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| 2. |
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- 2019
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Journal article (peer-reviewed)
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| 3. |
- Klionsky, Daniel J., et al.
(author)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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In: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Research review (peer-reviewed)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. |
- Kanoni, Stavroula, et al.
(author)
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Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
- 2022
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In: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1
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Journal article (peer-reviewed)abstract
- Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N=1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
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| 5. |
- Chen, Min-Wei, et al.
(author)
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H3K9 histone methyltransferase G9a promotes lung cancer invasion and metastasis by silencing the cell adhesion molecule Ep-CAM
- 2010
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In: Cancer Research. - : American Association for Cancer Research. - 0008-5472 .- 1538-7445. ; 70:20, s. 7830-7840
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Journal article (peer-reviewed)abstract
- G9a is a mammalian histone methyltransferase that contributes to the epigenetic silencing of tumor suppressor genes. Emerging evidence suggests that G9a is required to maintain the malignant phenotype, but the role of G9a function in mediating tumor metastasis has not been explored. Here, we show that G9a is expressed in aggressive lung cancer cells, and its elevated expression correlates with poor prognosis. RNAi-mediated knockdown of G9a in highly invasive lung cancer cells inhibited cell migration and invasion in vitro and metastasis in vivo. Conversely, ectopic G9a expression in weakly invasive lung cancer cells increased motility and metastasis. Mechanistic investigations suggested that repression of the cell adhesion molecule Ep-CAM mediated the effects of G9a. First, RNAi-mediated knockdown of Ep-CAM partially relieved metastasis suppression imposed by G9a suppression. Second, an inverse correlation between G9a and Ep-CAM expression existed in primary lung cancer. Third, Ep-CAM repression was associated with promoter methylation and an enrichment for dimethylated histone H3K9. G9a knockdown reduced the levels of H3K9 dimethylation and decreased the recruitment of the transcriptional cofactors HP1, DNMT1, and HDAC1 to the Ep-CAM promoter. Our findings establish a functional contribution of G9a overexpression with concomitant dysregulation of epigenetic pathways in lung cancer progression.
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| 6. |
- Luo, Yang, et al.
(author)
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Three-dimensional and temperature-dependent electronic structure of the heavy-fermion compound CePt2In7 studied by angle-resolved photoemission spectroscopy
- 2020
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In: Physical Review B. - : AMER PHYSICAL SOC. - 2469-9950 .- 2469-9969. ; 101:11
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Journal article (peer-reviewed)abstract
- The three-dimensional and temperature-dependent electronic structures of the heavy-fermion superconductor CePt2In7 are investigated. Angle-resolved photoemission spectroscopy using variable photon energy establishes the existence of quasi-two- and three-dimensional Fermi surface topologies. Temperature-dependent 4d-4f on-resonance photoemission spectroscopies data reveal that heavy quasiparticle bands begin to form at a temperature well above the characteristic (coherence) temperature T+. The emergence of low-lying crystal electric field excitation may be responsible for the "relocalization" or the precursor to the establishment of heavy electrons coherence in heavy-fermion compounds. These findings provide critical insight into understanding the hybridization in heavy-fermion systems.
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| 7. |
- Berndt, Sonja I., et al.
(author)
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Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture
- 2013
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:5, s. 501-U69
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Journal article (peer-reviewed)abstract
- Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
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| 8. |
- Chen, Zhishan, et al.
(author)
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Fine-mapping analysis including over 254 000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes
- 2024
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In: Nature Communications. - : Springer Nature. - 2041-1723. ; 15:1
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Journal article (peer-reviewed)abstract
- Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.
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| 9. |
- Fernandez-Rozadilla, Ceres, et al.
(author)
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Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries
- 2023
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In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 55, s. 89-99
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Journal article (peer-reviewed)abstract
- Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.
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| 10. |
- Kashtanov, Stepan, et al.
(author)
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Chemical and electronic structures of liquid methanol from x-ray emission spectroscopy and density functional theory.
