Analysis of neuronal iron deposits in Parkinson's disease brain tissue by synchrotron x-ray spectromicroscopy

Neuromelanin-pigmented neurons, which are highly susceptible to neurodegeneration in the Parkinson’s disease substantia nigra, harbour elevated iron levels in the diseased state. Whilst it is widely believed that neuronal iron is stored in an inert, ferric form, perturbations to normal metal homeostasis could potentially generate more reactive forms of iron capable of stimulating toxicity and cell death. However, non-disruptive analysis of brain metals is inherently challenging, since use of stains or chemical fixatives, for example, can significantly influence metal ion distributions and/or concentrations in tissues

Radio Sources in Low-Luminosity Active Galactic Nuclei. I. VLA Detections of Compact, Flat-Spectrum Cores

We report a 0.2" resolution, 15 GHz survey of a sample of 48 low-luminosity active galactic nuclei with the Very Large Array. Compact radio emission has been detected in 57% (17 of 30) of LINERs and low-luminosity Seyferts, at least 15 of which have a flat to inverted radio spectrum (alpha > -0.3). The compact radio cores are found in both type 1 (i.e. with broad Halpha) and type 2 (without broad Halpha) nuclei. The 2 cm radio power is significantly correlated with the emission-line ([OI] lambda6300) luminosity. While the present observations are consistent with the radio emission originating in star-forming regions, higher resolution radio observations of 10 of the detected sources, reported in a companion paper (Falcke et al. 2000), show that the cores are very compact (= 10^8K) and probably synchrotron self-absorbed, ruling out a starburst origin. Thus, our results suggest that at least 50% of low-luminosity Seyferts and LINERs in the sample are accretion powered, with the radio emission presumably coming from jets or advection-dominated accretion flows. We have detected only 1 of 18 `transition' (i.e. LINER + HII) nuclei observed, indicating their radio cores are significantly weaker than those of `pure' LINERs.Comment: To appear in the Astrophysical Journal, October 20, 200

Metal ion binding to the amyloid beta monomer studied by native top-down FTICR mass spectrometry

Native top-down mass spectrometry is a fast, robust biophysical technique that can provide molecular-scale information on the interaction between proteins or peptides and ligands, including metal cations. Here we have analyzed complexes of the full-length amyloid β (1-42) monomer with a range of (patho)physiologically relevant metal cations using native Fourier transform ion cyclotron resonance mass spectrometry and three different fragmentation methods—collision-induced dissociation, electron capture dissociation, and infrared multiphoton dissociation—all yielding consistent results. Amyloid β is of particular interest as its oligomerization and aggregation are major events in the etiology of Alzheimer’s disease, and it is known that interactions between the peptide and bioavailable metal cations have the potential to significantly damage neurons. Those metals which exhibited the strongest binding to the peptide (Cu2+, Co2+, Ni2+) all shared a very similar binding region containing two of the histidine residues near the N-terminus (His6, His13). Notably, Fe3+ bound to the peptide only when stabilized toward hydrolysis, aggregation, and precipitation by a chelating ligand, binding in the region between Ser8 and Gly25. We also identified two additional binding regions near the flexible, hydrophobic C-terminus, where other metals (Mg2+, Ca2+, Mn2+, Na+, and K+) bound more weakly—one centered on Leu34, and one on Gly38. Unexpectedly, collisional activation of the complex formed between the peptide and [CoIII(NH3)6]3+ induced gas-phase reduction of the metal to CoII, allowing the peptide to fragment via radical-based dissociation pathways. This work demonstrates how native mass spectrometry can provide new insights into the interactions between amyloid β and metal cations

Pharmaco-genomic investigations of organo-iridium anticancer complexes reveal novel mechanism of action

Resistance to platinum drugs (used in >50% of cancer chemotherapies) is a clinical problem. Other precious metal complexes with distinct mechanisms of action might overcome this. Half-sandwich organometallic complexes containing arene or cyclopentadienyl (Cp) ligands show promise. We screened two iridium(III) complexes [Ir(CpXbiph)(ppy)Cl] (ZL49, 1, ppy = phenylpyridine) and [Ir(CpXph)(azpyNMe2)Cl]PF6 (ZL109, 2, azpyNMe2 = N,N-dimethylphenylazopyridine) in 916 cancer cell lines from 28 tissue types. On average, complex 2 was 78× more potent than 1, 36× more active than cisplatin (CDDP), and strongly active (nanomolar) in patient-derived ovarian cancer cell lines. RNA sequencing of A2780 ovarian cells revealed upregulation of antioxidant responses (NRF2, AP-1) consistent with observed induction of reactive oxygen species (ROS). Protein microarrays, high content imaging and cell cycle analysis showed S/G2 arrest, and late-stage DNA damage response without p53 requirement. The triple-negative breast cancer cell line OCUB-M was highly sensitive to 2 as were cell lines with KIT mutations. Complex 2 exhibits a markedly different pattern of antiproliferative activity compared to the 253 drugs in the Sanger Cancer Genome database, but is most similar to osmium(II) arene complexes which share the same azopyridine ligand. Redox modulation and DNA damage can provide a multi-targeting strategy, allowing compounds such as 2 to overcome cellular resistance to platinum anticancer drugs

