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| 2. |
- 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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| 3. |
- Thomas, Minta, et al.
(author)
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Combining Asian and European genome-wide association studies of colorectal cancer improves risk prediction across racial and ethnic populations
- 2023
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In: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Journal article (peer-reviewed)abstract
- Polygenic risk scores (PRS) have great potential to guide precision colorectal cancer (CRC) prevention by identifying those at higher risk to undertake targeted screening. However, current PRS using European ancestry data have sub-optimal performance in non-European ancestry populations, limiting their utility among these populations. Towards addressing this deficiency, we expand PRS development for CRC by incorporating Asian ancestry data (21,731 cases; 47,444 controls) into European ancestry training datasets (78,473 cases; 107,143 controls). The AUC estimates (95% CI) of PRS are 0.63(0.62-0.64), 0.59(0.57-0.61), 0.62(0.60-0.63), and 0.65(0.63-0.66) in independent datasets including 1681-3651 cases and 8696-115,105 controls of Asian, Black/African American, Latinx/Hispanic, and non-Hispanic White, respectively. They are significantly better than the European-centric PRS in all four major US racial and ethnic groups (p-values < 0.05). Further inclusion of non-European ancestry populations, especially Black/African American and Latinx/Hispanic, is needed to improve the risk prediction and enhance equity in applying PRS in clinical practice.
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| 4. |
- Richards, Stephen, et al.
(author)
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The genome of the model beetle and pest Tribolium castaneum.
- 2008
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In: Nature. - 1476-4687. ; 452:7190, s. 949-55
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Journal article (peer-reviewed)abstract
- Tribolium castaneum is a representative of earth’s most numerous eukaryotic order, a powerful model organism for the study of generalized insect development, and also an important pest of stored agricultural products. We describe its genome sequence here. This omnivorous beetle has evolved an ability to interact with a diverse chemical environment as evidenced by large expansions in odorant and gustatory receptors, as well as p450 and other detoxification enzymes. Developmental patterns in Tribolium are more representative of other arthropods than those found in Drosophila, a fact represented in gene content and function. For one, Tribolium has retained more ancestral genes involved in cell-cell communication than Drosophila, and some are expressed in the growth zone crucial for axial elongation in short germ development. Systemic RNAi in T. castaneum appears to use mechanisms distinct from those found in C. elegans, but nevertheless offers similar power for the elucidation of gene function and identification of targets for selective insect control.
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| 5. |
- Breznau, Nate, et al.
(author)
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Observing many researchers using the same data and hypothesis reveals a hidden universe of uncertainty
- 2022
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In: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 119:44
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Journal article (peer-reviewed)abstract
- This study explores how researchers analytical choices affect the reliability of scientific findings. Most discussions of reliability problems in science focus on systematic biases. We broaden the lens to emphasize the idiosyncrasy of conscious and unconscious decisions that researchers make during data analysis. We coordinated 161 researchers in 73 research teams and observed their research decisions as they used the same data to independently test the same prominent social science hypothesis: that greater immigration reduces support for social policies among the public. In this typical case of social science research, research teams reported both widely diverging numerical findings and substantive conclusions despite identical start conditions. Researchers expertise, prior beliefs, and expectations barely predict the wide variation in research outcomes. More than 95% of the total variance in numerical results remains unexplained even after qualitative coding of all identifiable decisions in each teams workflow. This reveals a universe of uncertainty that remains hidden when considering a single study in isolation. The idiosyncratic nature of how researchers results and conclusions varied is a previously underappreciated explanation for why many scientific hypotheses remain contested. These results call for greater epistemic humility and clarity in reporting scientific findings.
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| 6. |
- Bundschuh, Jochen, et al.
(author)
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Medical geology in the framework of the sustainable development goals
- 2017
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In: Science of the Total Environment. - : Elsevier BV. - 0048-9697 .- 1879-1026. ; 581, s. 87-104
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Journal article (peer-reviewed)abstract
- Exposure to geogenic contaminants (GCs) such as metal(loid)s, radioactive metals and isotopes as well as transuraniums occurring naturally in geogenic sources (rocks, minerals) can negatively impact on environmental and human health. The GCs are released into the environment by natural biogeochemical processes within the near-surface environments and/or by anthropogenic activities such as mining and hydrocarbon exploitation as well as exploitation of geothermal resources. They can contaminate soil, water, air and biota and subsequently enter the food chain with often serious health impacts which are mostly underestimated and poorly recognized. Global population explosion and economic growth and the associated increase in demand for water, energy, food, and mineral resources result in accelerated release of GCs globally. The emerging science of "medical geology" assesses the complex relationships between geo-environmental factors and their impacts on humans and environments and is related to the majority of the 17 Sustainable Development Goals in the 2030 Agenda of the United Nations for Sustainable Development. In this paper, we identify multiple lines of evidence for the role of GCs in the incidence of diseases with as yet unknown etiology (causation). Integrated medical geology promises a more holistic understanding of the occurrence, mobility, bioavailability, bio-accessibility, exposure and transfer mechanisms of GCs to the food-chain and humans, and the related ecotoxicological impacts and health effects. Scientific evidence based on this approach will support adaptive solutions for prevention, preparedness and response regarding human and environmental health impacts originating from exposure to GCs.
