| 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. |
- Ferrari, Raffaele, et al.
(författare)
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Frontotemporal dementia and its subtypes: a genome-wide association study.
- 2014
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Ingår i: Lancet Neurology. - 1474-4465. ; 13:7, s. 686-699
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Tidskriftsartikel (refereegranskat)abstract
- Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72-have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder.
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| 3. |
- Escott-Price, Valentina, et al.
(författare)
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Gene-Wide Analysis Detects Two New Susceptibility Genes for Alzheimer's Disease
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:6, s. e94661-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. Principal Findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4x10(-6)) and 14 (IGHV1-67 p = 7.9x10(-8)) which indexed novel susceptibility loci. Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
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| 4. |
- Santoro, Aurelia, et al.
(författare)
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Combating inflammaging through a Mediterranean whole diet approach : The NU-AGE project's conceptual framework and design
- 2014
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Ingår i: Mechanisms of Ageing and Development. - Clare, Ireland : Elsevier BV. - 0047-6374 .- 1872-6216. ; 136-137, s. 3-13
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Tidskriftsartikel (refereegranskat)abstract
- The development of a chronic, low grade, inflammatory status named "inflammaging" is a major characteristic of ageing, which plays a critical role in the pathogenesis of age-related diseases. Inflammaging is both local and systemic, and a variety of organs and systems contribute inflammatory stimuli that accumulate lifelong. The NU-AGE rationale is that a one year Mediterranean whole diet (considered by UNESCO a heritage of humanity), newly designed to meet the nutritional needs of the elderly, will reduce inflammaging in fully characterized subjects aged 65-79 years of age, and will have systemic beneficial effects on health status (physical and cognitive). Before and after the dietary intervention a comprehensive set of analyses, including omics (transcriptomics, epigenetics, metabolomics and metagenomics) will be performed to identify the underpinning molecular mechanisms. NU-AGE will set up a comprehensive database as a tool for a systems biology approach to inflammaging and nutrition. NU-AGE is highly interdisciplinary, includes leading research centres in Europe on nutrition and ageing, and is complemented by EU multinational food industries and SMEs, interested in the production of functional and enriched/advanced traditional food tailored for the elderly market, and European Federations targeting policy makers and major stakeholders, from consumers to EU Food & Drink Industries.
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| 5. |
- van Assema, Daniëlle ME, et al.
(författare)
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Blood-brain barrier P-glycoprotein function in healthy subjects and Alzheimer's disease patients : effect of polymorphisms in the ABCB1 gene
- 2012
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Ingår i: EJNMMI Research. - 2191-219X. ; 2
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: P-glycoprotein is a blood-brain barrier efflux transporter involved in the clearance of amyloid-beta from the brain and, as such, might be involved in the pathogenesis of Alzheimer's disease. P-glycoprotein is encoded by the highly polymorphic ABCB1 gene. Single-nucleotide polymorphisms in the ABCB1 gene have been associated with altered P-glycoprotein expression and function. P-glycoprotein function at the blood-brain barrier can be quantified in vivo using the P-glycoprotein substrate tracer (R)-[11C]verapamil and positron emission tomography (PET). The purpose of this study was to assess the effects of C1236T, G2677T/A and C3435T single-nucleotide polymorphisms in ABCB1 on blood-brain barrier P-glycoprotein function in healthy subjects and patients with Alzheimer's disease.METHODS: Thirty-two healthy subjects and seventeen patients with Alzheimer's disease underwent 60-min dynamic (R)-[11C]verapamil PET scans. The binding potential of (R)-[11C]verapamil was assessed using a previously validated constrained two-tissue plasma input compartment model and used as outcome measure. DNA was isolated from frozen blood samples and C1236T, G2677T/A and C3435T single-nucleotide polymorphisms were amplified by polymerase chain reaction.RESULTS: In healthy controls, binding potential did not differ between subjects without and with one or more T present in C1236T, G2677T and C3435T. In contrast, patients with Alzheimer's disease with one or more T in C1236T, G2677T and C3435T had significantly higher binding potential values than patients without a T. In addition, there was a relationship between binding potential and T dose in C1236T and G2677T.CONCLUSIONS: In Alzheimer's disease patients, C1236T, G2677T/A and C3435T single-nucleotide polymorphisms may be related to changes in P-glycoprotein function at the blood-brain barrier. As such, genetic variations in ABCB1 might contribute to the progression of amyloid-beta deposition in the brain.
