Redox Couples of Inducible Nitric Oxide Synthase

We report direct electrochemistry of the iNOS heme domain in a DDAB film on the surface of a basal plane graphite electrode. Cyclic voltammetry reveals Fe^(III/II) and Fe^(II/I) couples at −191 and −1049 mV (vs Ag/AgCl). Imidazole and carbon monoxide in solution shift the Fe^(III/II) potential by +20 and +62 mV, while the addition of dioxygen results in large catalytic waves at the onset of Fe^(III) reduction. Voltammetry at higher scan rates (with pH variations) reveals that the Fe^(III/II) cathodic peak can be resolved into two components, which are attributable to Fe^(III/II) couples of five- and six-coordinate hemes. Digital simulation of our experimental data implicates water dissociation from the heme as a gating mechanism for ET in iNOS

Functional outcome and muscle wasting in adults with tetanus.

BACKGROUND: In many countries, in-hospital survival from tetanus is increasing, but long-term outcome is unknown. In high-income settings, critical illness is associated with muscle wasting and poor functional outcome, but there are few data from resource-limited settings. In this study we aimed to assess muscle wasting and long-term functional outcome in adults with tetanus. METHODS: In a prospective observational study involving 80 adults with tetanus, sequential rectus femoris ultrasound measurements were made at admission, 7 days, 14 days and hospital discharge. Functional outcome was assessed at hospital discharge using the Timed Up and Go test, Clinical Frailty Score, Barthel Index and RAND 36-item Short Form Health Survey (SF-36) and 3 and 6 months after discharge using the SF-36 and Barthel Index. RESULTS: Significant muscle wasting occurred between hospital admission and discharge (p70 y of age, functional recovery at 6 months was reduced compared with younger patients. Hospital-acquired infection and age were risk factors for muscle wasting. CONCLUSIONS: Significant muscle wasting during hospitalization occurred in patients with tetanus, the extent of which correlates with functional outcome

In situ detection of boron by ChemCam on Mars

We report the first in situ detection of boron on Mars. Boron has been detected in Gale crater at levels Curiosity rover ChemCam instrument in calcium-sulfate-filled fractures, which formed in a late-stage groundwater circulating mainly in phyllosilicate-rich bedrock interpreted as lacustrine in origin. We consider two main groundwater-driven hypotheses to explain the presence of boron in the veins: leaching of borates out of bedrock or the redistribution of borate by dissolution of borate-bearing evaporite deposits. Our results suggest that an evaporation mechanism is most likely, implying that Gale groundwaters were mildly alkaline. On Earth, boron may be a necessary component for the origin of life; on Mars, its presence suggests that subsurface groundwater conditions could have supported prebiotic chemical reactions if organics were also present and provides additional support for the past habitability of Gale crater

Rheumatoid synovial fluid interleukin-17-producing CD4 T cells have abundant tumor necrosis factor-alpha co-expression, but little interleukin-22 and interleukin-23R expression

Introduction\ud Th17 cells have been implicated in the pathogenesis of rheumatoid arthritis (RA). The aim of this study was to systematically analyse the phenotype, cytokine profile and frequency of interleukin-17 (IL-17) producing CD4-positive T cells in mononuclear cells isolated from peripheral blood, synovial fluid and synovial tissue of RA patients with established disease, and to correlate cell frequencies with disease activity. \ud \ud Methods\ud Flow cytometry was used to analyse the phenotype and cytokine production of mononuclear cells isolated from peripheral blood (PBMC) (n = 44), synovial fluid (SFMC) (n = 14) and synovium (SVMC) (n = 10) of RA patients and PBMC of healthy controls (n = 13). \ud \ud Results\ud The frequency of IL-17-producing CD4 T cells was elevated in RA SFMC compared with RA PBMC (P = 0.04). However, the frequency of this population in RA SVMC was comparable to that in paired RA PBMC. The percentage of IL-17-producing CD4 T cells coexpressing tumor necrosis factor alpha (TNFα) was significantly increased in SFMC (P = 0.0068). The frequency of IFNγ-producing CD4 T cells was also significantly higher in SFMC than paired PBMC (P = 0.042). The majority of IL-17-producing CD4 T cells coexpressed IFNγ. IL-17-producing CD4 T cells in RA PBMC and SFMC exhibited very little IL-22 or IL-23R coexpression. \ud \ud Conclusions\ud These findings demonstrate a modest enrichment of IL-17-producing CD4 T cells in RA SFMC compared to PBMC. Th17 cells in SFMC produce more TNFα than their PBMC counterparts, but are not a significant source of IL-22 and do not express IL-23R. However, the percentage of CD4 T cells which produce IL-17 in the rheumatoid joint is low, suggesting that other cells may be alternative sources of IL-17 within the joints of RA patients. \ud \u