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| 7. |
- Chapman, Henry N., et al.
(author)
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Femtosecond diffractive imaging with a soft-X-ray free-electron laser
- 2006
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In: Nature Physics. - : Springer Science and Business Media LLC. - 1745-2473 .- 1745-2481. ; 2:12, s. 839-843
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Journal article (peer-reviewed)abstract
- Theory predicts(1-4) that, with an ultrashort and extremely bright coherent X-ray pulse, a single diffraction pattern may be recorded from a large macromolecule, a virus or a cell before the sample explodes and turns into a plasma. Here we report the first experimental demonstration of this principle using the FLASH soft-X-ray free-electron laser. An intense 25 fs, 4 x 10(13) W cm(-2) pulse, containing 10(12) photons at 32 nm wavelength, produced a coherent diffraction pattern from a nanostructured non-periodic object, before destroying it at 60,000 K. A novel X-ray camera assured single-photon detection sensitivity by filtering out parasitic scattering and plasma radiation. The reconstructed image, obtained directly from the coherent pattern by phase retrieval through oversampling(5-9), shows no measurable damage, and is reconstructed at the diffraction-limited resolution. A three-dimensional data set may be assembled from such images when copies of a reproducible sample are exposed to the beam one by one(10).
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| 8. |
- Oeckl, Patrick, et al.
(author)
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Different neuroinflammatory profile in amyotrophic lateral sclerosis and frontotemporal dementia is linked to the clinical phase
- 2019
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In: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ Publishing Group Ltd. - 0022-3050 .- 1468-330X. ; 90:1, s. 4-10
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Journal article (peer-reviewed)abstract
- Objective: To investigate the role of neuroinflammation in asymptomatic and symptomatic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) mutation carriers.Methods: The neuroinflammatory markers chitotriosidase 1 (CHIT1), YKL-40 and glial fibrillary acidic protein (GFAP) were measured in cerebrospinal fluid (CSF) and blood samples from asymptomatic and symptomatic ALS/FTD mutation carriers, sporadic cases and controls by ELISA.Results: CSF levels of CHIT1, YKL-40 and GFAP were unaffected in asymptomatic mutation carriers (n=16). CHIT1 and YKL-40 were increased in gALS (p<0.001, n=65) whereas GFAP was not affected. Patients with ALS carrying a CHIT1 polymorphism had lower CHIT1 concentrations in CSF (-80%) whereas this polymorphism had no influence on disease severity. In gFTD (n=23), increased YKL-40 and GFAP were observed (p<0.05), whereas CHIT1 was nearly not affected. The same profile as in gALS and gFTD was observed in sALS (n=64/70) and sFTD (n=20/26). CSF and blood concentrations correlated moderately (CHIT1, r=0.51) to weak (YKL-40, r=0.30, GFAP, r=0.39). Blood concentrations of these three markers were not significantly altered in any of the groups except CHIT1 in gALS of the Ulm cohort (p<0.05).Conclusion: Our data indicate that neuroinflammation is linked to the symptomatic phase of ALS/FTD and shows a similar pattern in sporadic and genetic cases. ALS and FTD are characterised by a different neuroinflammatory profile, which might be one driver of the diverse presentations of the ALS/FTD syndrome.
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| 9. |
- Patterer, Lena, et al.
(author)
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Effect of Si on the hydrogen-based direct reduction of Fe2O3 studied by XPS of sputter-deposited thin-film model systems
- 2023
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In: Scripta Materialia. - : Elsevier. - 1359-6462 .- 1872-8456. ; 233
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Journal article (peer-reviewed)abstract
- Understanding the effect of gangue elements is of critical importance to optimize the efficiency of hydrogen -based direct reduction (HyDR) of iron ore, as one of the key steps towards climate-neutral steel production. Here, we demonstrate on the example of Si-doped Fe2O3, how thin films can be effectively utilized as a model system to facilitate systematic investigation of the solid-state reduction behavior. In-vacuo X-ray photoelectron spectroscopy (XPS) is used to probe the reduction kinetics by analyzing the chemical state of iron oxide thin films before and after annealing at 700 degrees C in an Ar+5%H2 atmosphere. It is demonstrated that even low Si concen-trations of 3.7 at.% inhibit the HyDR of Fe2O3 by the formation of a SiOx-enriched reduction barrier in the surface-near region.
