| 1. |
- 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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| 2. |
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| 3. |
- Brouzoulis, Jim, 1984, et al.
(author)
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Prediction of Wear and Plastic Flow in Rails - Test Rig Results, Model Calibration and Numerical Prediction
- 2011
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In: Wear. - : Elsevier BV. - 0043-1648. ; 271:1-2, s. 92-99
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Journal article (peer-reviewed)abstract
- Conventionally, laboratory measurements under idealized conditions are used to establish parameters needed in different kinds of wear models. This paper presents a procedure for determining the Archard's wear coefficient from data collected in a full-scale wheel-rail test rig, i.e. under realistic loading conditions. Moreover, a simulation procedure capable of simulating rail profile evolution in conformal contacts incorporating both wear and plasticity is presented. In each simulation step, dynamic responses are calculated using the commercial vehicle-track interaction software GENSYS. The conformal contact is treated by applying a multi-Hertzian approach. To account for plastic deformations, a 20 elasto-plastic FE analysis is carried out in conjunction with a 3D local contact analysis in the commercial finite element (FE) software ABAQUS. It is shown that, due to the conformal contact, elastic shakedown is obtained after only a few load cycles and is therefore disregarded in the subsequent analyses. Quantitatively good results, in terms of worn-off area and shape of the worn profile, are presented for simulations between 20k and 100k load cycles. However, dependence between the chosen wear step length and the profiles obtained from the simulations is found.
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| 4. |
- Ducharme, Simon, et al.
(author)
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Recommendations to distinguish behavioural variant frontotemporal dementia from psychiatric disorders
- 2020
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In: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 143:6, s. 1632-1650
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Journal article (peer-reviewed)abstract
- The behavioural variant of frontotemporal dementia (bvFTD) is a frequent cause of early-onset dementia. The diagnosis of bvFTD remains challenging because of the limited accuracy of neuroimaging in the early disease stages and the absence of molecular biomarkers, and therefore relies predominantly on clinical assessment. BvFTD shows significant symptomatic overlap with non-degenerative primary psychiatric disorders including major depressive disorder, bipolar disorder, schizophrenia, obsessive-compulsive disorder, autism spectrum disorders and even personality disorders. To date, ∼50% of patients with bvFTD receive a prior psychiatric diagnosis, and average diagnostic delay is up to 5-6 years from symptom onset. It is also not uncommon for patients with primary psychiatric disorders to be wrongly diagnosed with bvFTD. The Neuropsychiatric International Consortium for Frontotemporal Dementia was recently established to determine the current best clinical practice and set up an international collaboration to share a common dataset for future research. The goal of the present paper was to review the existing literature on the diagnosis of bvFTD and its differential diagnosis with primary psychiatric disorders to provide consensus recommendations on the clinical assessment. A systematic literature search with a narrative review was performed to determine all bvFTD-related diagnostic evidence for the following topics: bvFTD history taking, psychiatric assessment, clinical scales, physical and neurological examination, bedside cognitive tests, neuropsychological assessment, social cognition, structural neuroimaging, functional neuroimaging, CSF and genetic testing. For each topic, responsible team members proposed a set of minimal requirements, optimal clinical recommendations, and tools requiring further research or those that should be developed. Recommendations were listed if they reached a ≥ 85% expert consensus based on an online survey among all consortium participants. New recommendations include performing at least one formal social cognition test in the standard neuropsychological battery for bvFTD. We emphasize the importance of 3D-T1 brain MRI with a standardized review protocol including validated visual atrophy rating scales, and to consider volumetric analyses if available. We clarify the role of 18F-fluorodeoxyglucose PET for the exclusion of bvFTD when normal, whereas non-specific regional metabolism abnormalities should not be over-interpreted in the case of a psychiatric differential diagnosis. We highlight the potential role of serum or CSF neurofilament light chain to differentiate bvFTD from primary psychiatric disorders. Finally, based on the increasing literature and clinical experience, the consortium determined that screening for C9orf72 mutation should be performed in all possible/probable bvFTD cases or suspected cases with strong psychiatric features.
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| 5. |
- Ekberg, Anders, 1967, et al.
