| 1. |
- Klionsky, Daniel J., et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Forskningsöversikt (refereegranskat)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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| 2. |
- Agarwal, Suresh K., et al.
(författare)
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A pilot study assessing the bioavailability and pharmacokinetics of diazepam after intranasal and intravenous administration in healthy volunteers
- 2013
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Ingår i: Epilepsy Research. - : Elsevier BV. - 0920-1211 .- 1872-6844. ; 105:3, s. 362-367
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Tidskriftsartikel (refereegranskat)abstract
- Diazepam rectal gel (Diastat (R)) is the only FDA-approved product indicated for acute repetitive seizures. Despite its proven efficacy, most older children and adults object to this route of administration. As a result, many patients do not realize the benefit of a therapy that can improve outcomes and decrease healthcare costs. Intranasal administration of benzodiazepines offers a potential alternative. The primary objective of this study was to compare the bioavailability and pharmacokinetics of two novel intranasal (IN) diazepam (DZP) formulations versus intravenous (IV) administration in healthy volunteers. Twenty-four healthy volunteers were randomized into an open-label, three-way crossover study. 10 mg doses of two investigational intranasal DZP formulations (solution, suspension) and a 5 mg IV dose of commercially available DZP injectable, USP were given. A two-week washout period separated treatments. Plasma samples for DZP analysis were collected pre-dose and at regular intervals up to 240 h post-dose. DZP concentration-time data were analyzed using a non-compartmental pharmacokinetics approach. Exposure following administration of DZP IN solution (absolute bioavailability - 97%) was greater than the IN suspension (absolute bioavailability - 67%). Mean C-max values for the suspension and solution formulations were 221 ng/mL and 272 ng/mL, respectively. Median time to maximum concentration (T-max) was 1 h and 1.5 h for suspension and solution formulation, respectively. Both investigational intranasal formulations were well tolerated. The results of this pilot study indicate that development of an intranasal diazepam formulation with high bioavailability, reasonable variability, and good tolerability is feasible.
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| 3. |
- Bosch, Carme, et al.
(författare)
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Source-diagnostic dual-isotope composition and optical properties of water-soluble organic carbon and elemental carbon in the South Asian outflow intercepted over the Indian Ocean
- 2014
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Ingår i: Journal of Geophysical Research - Atmospheres. - 2169-897X .- 2169-8996. ; 119:20, s. 11743-11759
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Tidskriftsartikel (refereegranskat)abstract
- The dual carbon isotope signatures and optical properties of carbonaceous aerosols have been investigated simultaneously for the first time in the South Asian outflow during an intensive campaign at the Maldives Climate Observatory on Hanimaadhoo (MCOH) (February and March 2012). As one component of the Cloud Aerosol Radiative Forcing Dynamics Experiment, this paper reports on the sources and the atmospheric processing of elemental carbon (EC) and water-soluble organic carbon (WSOC) as examined by a dual carbon isotope approach. The radiocarbon (C-14) data show that WSOC has a significantly higher biomass/biogenic contribution (865%) compared to EC (594%). The more C-13-enriched signature of MCOH-WSOC (-20.80.7) compared to MCOH-EC (-25.8 +/- 0.3 parts per thousand) and megacity Delhi WSOC (-24.1 +/- 0.9 parts per thousand) suggests that WSOC is significantly more affected by aging during long-range transport than EC. The C-13-C-14 signal suggests that the wintertime WSOC intercepted over the Indian Ocean largely represents aged primary biomass burning aerosols. Since light-absorbing organic carbon aerosols (Brown Carbon (BrC)) have recently been identified as potential contributors to positive radiative forcing, optical properties of WSOC were also investigated. The mass absorption cross section of WSOC (MAC(365)) was 0.5 +/- 0.2 m(2)g(-1) which is lower than what has been observed at near-source sites, indicating a net decrease of WSOC light-absorption character during long-range transport. Near-surface WSOC at MCOH accounted for similar to 1% of the total direct solar absorbance relative to EC, which is lower than the BrC absorption inferred from solar spectral observations of ambient aerosols, suggesting that a significant portion of BrC might be included in the water-insoluble portion of organic aerosols.
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| 4. |
- Destouni, Georgia, et al.
(författare)
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Hydro-Biogeochemical and Environmental-Management Functions of Wetland Networks in Landscapes
- 2012
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Ingår i: 9th INTECOL International Wetlands Conference, Wetlands in a Complex World. ; , s. 915-
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- A main application goal of ecohydrological science is to amplify opportunities of achieving water quality improvements, biodiversity enhancements and sustainable development, by improved understanding and use of ecosystem properties as a management tool. This paper draws on and synthesizes main result implications for the function and possible enhanced use of wetland networks in the landscape as such a tool, from a series of hydro-biogeochemical and environmental economics studies of nutrient/pollutant loading and abatement in different Swedish hydrological catchments. Results show large potential of wetland networks to reduce the cost of abating nutrient and metal loads within and from hydrological catchments, and emphasize some main research questions for further investigations of actual possibilities to realize this potential. The questions regard in particular the ability of wetland networks to extend the travel times and reduce the uncertainty of hydrological nutrient/pollutant transport through catchments.The paper further presents and discusses some main joint conclusions of the participants in a recently held International Workshop on Ecohydrology and Integrated Water Resource Management (1) at the Navarino Environmental Observatory in Messinia, Greece (2), regarding essential goals for collaborative international efforts in wetland network research. The goals include to investigate on different spatiotemporal scales and in different world regions: a) the dynamics of natural and managed wetland networks across a gradient of different climate, human disturbance, energy and organization conditions; b) the reciprocal interactions between wetland networks and associated hydrological catchments; c) how climate change and different human activities in the wetland network catchments influence these interactions (in b) and generally the ecohydrology of individual wetlands and the whole wetland networks; and d) the ecosystem services provided by networks of wetlands.
