| 1. |
- Klionsky, Daniel J., et al.
(author)
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Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes
- 2008
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In: Autophagy. - : Landes Bioscience. - 1554-8627 .- 1554-8635. ; 4:2, s. 151-175
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Research review (peer-reviewed)abstract
- Research in autophagy continues to accelerate,1 and as a result many new scientists are entering the field. Accordingly, it is important to establish a standard set of criteria for monitoring macroautophagy in different organisms. Recent reviews have described the range of assays that have been used for this purpose.2,3 There are many useful and convenient methods that can be used to monitor macroautophagy in yeast, but relatively few in other model systems, and there is much confusion regarding acceptable methods to measure macroautophagy in higher eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers of autophagosomes versus those that measure flux through the autophagy pathway; thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from fully functional autophagy that includes delivery to, and degradation within, lysosomes (in most higher eukaryotes) or the vacuole (in plants and fungi). Here, we present a set of guidelines for the selection and interpretation of the methods that can be used by investigators who are attempting to examine macroautophagy and related processes, as well as by reviewers who need to provide realistic and reasonable critiques of papers that investigate these processes. This set of guidelines is 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 verify an autophagic response.
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| 2. |
- Zeggini, Eleftheria, et al.
(author)
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Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes
- 2008
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 40:5, s. 638-645
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Journal article (peer-reviewed)abstract
- Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly but reproducibly influence risk of type 2 diabetes (T2D)(1-11). Established associations to common and rare variants explain only a small proportion of the heritability of T2D. As previously published analyses had limited power to identify variants with modest effects, we carried out meta-analysis of three T2D GWA scans comprising 10,128 individuals of European descent and similar to 2.2 million SNPs (directly genotyped and imputed), followed by replication testing in an independent sample with an effective sample size of up to 53,975. We detected at least six previously unknown loci with robust evidence for association, including the JAZF1 (P=5.0 x 10(-14)), CDC123-CAMK1D (P=1.2 x 10(-10)), TSPAN8-LGR5 (P=1.1 x 10(-9)), THADA (P=1.1 x 10(-9)), ADAMTS9 (P=1.2 x 10(-8)) and NOTCH2 (P=4.1 x 10(-8)) gene regions. Our results illustrate the value of large discovery and follow-up samples for gaining further insights into the inherited basis of T2D.
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| 3. |
- Clocchiatti, Alejandro, et al.
(author)
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Late-time HST photometry of SN1994I : Hints of positron annihilation energy deposition
- 2008
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In: Publications of the Astronomical Society of the Pacific. - : IOP Publishing. - 0004-6280 .- 1538-3873. ; 120:865, s. 290-300
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Journal article (peer-reviewed)abstract
- We present multicolor Hubble Space Telescope ( HST) WFPC2 broadband observations of the Type Ic SN 1994I obtained similar to 280 d after maximum light. We measure the brightness of the SN and, relying on the detailed spectroscopic database of SN 1994I, we transform the ground-based photometry obtained at early times to the HST photometric system, deriving light curves for the WFPC2 F439W, F555W, F675W, and F814W passbands that extend from 7 days before to 280 days after maximum. We use the multicolor photometry to build a quasi-bolometric light curve of SN 1994I, and compare it with similarly constructed light curves of other supernovae. In doing so, we propose and test a scaling in energy and time that allows for a more meaningful comparison of the exponential tails of different events. Through comparison with models, we find that the late-time light curve of SN 1994I is consistent with that of spherically symmetric ejecta in homologous expansion, for which the ability to trap the gamma-rays produced by the radioactive decay of Co-56 diminishes roughly as the inverse of time squared. We also find that by the time of the HST photometry, the light curve was significantly energized by the annihilation of positrons.
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| 4. |
- O'Connor, Daniel T., et al.
(author)
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Heritability and genome-wide linkage in US and australian twins identify novel genomic regions controlling chromogranin a : implications for secretion and blood pressure
- 2008
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In: Circulation. - 0009-7322 .- 1524-4539. ; 118:3, s. 247-57
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Journal article (peer-reviewed)abstract
- BACKGROUND: Chromogranin A (CHGA) triggers catecholamine secretory granule biogenesis, and its catestatin fragment inhibits catecholamine release. We approached catestatin heritability using twin pairs, coupled with genome-wide linkage, in a series of twin and sibling pairs from 2 continents. METHODS AND RESULTS: Hypertensive patients had elevated CHGA coupled with reduction in catestatin, suggesting diminished conversion of precursor to catestatin. Heritability for catestatin in twins was 44% to 60%. Six hundred fifteen nuclear families yielded 870 sib pairs for linkage, with significant logarithm of odds peaks on chromosomes 4p, 4q, and 17q. Because acidification of catecholamine secretory vesicles determines CHGA trafficking and processing to catestatin, we genotyped at positional candidate ATP6N1, bracketed by peak linkage markers on chromosome 17q, encoding a subunit of vesicular H(+)-translocating ATPase. The minor allele diminished CHGA secretion and processing to catestatin. The ATP6N1 variant also influenced blood pressure in 1178 individuals with the most extreme blood pressure values in the population. In chromaffin cells, inhibition of H(+)-ATPase diverted CHGA from regulated to constitutive secretory pathways. CONCLUSIONS: We established heritability of catestatin in twins from 2 continents. Linkage identified 3 regions contributing to catestatin, likely novel determinants of sympathochromaffin exocytosis. At 1 such positional candidate (ATP6N1), variation influenced CHGA secretion and processing to catestatin, confirming the mechanism of a novel trans-QTL for sympathochromaffin activity and blood pressure.
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| 5. |
- Sage, Rebecca S., et al.
(author)
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Quadrupole mass spectrometry and time-of-flight analysis of ions resulting from 532 nm pulsed laser ablation of Ni, Al, and ZnO targets
- 2008
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In: Journal of Applied Physics. - : American Institute of Physics (AIP). - 0021-8979 .- 1089-7550. ; 103:9
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Journal article (peer-reviewed)abstract
- This work describes the design and validation of an instrument to measure the kinetic energies of ions ejected by the pulsed laser ablation (PLA) of a solid target. Mass spectra show that the PLA of Ni, Al, and ZnO targets, in vacuum, using the second harmonic of a Nd:YAG laser (532 nm, pulse duration similar to 10 ns) generates abundant X(n+) ions (n <= 3 for Ni, <= 2 for Al, <= 3 and <= 2 for Zn and O respectively from ZnO). Ions are selected by their mass/charge (m/z) ratio prior to the determination of their times of flight. PLA of Ni has been studied in most detail. The mean velocities of ablated Ni(n+) ions are shown to follow the trend v(Ni(3+))>v(Ni(2+))>v(Ni(+)). Data from Ni(2+) and Ni(3+) are fitted to shifted Maxwellian functions and agree well with a model which assumes both thermal and Coulombic contributions to ion velocities. The dependence of ion velocities on laser pulse energy (and fluence) is investigated, and the high energy data are shown to be consistent with an effective accelerating voltage of similar to 90 V within the plume. The distribution of velocities associated with Ni(3+) indicates a population at cooler temperature than Ni(2+).
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