(author)
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INNOTRACK Deliverable 4.2.1 -- Simplified relation for the influence of rail/joint degradation on operational loads and subsequent deterioration
- 2007
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Reports (other academic/artistic)abstract
- In this tentative report we present a summary of the work carried out during approximately the first nine months of the INNOTRACK project regarding the influence of rail/joint degradation on operational loads and subsequent deterioration. The focus is here on the vertical train–track interaction and related deterioration.The work within this field can be divided in two categories. The first concerns the collection of input and validation data. In this category the current deliverable includes measurements of in-field axle loads, in-field monitoring of squats and compilation of material data.The second category is the actual numerical simulation and resulting quantifications of increased operational loads and deteriorations. Here the deliverable includes a state-of-the-art study of the effect of material characteristics on material deterioration and the practical implications. Further, the deliverable contains reports of parametric studies of the influence of rail corrugation, the growth of larger rail cracks, the influence of the design of insulated joints and the influence of rail squats.
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| 6. |
- Holmfeldt, Linda, et al.
(author)
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The genomic landscape of hypodiploid acute lymphoblastic leukemia
- 2013
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:3, s. 242-252
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Journal article (peer-reviewed)abstract
- The genetic basis of hypodiploid acute lymphoblastic leukemia (ALL), a subtype of ALL characterized by aneuploidy and poor outcome, is unknown. Genomic profiling of 124 hypodiploid ALL cases, including whole-genome and exome sequencing of 40 cases, identified two subtypes that differ in the severity of aneuploidy, transcriptional profiles and submicroscopic genetic alterations. Near-haploid ALL with 24-31 chromosomes harbor alterations targeting receptor tyrosine kinase signaling and Ras signaling (71%) and the lymphoid transcription factor gene IKZF3 (encoding AIOLOS; 13%). In contrast, low-hypodiploid ALL with 32-39 chromosomes are characterized by alterations in TP53 (91.2%) that are commonly present in nontumor cells, IKZF2 (encoding HELIOS; 53%) and RB1 (41%). Both near-haploid and low-hypodiploid leukemic cells show activation of Ras-signaling and phosphoinositide 3-kinase (PI3K)-signaling pathways and are sensitive to PI3K inhibitors, indicating that these drugs should be explored as a new therapeutic strategy for this aggressive form of leukemia.
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| 7. |
- Lundgren, Markus, et al.
(author)
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Analgesic antipyretic use among young children in the TEDDY study : No association with islet autoimmunity
- 2017
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In: BMC Pediatrics. - : Springer Science and Business Media LLC. - 1471-2431. ; 17:1
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Journal article (peer-reviewed)abstract
- Background: The use of analgesic antipyretics (ANAP) in children have long been a matter of controversy. Data on their practical use on an individual level has, however, been scarce. There are indications of possible effects on glucose homeostasis and immune function related to the use of ANAP. The aim of this study was to analyze patterns of analgesic antipyretic use across the clinical centers of The Environmental Determinants of Diabetes in the Young (TEDDY) prospective cohort study and test if ANAP use was a risk factor for islet autoimmunity. Methods: Data were collected for 8542 children in the first 2.5 years of life. Incidence was analyzed using logistic regression with country and first child status as independent variables. Holm's procedure was used to adjust for multiplicity of intercountry comparisons. Time to autoantibody seroconversion was analyzed using a Cox proportional hazards model with cumulative analgesic use as primary time dependent covariate of interest. For each categorization, a generalized estimating equation (GEE) approach was used. Results: Higher prevalence of ANAP use was found in the U.S. (95.7%) and Sweden (94.8%) compared to Finland (78.1%) and Germany (80.2%). First-born children were more commonly given acetaminophen (OR 1.26; 95% CI 1.07, 1.49; p = 0.007) but less commonly Non-Steroidal Anti-inflammatory Drugs (NSAID) (OR 0.86; 95% CI 0.78, 0.95; p = 0.002). Acetaminophen and NSAID use in the absence of fever and infection was more prevalent in the U.S. (40.4%; 26.3% of doses) compared to Sweden, Finland and Germany (p < 0.001). Acetaminophen or NSAID use before age 2.5 years did not predict development of islet autoimmunity by age 6 years (HR 1.02, 95% CI 0.99-1.09; p = 0.27). In a sub-analysis, acetaminophen use in children with fever weakly predicted development of islet autoimmunity by age 3 years (HR 1.05; 95% CI 1.01-1.09; p = 0.024). Conclusions: ANAP use in young children is not a risk factor for seroconversion by age 6 years. Use of ANAP is widespread in young children, and significantly higher in the U.S. compared to other study sites, where use is common also in absence of fever and infection.
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| 8. |
- Ullrich, Detlev, et al.