Narrative and Interpretation on Twitter: Reading tweets by telling stories

Existing research on communication on Twitter has largely ignored the question of how users make sense of the fragmentary tweets with which they are presented. Focusing on the use of Twitter for political reporting in post-revolutionary Egypt, this article argues that the production of mental stories provides readers with a mechanism for interpreting the meaning of individual tweets in terms of their relationships to other material. Drawing on contemporary narratology, it argues that Twitter exhibits key elements of narrativity, but that a creative reading process is nonetheless required to transform this incipient narrativity into coherent, sense-making mental narratives. This foregrounding of the reader’s creative role makes stories on Twitter highly fluid and dynamic. Through reference to classic critical theory, I propose that this nonetheless represents an evolution rather than a radical break from earlier forms of narrative reception, which in many cases demanded similarly creative reading practices

Using affective judgement to increase physical activity in British adults.

Mobile phone apps have been shown to increase physical activity (PA), but existing apps fail to target the emotional aspects of PA, which influence whether individuals are active. We developed an app that encourages individuals to focus on the emotional aspects of PA. We aimed to assess the acceptability of this app, and conduct a preliminary evaluation of efficacy. The app was developed in collaboration with users through focus groups. Seven users tested the app over 4 months and provided feedback on acceptability, aesthetics and functionality in a follow-up focus group. Results were summarized descriptively. Before testing the app, participants completed a questionnaire assessing their current PA and psychological antecedents of PA. A second questionnaire was completed at the follow-up focus group. Change scores are reported for each participant and overall. The social and reminder aspects facilitated motivation to be active and many found it easy to integrate into their lives. Most suggested modifications. Small improvements in number of minutes spent walking per week were observed (overall mean change +25 min) and some psychological antecedents of PA (overall mean change for social support for PA +0.14, self-efficacy for PA +0.17, outcome expectations about PA +0.20; all five-point scales), but reductions were seen in other domains. The app was acceptable to users, although developments are required. Testing with a small number of individuals, offering preliminary evidence of efficacy of this app, provides justification for further evaluation on a larger scale

Attainment of clinical performance targets and improvement in clinical outcomes and resource use in hemodialysis care: a prospective cohort study

BACKGROUND: Clinical performance targets are intended to improve patient outcomes in chronic disease through quality improvement, but evidence of an association between multiple target attainment and patient outcomes in routine clinical practice is often lacking. METHODS: In a national prospective cohort study (ESRD Quality, or EQUAL), we examined whether attainment of multiple targets in 668 incident hemodialysis patients from 74 U.S. not-for-profit dialysis clinics was associated with better outcomes. We measured whether the following accepted clinical performance targets were met at 6 months after study enrollment: albumin (≥4.0 g/dl), hemoglobin (≥11 g/dl), calcium-phosphate product (<55 mg(2)/dl(2)), dialysis dose (Kt/V≥1.2), and vascular access type (fistula). Outcomes included mortality, hospital admissions, hospital days, and hospital costs. RESULTS: Attainment of each of the five targets was associated individually with better outcomes; e.g., patients who attained the albumin target had decreased mortality [relative hazard (RH) = 0.55, 95% confidence interval (CI), 0.41–0.75], hospital admissions [incidence rate ratio (IRR) = 0.67, 95% CI, 0.62–0.73], hospital days (IRR = 0.61, 95% CI, 0.58–0.63), and hospital costs (average annual cost reduction = $3,282, P = 0.002), relative to those who did not. Increasing numbers of targets attained were also associated, in a graded fashion, with decreased mortality (P = 0.030), fewer hospital admissions and days (P < 0.001 for both), and lower costs (P = 0.029); these trends remained statistically significant for all outcomes after adjustment (P < 0.001), except cost, which was marginally significant (P = 0.052). CONCLUSION: Attainment of more clinical performance targets, regardless of which targets, was strongly associated with decreased mortality, hospital admissions, and resource use in hemodialysis patients

Does urbanization explain differences in interactions between an insect herbivore and its natural enemies and mutualists?

Urbanization can alter the composition of arthropod communities. However, little is known about how urbanization affects ecological interactions. Using experimental colonies of the black bean aphid Aphis fabae Scopoli reared on Vicia faba L, we asked if patterns of predator-prey, host-parasitoid and ant-aphid mutualisms varied along an urbanization gradient across a large town in southern England. We recorded the presence of naturally occurring predators, parasitoid wasps and mutualistic ants together with aphid abundance. We examined how biotic (green areas and plant richness) and abiotic features (impervious surfaces and distance to town center) affected (1) aphid colony size, (2) the likelihood of finding predators, mutualistic ants and aphid mummies (indicating the presence of parasitoids), and (3) how the interplay among these factors affected patterns of parasitoid attack, predator abundance, mutualistic interactions and aphid abundance. The best model to predict aphid abundance was the number of mutualistic ants attending the colonies. Aphid predators responded negatively to both the proportion of impervious surfaces and to the number of mutualistic ants farming the colonies, and positively to aphid population size, whereas parasitized aphids were found in colonies with higher numbers of aphids and ants. The number of mutualistic ants attending was positively associated with aphid colony size and negatively with the number of aphid predators. Our findings suggest that for insect-natural enemy interactions, urbanization may affect some groups, while not influencing others, and that local effects (mutualists, host plant presence) will also be key determinants of how urban ecological communities are formed