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| 6. |
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| 7. |
- Bufano, Filomena, et al.
(författare)
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THE HIGHLY ENERGETIC EXPANSION OF SN 2010bh ASSOCIATED WITH GRB 100316D
- 2012
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Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 753:1, s. 67-
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Tidskriftsartikel (refereegranskat)abstract
- We present the spectroscopic and photometric evolution of the nearby (z = 0.059) spectroscopically confirmed Type Ic supernova, SN 2010bh, associated with the soft, long-duration gamma-ray burst (X-ray flash) GRB 100316D. Intensive follow-up observations of SN 2010bh were performed at the ESO Very Large Telescope (VLT) using the X-shooter and FORS2 instruments. Thanks to the detailed temporal coverage and the extended wavelength range (3000-24800 angstrom), we obtained an unprecedentedly rich spectral sequence among the hypernovae, making SN 2010bh one of the best studied representatives of this SN class. We find that SN 2010bh has a more rapid rise to maximum brightness (8.0 +/- 1.0 rest-frame days) and a fainter absolute peak luminosity (L-bol approximate to 3 x 10(42) erg s(-1)) than previously observed SN events associated with GRBs. Our estimate of the ejected Ni-56 mass is 0.12 +/- 0.02 M-circle dot. From the broad spectral features, we measure expansion velocities up to 47,000 km s(-1), higher than those of SNe 1998bw (GRB 980425) and 2006aj (GRB 060218). Helium absorption lines He I lambda 5876 and He I 1.083 mu m, blueshifted by similar to 20,000-30,000 km s(-1) and similar to 28,000-38,000 km s(-1), respectively, may be present in the optical spectra. However, the lack of coverage of the He I 2.058 mu m line prevents us from confirming such identifications. The nebular spectrum, taken at similar to 186 days after the explosion, shows a broad but faint [O I] emission at 6340 angstrom. The light curve shape and photospheric expansion velocities of SN 2010bh suggest that we witnessed a highly energetic explosion with a small ejected mass (E-k approximate to 10(52) erg and M-ej approximate to 3 M-circle dot). The observed properties of SN 2010bh further extend the heterogeneity of the class of GRB SNe.
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| 8. |
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| 9. |
- Valent, Peter, et al.
(författare)
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European Competence Network on Mastocytosis (ECNM) : 10-year jubilee, update, and future perspectives
- 2012
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Ingår i: Wiener Klinische Wochenschrift. - : Springer Science and Business Media LLC. - 0043-5325 .- 1613-7671. ; 124:23-24, s. 807-814
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Tidskriftsartikel (refereegranskat)abstract
- The European Competence Network on Mastocytosis (ECNM) was initiated in 2002 as a multidisciplinary and multinational cooperative approach to increase awareness and to improve diagnosis and therapy of mastocytosis. The network is composed of local centers, physicians, and scientists who have dedicated their work to patients with mastocytosis. A strategic goal of the ECNM is to provide the best available information about the disease to patients and physicians. During the past 10 years, the ECNM has expanded to various countries and contributed successfully to the development of markers, definitions, and standards in the field of mastocytosis. Members of the ECNM organized Annual Meetings in Europe and two Working Conferences on Mastocytosis in Vienna (in 2005 and 2010), and initiated and supported several preclinical and clinical trials. In all these activities, representatives of the ECNM cooperate closely with their US colleagues, with patient-organizations in Europe and in the USA, and with other scientific networks. The ECNM also launched a mastocytosis registry that has been activated in 2012. Using the central database of this registry, cooperative multicenter studies, which should include sufficient numbers of patients and robust evaluations, will be conducted. These studies will increase our knowledge about optimal management and therapy of patients with mastocytosis in the future.
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