Prime Focus Spectrograph (PFS) for the Subaru Telescope: Overview, recent progress, and future perspectives

PFS (Prime Focus Spectrograph), a next generation facility instrument on the 8.2-meter Subaru Telescope, is a very wide-field, massively multiplexed, optical and near-infrared spectrograph. Exploiting the Subaru prime focus, 2394 reconfigurable fibers will be distributed over the 1.3 deg field of view. The spectrograph has been designed with 3 arms of blue, red, and near-infrared cameras to simultaneously observe spectra from 380nm to 1260nm in one exposure at a resolution of ~1.6-2.7A. An international collaboration is developing this instrument under the initiative of Kavli IPMU. The project is now going into the construction phase aiming at undertaking system integration in 2017-2018 and subsequently carrying out engineering operations in 2018-2019. This article gives an overview of the instrument, current project status and future paths forward.Comment: 17 pages, 10 figures. Proceeding of SPIE Astronomical Telescopes and Instrumentation 201

Circuit dissection of the role of somatostatin in itch and pain

Stimuli that elicit itch are detected by sensory neurons that innervate the skin. This information is processed by the spinal cord; however, the way in which this occurs is still poorly understood. Here we investigated the neuronal pathways for itch neurotransmission, particularly the contribution of the neuropeptide somatostatin. We find that in the periphery, somatostatin is exclusively expressed in Nppb+ neurons, and we demonstrate that Nppb+somatostatin+ cells function as pruriceptors. Employing chemogenetics, pharmacology and cell-specific ablation methods, we demonstrate that somatostatin potentiates itch by inhibiting inhibitory dynorphin neurons, which results in disinhibition of GRPR+ neurons. Furthermore, elimination of somatostatin from primary afferents and/or from spinal interneurons demonstrates differential involvement of the peptide released from these sources in itch and pain. Our results define the neural circuit underlying somatostatin-induced itch and characterize a contrasting antinociceptive role for the peptide

Efficacy of the New Neuraminidase Inhibitor CS-8958 against H5N1 Influenza Viruses

Currently, two neuraminidase (NA) inhibitors, oseltamivir and zanamivir, which must be administrated twice daily for 5 days for maximum therapeutic effect, are licensed for the treatment of influenza. However, oseltamivir-resistant mutants of seasonal H1N1 and highly pathogenic H5N1 avian influenza A viruses have emerged. Therefore, alternative antiviral agents are needed. Recently, a new neuraminidase inhibitor, R-125489, and its prodrug, CS-8958, have been developed. CS-8958 functions as a long-acting NA inhibitor in vivo (mice) and is efficacious against seasonal influenza strains following a single intranasal dose. Here, we tested the efficacy of this compound against H5N1 influenza viruses, which have spread across several continents and caused epidemics with high morbidity and mortality. We demonstrated that R-125489 interferes with the NA activity of H5N1 viruses, including oseltamivir-resistant and different clade strains. A single dose of CS-8958 (1,500 µg/kg) given to mice 2 h post-infection with H5N1 influenza viruses produced a higher survival rate than did continuous five-day administration of oseltamivir (50 mg/kg twice daily). Virus titers in lungs and brain were substantially lower in infected mice treated with a single dose of CS-8958 than in those treated with the five-day course of oseltamivir. CS-8958 was also highly efficacious against highly pathogenic H5N1 influenza virus and oseltamivir-resistant variants. A single dose of CS-8958 given seven days prior to virus infection also protected mice against H5N1 virus lethal infection. To evaluate the improved efficacy of CS-8958 over oseltamivir, the binding stability of R-125489 to various subtypes of influenza virus was assessed and compared with that of other NA inhibitors. We found that R-125489 bound to NA more tightly than did any other NA inhibitor tested. Our results indicate that CS-8958 is highly effective for the treatment and prophylaxis of infection with H5N1 influenza viruses, including oseltamivir-resistant mutants