- 2005
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In: Physical Review B. Condensed Matter and Materials Physics. - 1098-0121 .- 1550-235X. ; 71:10
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Journal article (peer-reviewed)abstract
- We have applied x-ray emission spectroscopy and density functional theory (DFT) to study the chemical and electronic structures of liquid methanol. The x-ray emission spectra at carbon and oxygen K edges of methanol in different hydrogen-bonded clusters are simulated. It is shown that hydrogen bonding strongly influences the spectral profile of O K emission, but not the C K emission. The methanol chain and ring conformations show a distinct difference in their electronic structures. The molecular orbitals of chains are strongly localized, whereas for the ring structures they show strong delocalization characteristics and behaviorlike covalent pi orbitals in a conjugated system. A comparison of experimental spectra and DFT calculations suggests that liquid methanol comprises combinations of rings and chains of methanol molecules linked with hydrogen bonds and is dominated by structures with the size of six and eight molecules.
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| 11. |
- Song, Jiao-Jiao, et al.
(author)
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Relocalization of uranium 5f electrons in the antiferromagnetic heavy-fermion superconductor UPd2Al3 : Insights from angle-resolved photoemission spectroscopy
- 2024
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In: Physical Review B. - : American Physical Society. - 2469-9950 .- 2469-9969. ; 109:20
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Journal article (peer-reviewed)abstract
- We investigate the antiferromagnetic heavy fermion superconductor UPd2Al3, employing angle-resolved photoemission spectroscopy to unravel the complex electronic structure of its U 5? electrons. We observe unexpected characteristics that challenge the conventional temperature-dependent behavior of heavy fermion systems, revealing unexpected characteristics. At temperatures above the anticipated coherence temperature (?*), we observe itinerant U 5? electrons at temperatures higher than previously postulated. Additionally, a previously unidentified dispersionless band emerges around 600 meV below the Fermi energy, potentially linked to spin-orbit splitting within the U 5? states. Hybridization between the 5? electrons and conduction band was observed with an energy dispersion of 10 meV at low temperatures, suggesting that U 5? electrons near and at the Fermi surface have an itinerant nature. Temperature-dependent 5?−5? resonance spectra reveal that the 5? electron spectrum weight increases with lowering temperature and begins to decrease at temperatures significantly higher than the Néel temperature (??). We further show that the competition between the Kondo effect and Ruderman-Kittel-Kasuya-Yosida (RKKY) interactions may be responsible for the relocalization of 5? electrons, making relocalization a precursor to the establishment of magnetic order at lower temperatures. Our experiments also provide evidence that 5? electrons with the same orbital are involved in both the Kondo effect and RKKY interactions, suggesting that the two coexist at lower temperatures.
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| 12. |
- Song, Jiao-Jiao, et al.
(author)
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The 4f-Hybridization Strength in CemMnIn3m+2n Heavy-Fermion Compounds Studied by Angle-Resolved Photoemission Spectroscopy
- 2021
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In: Chinese Physics Letters. - : IOP Publishing. - 0256-307X .- 1741-3540. ; 38:10
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Journal article (peer-reviewed)abstract
- We systemically investigate the nature of Ce 4f electrons in structurally layered heavy-fermion compounds CemMnIn3m+2n (with M = Co, Rh, Jr, and Pt, m = 1, 2, n = 0-2), at low temperature using on-resonance angle-resolved photoemission spectroscopy. Three heavy quasiparticle bands f(0), f(7/2)(1) and f(5/2)(1), are observed in all compounds, whereas their intensities and energy locations vary greatly with materials. The strong f(0) states imply that the localized electron behavior dominates the Ce 4f states. The Ce 4f electrons are partially hybridized with the conduction electrons, making them have the dual nature of localization and itinerancy. Our quantitative comparison reveals that the f(5/2)(1)-f (0) intensity ratio is more suitable to reflect the 4f-state hybridization strength.
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| 13. |
- Yi, Huan, et al.
(author)
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Association of Levonorgestrel-Releasing Intrauterine Device with Gynecologic and Breast Cancers: National Cohort Study in Sweden
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In: American Journal of Obstetrics and Gynecology. - 1097-6868.