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| 5. |
- Ellinghaus, David, et al.
(författare)
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Association between variants of PRDM1 and NDP52 and Crohn's disease, based on exome sequencing and functional studies
- 2013
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Ingår i: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 145:2, s. 339-347
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: Genome-wide association studies (GWAS) have identified 140 Crohn's disease (CD) susceptibility loci. For most loci, the variants that cause disease are not known and the genes affected by these variants have not been identified. We aimed to identify variants that cause CD through detailed sequencing, genetic association, expression, and functional studies.METHODS: We sequenced whole exomes of 42 unrelated subjects with CD and 5 healthy subjects (controls) and then filtered single nucleotide variants by incorporating association results from meta-analyses of CD GWAS and in silico mutation effect prediction algorithms. We then genotyped 9348 subjects with CD, 2868 subjects with ulcerative colitis, and 14,567 control subjects and associated variants analyzed in functional studies using materials from subjects and controls and in vitro model systems.RESULTS: We identified rare missense mutations in PR domain-containing 1 (PRDM1) and associated these with CD. These mutations increased proliferation of T cells and secretion of cytokines on activation and increased expression of the adhesion molecule L-selectin. A common CD risk allele, identified in GWAS, correlated with reduced expression of PRDM1 in ileal biopsy specimens and peripheral blood mononuclear cells (combined P = 1.6 x 10(-8)). We identified an association between CD and a common missense variant, Val248Ala, in nuclear domain 10 protein 52 (NDP52) (P = 4.83 x 10(-9)). We found that this variant impairs the regulatory functions of NDP52 to inhibit nuclear factor kappa B activation of genes that regulate inflammation and affect the stability of proteins in Toll-like receptor pathways.CONCLUSIONS: We have extended the results of GWAS and provide evidence that variants in PRDM1 and NDP52 determine susceptibility to CD. PRDM1 maps adjacent to a CD interval identified in GWAS and encodes a transcription factor expressed by T and B cells. NDP52 is an adaptor protein that functions in selective autophagy of intracellular bacteria and signaling molecules, supporting the role of autophagy in the pathogenesis of CD.
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| 6. |
- Nagaraju, D H., et al.
(författare)
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Green Chemistry Route to the Synthesis of Palladium Nanoparticles on Reduced Graphene Oxide for Ethanol Fuel Cells Applications
- 2012
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Ingår i: ECS ELECTROCHEMISTRY LETTERS. - : Electrochemical Society. - 2162-8726 .- 2162-8734. ; 1:3, s. F21-F23
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Tidskriftsartikel (refereegranskat)abstract
- In this article, we have demonstrated the synthesis of palladium nanoparticles decorated on reduced graphene oxide (RGO-Pd NPs) film via green chemistry route, one pot electrochemical reduction of graphene oxide and palladium ions without using any chemical reducing agents. Cyclic voltammetry in acid medium shows the characteristic nanosized palladium nanoparticles. The RGO-Pd NPs poses very high electrochemically active surface area and shows good catalytic properties for the elctrooxidation of ethanol in alkaline medium.
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| 7. |
- Orwoll, Eric, et al.
(författare)
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A Randomized, Placebo-Controlled Study of the Effects of Denosumab for the Treatment of Men with Low Bone Mineral Density
- 2012
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 97:9, s. 3161-3169
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Tidskriftsartikel (refereegranskat)abstract
- Context: Men with low bone mineral density (BMD) were treated with denosumab.Objective: Our objective was to investigate the effects of denosumab compared with placebo in men with low BMD after 1 yr of treatment.Design, Subjects, and Intervention: This was a placebo-controlled, phase 3 study to investigate the efficacy and safety of denosumab 60 mg every 6 months vs. placebo in men with low BMD.Main Outcome Measure: The primary endpoint was the percent change from baseline in lumbar spine (LS) BMD at month 12.Results: Of the 242 randomized subjects (mean age 65 yr), 228 (94.2%) completed 1 yr of denosumab therapy. After 12 months, denosumab resulted in BMD increases of 5.7% at the LS, 2.4% at the total hip, 2.1% at the femoral neck, 3.1% at the trochanter, and 0.6% at the one third radius (adjusted P <= 0.0144 for BMD percent differences at all sites compared with placebo). Sensitivity analyses done by controlling for baseline covariates (such as baseline testosterone levels, BMD T-scores, and 10-yr osteoporotic fracture risk) demonstrated that the results of the primary endpoint were robust. Subgroup analyses indicate that treatment with denosumab was effective across a spectrum of clinical situations. Treatment with denosumab significantly reduced serum CTX levels at d 15 (adjusted P < 0.0001). The incidence of adverse events was similar between groups.Conclusions: One year of denosumab therapy in men with low BMD was well tolerated and resulted in a reduction in bone resorption and significant increases in BMD at all skeletal sites assessed.
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