| 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. |
- Han, Ning, et al.
(författare)
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Achieving Efficient Electrocatalytic Oxygen Evolution in Acidic Media on Yttrium Ruthenate Pyrochlore through Cobalt Incorporation
- 2023
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Ingår i: Advanced Functional Materials. - : Wiley. - 1616-301X .- 1616-3028. ; 33:20
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Tidskriftsartikel (refereegranskat)abstract
- The development of electrocatalysts for the oxygen evolution reaction (OER) especially in acidic media remains the major challenge that still requires significant advances, both in material design and mechanistic exploration. In this study, the incorporation of cobalt in Y2-xCoxRu2O7−δ results in an ultrahigh OER activity because of the charge redistribution at eg orbitals between Ru and Co atoms. The Y1.75Co0.25Ru2O7−δ electrocatalyst exhibits an extremely small overpotential of 275 mV in 0.5 m H2SO4 at the current density of 10 mA cm−2, which is smaller than that of parent Y2Ru2O7−δ (360 mV) and commercial RuO2 (286 mV) catalysts. The systematic investigation of the composition related to OER activity shows that the Co substitution will also bring other effective changes, such as reducing the bandgap, and creating oxygen vacancies, which result in fast OER charge transfer. Meanwhile, the strengthening of the bond hybridization between the d orbitals of metal (Y and Ru) and the 2p orbitals of O will intrinsically enhance the chemical stability. Finally, theoretical calculations indicate that cobalt substitution reduces the theoretical overpotential both through an adsorbate evolution mechanism and a lattice oxygen-mediated mechanism.
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| 3. |
- Han, Ning, et al.
(författare)
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Rational design of Ruddlesden–Popper perovskite electrocatalyst for oxygen reduction to hydrogen peroxide
- 2022
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Ingår i: SusMat. - : Wiley. - 2766-8479 .- 2692-4552. ; 2:4, s. 456-465
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Tidskriftsartikel (refereegranskat)abstract
- Although the oxygen reduction process to hydrogen peroxide (H2O2) is a green option for H2O2 generation, the low activity and selectivity hindered the industry's process. In recent years, the electrochemical synthesis of H2O2 through a 2e– transfer method of oxygen reduction reaction (ORR) has piqued the interest of both academics and industry. Metal oxide catalysts have emerged as a novel family of electrochemical catalysts due to their unusual physical, chemical, and electrical characteristics. In this work, we first developed a Ruddlesden–Popper perovskite oxide (Pr2NiO4+δ) as a highly selective and active catalyst for 2e– ORR to produce H2O2. Molybdenum was introduced here to adjust the oxidation states of these transition metals with successful substitution into Ni-site to prepare Pr2Ni1-xMoxO4+δ, and the molybdenum substitution improves the H2O2 selectivity during the ORR process, in 0.1 M KOH, from 60% of Pr2NiO4+δ to 79% of Pr2Ni0.8Mo0.2O4+δ at 0.55 V versus RHE. A limiting H2O2 concentration of 0.24 mM for Pr2NiO4+δ and 0.42 mM for Pr2Ni0.8Mo0.2O4+δ was obtained at a constant current of 10 mA/cm2 using a flow-cell reactor using a gas-diffusion electrode.
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| 4. |
- Haycock, Philip C., et al.
(författare)
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Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases A Mendelian Randomization Study
- 2017
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Ingår i: JAMA Oncology. - : American Medical Association. - 2374-2437 .- 2374-2445. ; 3:5, s. 636-651
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. OBJECTIVE: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases. DATA SOURCES: Genomewide association studies (GWAS) published up to January 15, 2015. STUDY SELECTION: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available. DATA EXTRACTION AND SYNTHESIS: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population. MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation. RESULTS: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [ 95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [ 95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [ 95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [ 95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [ 95% CI, 0.05-0.15]). CONCLUSIONS AND RELEVANCE: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.
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| 5. |
- Kamada, Ayaka, et al.
(författare)
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Hierarchical propagation of structural features in protein nanomaterials
- 2022
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Ingår i: Nanoscale. - : Royal Society of Chemistry (RSC). - 2040-3372 .- 2040-3364. ; 14:6, s. 2502-2510
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Tidskriftsartikel (refereegranskat)abstract
- Natural high-performance materials have inspired the exploration of novel materials from protein building blocks. The ability of proteins to self-organize into amyloid-like nanofibrils has opened an avenue to new materials by hierarchical assembly processes. As the mechanisms by which proteins form nanofibrils are becoming clear, the challenge now is to understand how the nanofibrils can be designed to form larger structures with defined order. We here report the spontaneous and reproducible formation of ordered microstructure in solution cast films from whey protein nanofibrils. The structural features are directly connected to the nanostructure of the protein fibrils, which is itself determined by the molecular structure of the building blocks. Hence, a hierarchical assembly process ranging over more than six orders of magnitude in size is described. The fibril length distribution is found to be the main determinant of the microstructure and the assembly process originates in restricted capillary flow induced by the solvent evaporation. We demonstrate that the structural features can be switched on and off by controlling the length distribution or the evaporation rate without losing the functional properties of the protein nanofibrils.
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| 6. |
- Wuttke, Matthias, et al.
(författare)
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A catalog of genetic loci associated with kidney function from analyses of a million individuals
- 2019
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Ingår i: Nature Genetics. - : NATURE PUBLISHING GROUP. - 1061-4036 .- 1546-1718. ; 51:6, s. 957-972
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Tidskriftsartikel (refereegranskat)abstract
- Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
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| 7. |
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| 8. |
- Carraro, Marco, et al.