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Journal article (peer-reviewed)abstract
- BackgroundThe levonorgestrel-releasing intrauterine device (LNG-IUD) is widely used for the treatment of menorrhagia, dysmenorrhea, and for contraception. However, the association between the use of LNG-IUD and the risk of site-specific gynecologic and breast cancers remains inconclusive.ObjectiveWe aim to address this knowledge gap by investigating whether the use of LNG-IUD is associated with a significant risk of site-specific gynecologic and breast cancers. This will be achieved by accessing the nationwide Swedish Registers, with consideration given to the influence and potential interaction of family history of cancer.Study DesignA total of 514719 women aged 18 to 50 years who have used LNG-IUD between July 2005 and December 2018 were identified from the Swedish Prescribed Drug Register and randomly matched with 1544157 comparisons who did not use LNG-IUD at a ratio of 1:3. The propensity score was calculated and matched among women who used LNG-IUD and the matched comparisons. The follow-up period started from the date of the first prescription of LNG-IUD for users as well as for their matched comparisons and ended at the date of diagnosis of gynecologic and breast cancers, date of death from any cause, and the end of the study period, whichever came first. The Cox proportional hazard model with a competing risk analysis was used to calculate hazard ratios and 95% confidence intervals. Additive interaction was calculated as the relative excess risk for interaction, while multiplicative interaction was calculated by including a product term in the regression model.ResultsThe use of LNG-IUD was associated with a 13% higher risk of breast cancer (adjusted HR, 1.13; 95% CI, 1.10-1.17), a 33% lower risk of endometrial cancer (adjusted HR, 0.67; 95% CI, 0.56-0.80), a 14% lower risk of ovarian cancer (adjusted HR, 0.86; 95% CI, 0.75-0.99) and a 9% reduced risk of cervical cancer (adjusted HR, 0.91; 95% CI, 0.84-0.99) compared to women who did not use LNG-IUD. A significant additive interaction between LNG-IUD use and family history of cancer was observed in breast cancer, indicating a relative 19% excess risk for interaction (P < 0.002), and 1.63 additional cases per 10,000 person-years.ConclusionsThe risk of gynecologic and breast cancers exhibits a site-specific effect among LNG-IUD users. It's important to note that the observed effect is small for breast cancer and the results are limited by the observational study design. Clinical recommendations regarding the use of LNG-IUD should carefully weigh its potential benefits and risks. Close monitoring is advisable for the potential development of breast cancer, particularly among women with a family history of breast cancer.
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| 14. |
- Yuan, Ya Hua, et al.
(author)
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Angle-resolved photoemission spectroscopy view on the nature of Ce 4f electrons in the antiferromagnetic Kondo lattice CePd5Al2
- 2021
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In: Physical Review B. - : American Physical Society (APS). - 2469-9969 .- 2469-9950. ; 103:12
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Journal article (peer-reviewed)abstract
- We report an angle-resolved photoemission spectroscopy study of the antiferromagnetic Kondo lattice CePd5Al2, focusing on the quasi-two-dimensional k-space nature of its Fermi surface and, tuning photon energy to the Ce 4d-4f on-resonance transition, the hybridization of the Ce 4f state. A strong shoulder feature on the f0 peak was detected, suggesting hybridization between conduction and f bands. On-resonance spectra revealed narrow, yet hybridized quasiparticle bands with sharp peaks and ∼ 9 meV energy dispersion near the Fermi energy EF. The observed dispersive hybridized f band can be well described by a hybridization-band picture based on the periodic Anderson model (PAM). Hence, the 4f electrons in CePd5Al2 display a dual nature, with both localized and itinerant features, but with dominantly localized character.
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| 15. |
- Zhang, Chen, et al.
(author)
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Antiferromagnetic order in Kondo lattice CePd5Al2 possibly driven by nesting
- 2023
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In: Physical Review B. - : American Physical Society (APS). - 2469-9950 .- 2469-9969. ; 108:3
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Journal article (peer-reviewed)abstract
- We investigated the electronic structure of the antiferromagnetic Kondo lattice CePd5Al2 using high-resolution angle-resolved photoemission spectroscopy. The experimentally determined band structure of the conduction electrons is predominated by the Pd 4d character. It contains multiple hole and electron Fermi pockets, in good agreement with density functional theory calculations. The Fermi surface is folded over Q0=(0,0,1), manifested by Fermi surface reconstruction and band folding. Our results suggest that Fermi surface nesting drives the formation of antiferromagnetic order in CePd5Al2.
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