired motor control is caused by a loss of midbrain substantia nigra dopamine neurons that have a high α-synuclein (α-syn) and iron content. α-Syn is a neuronal protein that is highly modified post-translationally and central to the Lewy body neuropathology of the disease. This review provides an overview of findings on the role post translational modifications to α-syn have in membrane binding and intracellular vesicle trafficking. Furthermore, we propose a concept in which acetylation and phosphorylation of α-syn modulate endocytic import of iron and vesicle transport of dopamine during normal physiology. Disregulated phosphorylation and oxidation of α-syn mediate iron and dopamine dependent oxidative stress through impaired cellular location and increase propensity for α-syn aggregation. The proposition highlights a connection between α-syn, iron and dopamine, three pathological components associated with disease progression in sporadic Parkinson's disease