(författare)
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Performance of in silico tools for the evaluation of p16INK4a (CDKN2A) variants in CAGI
- 2017
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 38:9, s. 1042-1050
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Tidskriftsartikel (refereegranskat)abstract
- Correct phenotypic interpretation of variants of unknown significance for cancer-associated genes is a diagnostic challenge as genetic screenings gain in popularity in the next-generation sequencing era. The Critical Assessment of Genome Interpretation (CAGI) experiment aims to test and define the state of the art of genotype-phenotype interpretation. Here, we present the assessment of the CAGI p16INK4a challenge. Participants were asked to predict the effect on cellular proliferation of 10 variants for the p16INK4a tumor suppressor, a cyclin-dependent kinase inhibitor encoded by the CDKN2A gene. Twenty-two pathogenicity predictors were assessed with a variety of accuracy measures for reliability in a medical context. Different assessment measures were combined in an overall ranking to provide more robust results. The R scripts used for assessment are publicly available from a GitHub repository for future use in similar assessment exercises. Despite a limited test-set size, our findings show a variety of results, with some methods performing significantly better. Methods combining different strategies frequently outperform simpler approaches. The best predictor, Yang&Zhou lab, uses a machine learning method combining an empirical energy function measuring protein stability with an evolutionary conservation term. The p16INK4a challenge highlights how subtle structural effects can neutralize otherwise deleterious variants.
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| 9. |
- Chen, Jie, et al.
(författare)
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Northwestward shift of the northern boundary of the East Asian summer monsoon during the mid-Holocene caused by orbital forcing and vegetation feedbacks
- 2021
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Ingår i: Quaternary Science Reviews. - : Elsevier BV. - 0277-3791 .- 1873-457X. ; 268
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Tidskriftsartikel (refereegranskat)abstract
- The East Asian summer monsoon (EASM) northern boundary is a critical indicator of EASM variations. Movement of the boundary is modulated by both the EASM and the mid-latitude westerlies. Here, we use the Earth system model EC-Earth to quantify the contribution of orbital forcing and vegetation feedbacks in modulating the movement of EASM northern boundary. The results show that the simulated EASM northern boundary during the mid-Holocene shifts by a maximum of ∼213 km northwestward due to orbital forcing. When the model was coupled with a dynamic vegetation module LPJ-GUESS, the northern boundary shifts further northwestward by a maximum of ∼90 km, indicating the importance of vegetation feedbacks. During the mid-Holocene, temperature increased in the mid-latitude during the boreal summer due to insolation, leading to increased meridional air temperature differences (MTDs) over the region north of 45°N and to decreased MTDs to the south. The changes in the temperature gradient weakened the East Asian Westly Jet (EAWJ) and displaced it northward, resulting in an earlier transition of the Meiyu stage and a more prolonged Midsummer stage. The northward movement of EAWJ, combined with the enhanced southerly moisture flow from South China, caused more precipitation in North China and eventually to a northwestward shift of the northern boundary of the EASM. The coupled dynamic vegetation module LPJ-GUESS simulated more grassland and less forest over Northeast Asia during the mid-Holocene. The increased surface albedo tended to lower the temperature in the region, and further enhanced the MTDs in mid-latitude East Asia, leading to the further northward movement of the EAWJ and a northwestward shift of the EASM northern boundary. Although the simulated vegetation distribution in several regions may be not accurate, it reflects the substantial contribution of climate-vegetation interaction on modulating the EASM.
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| 10. |
- Chen, Jie, et al.
(författare)
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Origin of the spatial consistency of summer precipitation variability between the Mongolian Plateau and the mid-latitude East Asian summer monsoon region
- 2020
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Ingår i: Science China. Earth Sciences. - : Springer Science and Business Media LLC. - 1674-7313 .- 1869-1897. ; 63:8, s. 1199-1208
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Tidskriftsartikel (refereegranskat)abstract
- The Mongolian Plateau (MP) is located in the eastern part of arid Central Asia (ACA). Climatically, much of the MP is dominated by the westerly circulation and has an arid and semi-arid climate; however, the eastern part of the MP is also influenced by the East Asian summer monsoon (EASM) and has a humid and semi-humid climate. Several studies have shown that precipitation variability in the MP differs from that in western ACA but is consistent with that in the EASM region. Here we use monthly precipitation data for 1979-2016 to characterize and determine the origin of the summer precipitation variability of the MP and the EASM region. The results show that the MP and the mid-latitude EASM region exhibit a consistent pattern of precipitation variability on interannual and decadal timescales; specifically, the consistent regions are the MP and North and Northeast China. We further investigated the physical mechanisms responsible for the consistent interdecadal precipitation variability between the MP and the mid-latitude EASM region, and found that the mid-latitude wave train over Eurasia, with positive (negative) geopotential height anomalies over the North Atlantic and ACA and negative (positive) geopotential height anomalies over Europe and the MP, is the key factor responsible for the consistency of precipitation variability in the MP and the mid-latitude EASM region. The positive anomalies over the North Atlantic and ACA and negative anomalies over Europe and the MP would enhance the transport of westerly and monsoon moisture to the MP and North and Northeast China. They could also strengthen the Northeast Asian low, enhance the EASM, and trigger the anomalous ascending motion over the MP which promotes precipitation in the MP and in the mid-latitude EASM region. Overall, our results help explain the spatial variations of paleo-precipitation/humidity reconstructions in East Asia and clarify the reasons for the consistency of the regional climate.
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