| 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. |
- Speliotes, Elizabeth K., et al.
(författare)
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Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 937-948
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ~2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10−8), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
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| 3. |
- Kirchhoff, Tomas, et al.
(författare)
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Breast cancer risk and 6q22.33 : combined results from Breast Cancer Association Consortium and Consortium of Investigators on Modifiers of BRCA1/2
- 2012
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Ingår i: PLOS ONE. - : Public library of science. - 1932-6203. ; 7:6
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Tidskriftsartikel (refereegranskat)abstract
- Recently, a locus on chromosome 6q22.33 (rs2180341) was reported to be associated with increased breast cancer risk in the Ashkenazi Jewish (AJ) population, and this association was also observed in populations of non-AJ European ancestry. In the present study, we performed a large replication analysis of rs2180341 using data from 31,428 invasive breast cancer cases and 34,700 controls collected from 25 studies in the Breast Cancer Association Consortium (BCAC). In addition, we evaluated whether rs2180341 modifies breast cancer risk in 3,361 BRCA1 and 2,020 BRCA2 carriers from 11 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Based on the BCAC data from women of European ancestry, we found evidence for a weak association with breast cancer risk for rs2180341 (per-allele odds ratio (OR) = 1.03, 95% CI 1.00-1.06, p = 0.023). There was evidence for heterogeneity in the ORs among studies (I(2) = 49.3%; p = <0.004). In CIMBA, we observed an inverse association with the minor allele of rs2180341 and breast cancer risk in BRCA1 mutation carriers (per-allele OR = 0.89, 95%CI 0.80-1.00, p = 0.048), indicating a potential protective effect of this allele. These data suggest that that 6q22.33 confers a weak effect on breast cancer risk.
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| 4. |
- Stevens, Kristen N, et al.
(författare)
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19p13.1 is a triple negative-specific breast cancer susceptibility locus
- 2012
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 72, s. 1795-
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Tidskriftsartikel (refereegranskat)abstract
- The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with risk of ovarian cancer. Here we investigated 19p13.1 variation and risk of breast cancer subtypes, defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status, using 48,869 breast cancer cases and 49,787 controls from the Breast Cancer Association Consortium (BCAC). Variants from 19p13.1 were not associated with breast cancer overall or with ER-positive breast cancer but were significantly associated with ER-negative breast cancer risk [rs8170 Odds Ratio (OR)=1.10, 95% Confidence Interval (CI) 1.05 - 1.15, p=3.49 x 10-5] and triple negative (TN) (ER, PR and HER2 negative) breast cancer [rs8170 OR=1.22, 95% CI 1.13 - 1.31, p=2.22 x 10-7]. However, rs8170 was no longer associated with ER-negative breast cancer risk when TN cases were excluded [OR=0.98, 95% CI 0.89 - 1.07, p=0.62]. In addition, a combined analysis of TN cases from BCAC and the Triple Negative Breast Cancer Consortium (TNBCC) (n=3,566) identified a genome-wide significant association between rs8170 and TN breast cancer risk [OR=1.25, 95% CI 1.18 - 1.33, p=3.31 x 10-13]. Thus, 19p13.1 is the first triple negative-specific breast cancer risk locus and the first locus specific to a histological subtype defined by ER, PR, and HER2 to be identified. These findings provide convincing evidence that genetic susceptibility to breast cancer varies by tumor subtype and that triple negative tumors and other subtypes likely arise through distinct etiologic pathways.
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| 5. |
- Alm, Ann-Sophie, et al.
(författare)
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Variation of lipopolysaccharide-induced acute lung injury in eight strains of mice.
- 2010
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Ingår i: Respiratory Physiology & Neurobiology. - : Elsevier BV. - 1878-1519 .- 1569-9048. ; 171, s. 157-164
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Tidskriftsartikel (refereegranskat)abstract
- Clinical and experimental evidence suggests that genetic variations may play an important role in the development of acute lung injury (ALI). Lipopolysaccharide (LPS)-induced ALI models has been widely applied for pathophysiological and pharmacological research. In order to understand the variation of acute pulmonary reactions between mouse strains and find the optimal strain for target-oriented study, the present study investigated the alterations of acute lung hyperinflation, inflammation and injury in C57BL/6J, Balb/cJ, DBA/1J, CD-1, NMRI, DBA/2J, A/J and C3H/HeN mice after the intra-tracheal challenge with LPS. We found that LPS-induced ALI varied between measured variables, durations and strains. General score of LPS-induced acute lung hyperinflation, inflammation and edema followed the order CD-1, A/J, Balb/c, DBA/2J, C57BL/6J, DBA/1J, NMRI, C3H/HeN mice at 4h, and CD-1, C57BL/6J, Balb/c, C3H/HeN, NMRI, A/J, DBA/2J, DBA/1 mice at 24h. Thus, these data provide useful information to select sensitive or resistant strain mouse for understanding genetic variation of pathogenesis and screening of target-oriented drugs.
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| 10. |
- Chen, Donglei, et al.
(författare)
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Three-dimensional histology of tooth cushions of Lophosteus from the Upper Silurian of Estonia
- 2011
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Ingår i: Abstracts. ; , s. 5-6
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Lophosteus superbus from the Late Silurian of Estonia is one of the oldest and most plesiomorphic osteichthyans described to date. Unfortunately at present it is known only from fragmented dermal microremains. The affinities of Lophosteus are therefore controversial with the taxon placed as either basal to both actinopterygians and sarcopterygians, or ambiguously linked to either placoderms or acanthodians. To confound matters further, the character states diagnosing actinopterygians and sarcopterygians have recently been brought into question, and even monophyly of the traditional placoderm and acanthodian clades has been challenged. As a possible stem osteichthyan, Lophosteus could thus be central to our understanding of early gnathostome evolution and the origin of the osteichthyan body plan. Often the best-preserved, although incompletely documented, elements of Lophosteus are tooth cushions. These tooth-bearing arched ossicles could arguably be homologous with the parasymphysial tooth whorls in chondrichthyans, acanthodians, and sarcopterygians, or even the parasymphysial tooth plates in tetrapodomorphs. High-resolution synchrotron scans of 6 isolated tooth cushions from the Upper Silurian of Estonia has permitted a detailed reconstruction of their three-dimensional architecture. The absence of an enamel layer and the presence of large hollows (bigger than normal osteocytes) in the deepest lamellar layer confirmed assignment of the specimens to Lophosteus. The external surface displays irregularly distributed denticles and there are large parallel vessels running horizontally on the basal bone that feed the denticle rows internally. The odontodes have two distinct generations (with successive odontodes accreted between those of the preceding buried generation) and are organised in a similar manner to those found on Lophosteus scales. This new histological data on vascularization provides insight into early gnathostome tooth patterning and could contribute to future phylogenetic assessments.
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