(author)
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INNOTRACK Deliverable D4.3.7, Innovative laboratory tests for rail steels – Final report
- 2009
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Reports (other academic/artistic)abstract
- This paper presents a first thorough investigation of different laboratory tests for rail materials combined with numerical simulations and metallographic investigations. A specific methodology for the latter is given in the Appendix. Laboratory tests for new rail materials are desirable supplements to field tests in order to save time and money. Thus, less valuable products can be early withdrawn from expensive field tests. Within this work package, test conditions for laboratory tests of rail materials have been defined and compared to field conditions. Existing test equipment and evaluation methods of the WP partners have been exploited for the laboratory tests in order to find out the applicability to the pre-defined field conditions.The tests were performed at the SUROS twin disk test machine, at the VAS linear full-scale test rig and at DB full-scale roller rigs. The results were compared among other with respect to metallography and material deterioration.Subsequent numerical calculations showed that the full-scale tests more or less deviate systematically from the expected contact conditions due to bending of wheel and rail. In addition, predictions regarding RCF have been carried out and compared to test results.It is shown that twin disk tests as well as tests on a full-scale linear test rig are suitable for practical use. The tests on full-scale roller rigs failed due to the need for specific rail samples, which ultimately destroyed the fixtures during the tests. An evaluation of the different tests including a rough estimate of effort is given.
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| 9. |
- Ullrich, Detlev, et al.
(author)
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INNOTRACK Deliverable D4.3.8, Innovative laboratory tests for rail steels
- 2009
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Reports (other academic/artistic)abstract
- There is a need for laboratory tests of rail material by railway opera-tors as well as by manufactures. The tests should represent oper-ational conditions for the rail material. They should allow withdraw-ing less valuable products from far more expensive field tests.This guideline is based on the experience from the WP4.3 partners with respect to laboratory tests for rail steels. As the operational demands on rail material may differ from site to site (with respect to the curvature etc.), a suitable preparation of the laboratory tests is necessary. It should start with a definition of the conditions to be tested, e.g. with a testing matrix. According to present knowledge, related tests can be done at twin disk test rigs or at specialized full-scale linear test rigs. Full-scale roller rigs are not recommended because the fixing of the samples is difficult and the preparation of the rail material requires a huge effort. After testing the wear, RCF and deformation should be evaluated in accordance with a consistent evaluation scheme. Metallographic in-vestigations could be applied especially with respect to quantifying material deterioration.The compliance with the pre-defined requirements should be moni-tored throughout the test since contact conditions may vary due to profile wear and specific test rig deviations. If such deviations occur, the test conditions should be re-evaluated through numerical simula-tions. Thus, the effect on the test results may be estimated.The results of testing on twin disk tests as well as those on a linear test rig can provide results suitable for practical use. An evaluation of the different tests including a rough estimate of effort is given.
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| 10. |
- Yates, James A. Fellows, et al.
(author)
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The evolution and changing ecology of the African hominid oral microbiome
- 2021
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In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences (PNAS). - 0027-8424 .- 1091-6490. ; 118:20
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Journal article (peer-reviewed)abstract
- The oral microbiome plays key roles in human biology, health, and disease, but little is known about the global diversity, variation, or evolution of this microbial community. To better understand the evolution and changing ecology of the human oral microbiome, we analyzed 124 dental biofilm metagenomes from humans, including Neanderthals and Late Pleistocene to present-day modern humans, chimpanzees, and gorillas, as well as New World howler monkeys for comparison. We find that a core microbiome of primarily biofilm structural taxa has been maintained throughout African hominid evolution, and these microbial groups are also shared with howler monkeys, suggesting that they have been important oral members since before the catarrhine-platyrrhine split ca. 40 Mya. However, community structure and individual microbial phylogenies do not closely reflect host relationships, and the dental biofilms of Homo and chimpanzees are distinguished by major taxonomic and functional differences. Reconstructing oral metagenomes from up to 100 thousand years ago, we show that the microbial profiles of both Neanderthals and modern humans are highly similar, sharing functional adaptations in nutrient metabolism. These include an apparent Homo-specific acquisition of salivary amylase-binding capability by oral streptococci, suggesting microbial coadaptation with host diet. We additionally find evidence of shared genetic diversity in the oral bacteria of Neanderthal and Upper Paleolithic modern humans that is not observed in later modern human populations. Differences in the oral microbiomes of African hominids provide insights into human evolution, the ancestral state of the human microbiome, and a temporal framework for understanding microbial health and disease.
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