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| 12. |
- Schneider, J., et al.
(author)
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Potential of different AM fungi (native from As-contaminated and uncontaminated soils) for supporting Leucaena leucocephala growth in As-contaminated soil
- 2017
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In: Environmental Pollution. - : Elsevier Ltd. - 0269-7491 .- 1873-6424. ; 224, s. 125-135
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Journal article (peer-reviewed)abstract
- Arbuscular mycorrhizal (AM) fungi inoculation is considered a potential biotechnological tool for an eco-friendly remediation of hazardous contaminants. However, the mechanisms explaining how AM fungi attenuate the phytotoxicity of metal(oid)s, in particular arsenic (As), are still not fully understood. The influence of As on plant growth and the antioxidant system was studied in Leucaena leucocephala plants inoculated with different isolates of AM fungi and exposed to increasing concentrations of As (0, 35, and 75 mg dm−3) in a Typic Quartzipsamment soil. The study was conducted under greenhouse conditions using isolates of AM fungi selected from uncontaminated soils (Acaulospora morrowiae, Rhizophagus clarus, Gigaspora albida; and a mixed inoculum derived from combining these isolates, named AMF Mix) as well as a mix of three isolates from an As-contaminated soil (A. morrowiae, R. clarus, and Paraglomus occultum). After 21 weeks, the activities of superoxide dismutase (SOD), catalase (CAT), ascorbate peroxidase (APX), and glutathione reductase (GR) were determined in the shoots in addition to measuring plant height and mineral contents. In general, AM fungi have shown multiple beneficial effects on L. leucocephala growth. Although the activity of most of the stress-related enzymes increased in plants associated with AM fungi, the percentage increase caused by adding As to the soil was even greater for non-mycorrhizal plants when compared to AM-fungi inoculated ones, which highlights the phytoprotective effect provided by the AM symbiosis. The highest P/As ratio observed in AM-fungi plants, compared to non-mycorrhizal ones, can be considered a good indicator that the AM fungi alter the pattern of As(V) uptake from As-contaminated soil. Our results underline the role of AM fungi in increasing the tolerance of L. leucocephala to As stress and emphasize the potential of the symbiosis L. leucocephala-R. clarus for As-phytostabilization at moderately As-contaminated soils.
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| 13. |
- Su, Yu-Ru, et al.
(author)
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Validation of a genetic-enhanced risk prediction model for colorectal cancer in a large community-based cohort
- 2023
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In: Cancer Epidemiology, Biomarkers and Prevention. - : American association for cancer research. - 1055-9965 .- 1538-7755. ; 32:3, s. 353-362
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Journal article (peer-reviewed)abstract
- BACKGROUND: Polygenic risk scores (PRS) which summarize individuals' genetic risk profile may enhance targeted colorectal cancer screening. A critical step towards clinical implementation is rigorous external validations in large community-based cohorts. This study externally validated a PRS-enhanced colorectal cancer risk model comprising 140 known colorectal cancer loci to provide a comprehensive assessment on prediction performance.METHODS: The model was developed using 20,338 individuals and externally validated in a community-based cohort (n = 85,221). We validated predicted 5-year absolute colorectal cancer risk, including calibration using expected-to-observed case ratios (E/O) and calibration plots, and discriminatory accuracy using time-dependent AUC. The PRS-related improvement in AUC, sensitivity and specificity were assessed in individuals of age 45 to 74 years (screening-eligible age group) and 40 to 49 years with no endoscopy history (younger-age group).RESULTS: In European-ancestral individuals, the predicted 5-year risk calibrated well [E/O = 1.01; 95% confidence interval (CI), 0.91-1.13] and had high discriminatory accuracy (AUC = 0.73; 95% CI, 0.71-0.76). Adding the PRS to a model with age, sex, family and endoscopy history improved the 5-year AUC by 0.06 (P < 0.001) and 0.14 (P = 0.05) in the screening-eligible age and younger-age groups, respectively. Using a risk-threshold of 5-year SEER colorectal cancer incidence rate at age 50 years, adding the PRS had a similar sensitivity but improved the specificity by 11% (P < 0.001) in the screening-eligible age group. In the younger-age group it improved the sensitivity by 27% (P = 0.04) with similar specificity.CONCLUSIONS: The proposed PRS-enhanced model provides a well-calibrated 5-year colorectal cancer risk prediction and improves discriminatory accuracy in the external cohort.IMPACT: The proposed model has potential utility in risk-stratified colorectal cancer prevention.
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