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- 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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| 4. |
- Tragante, Vinicius, et al.
(författare)
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Gene-centric Meta-analysis in 87,736 Individuals of European Ancestry Identifies Multiple Blood-Pressure-Related Loci.
- 2014
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 94:3, s. 349-360
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Tidskriftsartikel (refereegranskat)abstract
- Blood pressure (BP) is a heritable risk factor for cardiovascular disease. To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP), we genotyped ∼50,000 SNPs in up to 87,736 individuals of European ancestry and combined these in a meta-analysis. We replicated findings in an independent set of 68,368 individuals of European ancestry. Our analyses identified 11 previously undescribed associations in independent loci containing 31 genes including PDE1A, HLA-DQB1, CDK6, PRKAG2, VCL, H19, NUCB2, RELA, HOXC@ complex, FBN1, and NFAT5 at the Bonferroni-corrected array-wide significance threshold (p < 6 × 10(-7)) and confirmed 27 previously reported associations. Bioinformatic analysis of the 11 loci provided support for a putative role in hypertension of several genes, such as CDK6 and NUCB2. Analysis of potential pharmacological targets in databases of small molecules showed that ten of the genes are predicted to be a target for small molecules. In summary, we identified previously unknown loci associated with BP. Our findings extend our understanding of genes involved in BP regulation, which may provide new targets for therapeutic intervention or drug response stratification.
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| 5. |
- Ganesh, Santhi K., et al.
(författare)
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Loci influencing blood pressure identified using a cardiovascular gene-centric array
- 2013
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 22:8, s. 1663-1678
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Tidskriftsartikel (refereegranskat)abstract
- Blood pressure (BP) is a heritable determinant of risk for cardiovascular disease (CVD). To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP) and pulse pressure (PP), we genotyped 50 000 single-nucleotide polymorphisms (SNPs) that capture variation in 2100 candidate genes for cardiovascular phenotypes in 61 619 individuals of European ancestry from cohort studies in the USA and Europe. We identified novel associations between rs347591 and SBP (chromosome 3p25.3, in an intron of HRH1) and between rs2169137 and DBP (chromosome1q32.1 in an intron of MDM4) and between rs2014408 and SBP (chromosome 11p15 in an intron of SOX6), previously reported to be associated with MAP. We also confirmed 10 previously known loci associated with SBP, DBP, MAP or PP (ADRB1, ATP2B1, SH2B3/ATXN2, CSK, CYP17A1, FURIN, HFE, LSP1, MTHFR, SOX6) at array-wide significance (P 2.4 10(6)). We then replicated these associations in an independent set of 65 886 individuals of European ancestry. The findings from expression QTL (eQTL) analysis showed associations of SNPs in the MDM4 region with MDM4 expression. We did not find any evidence of association of the two novel SNPs in MDM4 and HRH1 with sequelae of high BP including coronary artery disease (CAD), left ventricular hypertrophy (LVH) or stroke. In summary, we identified two novel loci associated with BP and confirmed multiple previously reported associations. Our findings extend our understanding of genes involved in BP regulation, some of which may eventually provide new targets for therapeutic intervention.
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| 6. |
- Ganesh, Anuradha, et al.