An exploration of patient-reported symptoms in systemic lupus erythematosus and the relationship to health-related quality of life

Objective: The aim of this study was to explore the most distressing symptoms of systemic lupus erythematosus (SLE) and determine how these relate to health-related quality of life (HRQoL), anxiety/depression, patient demographics and disease characteristics (duration, activity, organ damage). Methods: In a cross-sectional study, patients with SLE (n=324, age 18-84 years) gave written responses regarding which SLE-related symptoms they experienced as most difficult. Their responses were categorized. Within each category, patients reporting a specific symptom were compared with non-reporters and analyzed for patient demographics, disease duration, results from the questionnaires: Medical Outcomes Study Short-Form 36, Hospital Anxiety and Depression Scale, Systemic Lupus Activity Measure, SLE disease activity index and the Systemic Lupus International Collaboration Clinics/American College of Rheumatology damage index. Results: 23 symptom categories were identified. Fatigue (51%), Pain (50%) and Musculoskeletal distress (46%) were most frequently reported. Compared with non-reporters, only patients reporting Fatigue showed statistically significant impact on both mental and physical components of HRQoL.. Patients with no present symptoms (10%) had higher HRQoL (p<0.001) and lower levels of depression (p<0.001), anxiety (p<0.01) and disease activity (SLAM) (p<0.001). Conclusion: Fatigue, pain or musculoskeletal distress dominated the reported symptoms in approximately half of the patients. Only patients reporting Fatigue scored lower on both mental and physical aspects of HRQoL. Our results emphasize the need for further support and interventions to ease the symptom load and improve HRQoL in patients with SLE. Our findings further indicate that this need is particularly urgent for patients with symptoms of pain or fatigue

Geochemical and mineralogical indicators for aqueous processes in the Columbia Hills of Gusev crater, Mars

Water played a major role in the formation and alteration of rocks and soils in the Columbia Hills. The extent of alteration ranges from moderate to extensive. Five distinct rock compositional classes were identified; the order for degree of alteration is Watchtower = Clovis &gt;Wishstone = Peace &gt; Backstay. The rover&rsquo;s wheels uncovered one unusual soil (Paso Robles) that is the most S-rich material encountered. Clovis class rocks have compositions similar to Gusev plains soil but with higher Mg, Cl, and Br and lower Ca and Zn; Watchtower and Wishstone classes have high Al, Ti, and P and low Cr and Ni; Peace has high Mg and S and low Al, Na, and K; Backstay basalts have high Na and K compared to plains Adirondack basalts; and Paso Robles soil has high S and P. Some rocks are corundum-normative, indicating that their primary compositions were changed by loss and/or gain of rock-forming elements. Clovis materials consist of magnetite, nanophase ferric-oxides (npOx), hematite, goethite, Ca-phosphates, Ca- and Mg-sulfates, pyroxene, and secondary aluminosilicates. Wishstone and Watchtower rocks consist of Fe-oxides/oxyhydroxides, ilmenite, Ca-phosphate, pyroxene, feldspar, Mg-sulfates, and secondary aluminosilicates. Peace consists of magnetite, npOx, Mg- and Ca-sulfates, pyroxene, olivine, feldspar, apatite, halides, and secondary aluminosilicates. Paso Robles consists of Fe3+-, Mg-, Ca-, and other sulfates, Ca-phosphates, hematite, halite, allophane, and amorphous silica. Columbia Hills outcrops and rocks may have formed by the aqueous alteration of basaltic rocks, volcaniclastic materials, and/or impact ejecta by solutions that were rich in acid-volatile elements