(författare)
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Consecutive exotropia after surgical treatment of childhood esotropia: a 40-year follow-up study
- 2011
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Ingår i: Acta Ophthalmologica. - : Wiley-Blackwell. - 1755-375X .- 1755-3768. ; 89:7, s. 691-695
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To determine the incidence of consecutive exotropia (XT) following successful surgical correction of childhood esotropia (ET) and identify factors associated with its development. less thanbrgreater than less thanbrgreater thanMaterial and Methods: This is a retrospective study of 85 patients with ET, aged 2-24, who underwent strabismus surgery by a single surgeon between 1958 and 1969 in Sweden, until they were successfully aligned to ET within 10 prism dioptre, after primary or reoperation(s). The charts of these patients were reviewed, and data regarding age at onset of strabismus, surgery performed and outcome were recorded. The patients were recalled for a complete orthoptic examination in 2001-2003. less thanbrgreater than less thanbrgreater thanResults: The incidence of consecutive XT in this cohort was 21% (18/85). Patients who had undergone multiple surgeries had a higher risk of developing consecutive XT compared to those successfully aligned with one surgery (p = 0.00036). Restriction of adduction and convergence postoperatively was associated with a high risk of consecutive XT (p = 0.0437). The incidence of consecutive XT did not vary with the level of visual acuity in the operated eye (p = 0.6428). Age of onset, age at surgery and amount of surgery did not appear to influence the risk for developing consecutive XT (p andgt; 0.05). less thanbrgreater than less thanbrgreater thanConclusion: This 40-year postoperative follow-up of patients with childhood ET who underwent strabismus surgery by a single surgeon in Sweden showed that multiple surgeries and presence of postoperative adduction deficit were the most important factors influencing the incidence of consecutive XT after surgery. Presence of uncorrected amblyopia did not alter the prognosis for long-term development of consecutive XT.
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| 7. |
- Meyer, M. L., et al.
(författare)
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Rotational properties of two-component Bose gases in the lowest Landau level
- 2014
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Ingår i: Physical Review A. Atomic, Molecular, and Optical Physics. - 1050-2947 .- 1094-1622. ; 89:4, s. 043625-
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Tidskriftsartikel (refereegranskat)abstract
- We study the rotational (yrast) spectra of dilute two-component atomic Bose gases in the low angular momentum regime, assuming equal interspecies and intraspecies interaction. Our analysis employs the composite fermion (CF) approach including a pseudospin degree of freedom. While the CF approach is not a priori expected to work well in this angular momentum regime, we show that composite fermion diagonalization gives remarkably accurate approximations to low-energy states in the spectra. For angular momenta 0 < L < M ( where N and M denote the numbers of particles of the two species, and M >= N), we find that the CF states span the full Hilbert space and provide a convenient set of basis states which, by construction, are eigenstates of the symmetries of the Hamiltonian. Within this CF basis, we identify a subset of the basis states with the lowest A-level kinetic energy. Diagonalization within this significantly smaller subspace constitutes a major computational simplification and provides very close approximations to ground states and a number of low-lying states within each pseudospin and angular momentum channel.
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| 8. |
- Umapathy, Ganesh, et al.
(författare)
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The kinase ALK stimulates the kinase ERK5 to promote the expression of the oncogene MYCN in neuroblastoma
- 2014
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Ingår i: Science Signaling. - : American Association for the Advancement of Science (AAAS). - 1945-0877 .- 1937-9145. ; 7:349
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Tidskriftsartikel (refereegranskat)abstract
- Anaplastic lymphoma kinase (ALK) is an important molecular target in neuroblastoma. Although tyrosine kinase inhibitors abrogating ALK activity are currently in clinical use for the treatment of ALK-positive (ALK(+)) disease, monotherapy with ALK tyrosine kinase inhibitors may not be an adequate solution for ALK(+) neuroblastoma patients. Increased expression of the gene encoding the transcription factor MYCN is common in neuroblastomas and correlates with poor prognosis. We found that the kinase ERK5 [also known as big mitogen-activated protein kinase (MAPK) 1 (BMK1)] is activated by ALK through a pathway mediated by phosphoinositide 3-kinase (PI3K), AKT, MAPK kinase kinase 3 (MEKK3), and MAPK kinase 5 (MEK5). ALK-induced transcription of MYCN and stimulation of cell proliferation required ERK5. Pharmacological or RNA interference-mediated inhibition of ERK5 suppressed the proliferation of neuroblastoma cells in culture and enhanced the antitumor efficacy of the ALK inhibitor crizotinib in both cells and xenograft models. Together, our results indicate that ERK5 mediates ALK-induced transcription of MYCN and proliferation of neuroblastoma, suggesting that targeting both ERK5 and ALK may be beneficial in neuroblastoma patients.
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