| 1. |
- Blauw, Hylke M, et al.
(författare)
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A large genome scan for rare CNVs in amyotrophic lateral sclerosis
- 2010
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Ingår i: Human Molecular Genetics. - : Oxford Journals. - 0964-6906 .- 1460-2083. ; 19:20, s. 4091-4099
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Tidskriftsartikel (refereegranskat)abstract
- Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease selectively affecting motor neurons in the brain and spinal cord. Recent genome-wide association studies (GWASs) have identified several common variants which increase disease susceptibility. In contrast, rare copy-number variants (CNVs), which have been associated with several neuropsychiatric traits, have not been studied for ALS in well-powered study populations. To examine the role of rare CNVs in ALS susceptibility, we conducted a CNV association study including over 19,000 individuals. In a genome-wide screen of 1875 cases and 8731 controls, we did not find evidence for a difference in global CNV burden between cases and controls. In our association analyses, we identified two loci that met our criteria for follow-up: the DPP6 locus (OR = 3.59, P = 6.6 × 10(-3)), which has already been implicated in ALS pathogenesis, and the 15q11.2 locus, containing NIPA1 (OR = 12.46, P = 9.3 × 10(-5)), the gene causing hereditary spastic paraparesis type 6 (HSP 6). We tested these loci in a replication cohort of 2559 cases and 5887 controls. Again, results were suggestive of association, but did not meet our criteria for independent replication: DPP6 locus: OR = 1.92, P = 0.097, pooled results: OR = 2.64, P = 1.4 × 10(-3); NIPA1: OR = 3.23, P = 0.041, pooled results: OR = 6.20, P = 2.2 × 10(-5)). Our results highlight DPP6 and NIPA1 as candidates for more in-depth studies. Unlike other complex neurological and psychiatric traits, rare CNVs with high effect size do not play a major role in ALS pathogenesis.
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| 2. |
- Breznau, Nate, et al.
(författare)
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Observing many researchers using the same data and hypothesis reveals a hidden universe of uncertainty
- 2022
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Ingår i: 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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Tidskriftsartikel (refereegranskat)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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| 3. |
- Hartl, Darren J., et al.
(författare)
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Computationally-efficient modeling of inelastic single crystal responses via anisotropic yield surfaces : Applications to shape memory alloys
- 2018
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Ingår i: International Journal of Solids and Structures. - : Elsevier BV. - 0020-7683. ; 136-137, s. 38-59
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Tidskriftsartikel (refereegranskat)abstract
- Phenomenological constitutive models of inelastic responses based on the methods of classical plasticity provide several advantages, especially in terms of computational efficiency. For this reason, they are attractive for the analysis of complex boundary value problems comprising large computational domains. However, for the analysis of problems dominated by single crystal behavior (e.g., inclusion, granular interaction problems or inter-granular fracture), such approaches are often limited by the symmetry assumptions inherent in the stress invariants used to form yield-type criteria. On the other hand, the high computational effort associated with micro-mechanical or crystal plasticity-type models usually prevents their use in large structural simulations, multi-scale analyses, or design and property optimization computations. The goal of the present work is to establish a modeling strategy that captures micro-scale single-crystalline sma responses with sufficient fidelity at the computational cost of a phenomenological macro-scale model. Its central idea is to employ an anisotropic transformation yield criterion with sufficiently rich symmetry class-which can directly be adopted from the literature on plasticity theory-at the single crystal level. This approach is conceptually fundamentally different from the common use of anisotropic yield functions to capture tension-compression asymmetry and texture-induced anisotropy in poly-crystalline SMAs. In our model, the required anisotropy parameters are calibrated either from experimental data for single crystal responses, theoretical considerations or micro-scale computations. The model thus efficiently predicts single crystal behaviors and can be applied to the analysis of complex boundary value problems. In this work we consider the application of this approach to the modeling of shape memory alloys (SMAs), though its potential utility is much broader. Example analyses of SMA single crystals that include non-transforming precipitates and poly-crystalline aggregates are considered and the effects of both elastic and transformation anisotropy in these materials are demonstrated.
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| 4. |
- Schulte, Peter, et al.
(författare)
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Cretaceous Extinctions: Evidence Overlooked Response
- 2010
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 328:5981, s. 975-976
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 5. |
- Schulte, Peter, et al.
(författare)
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The Chicxulub Asteroid Impact and Mass Extinction at the Cretaceous-Paleogene Boundary
- 2010
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 327:5970, s. 1214-1218
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Tidskriftsartikel (refereegranskat)abstract
- The Cretaceous-Paleogene boundary similar to 65.5 million years ago marks one of the three largest mass extinctions in the past 500 million years. The extinction event coincided with a large asteroid impact at Chicxulub, Mexico, and occurred within the time of Deccan flood basalt volcanism in India. Here, we synthesize records of the global stratigraphy across this boundary to assess the proposed causes of the mass extinction. Notably, a single ejecta-rich deposit compositionally linked to the Chicxulub impact is globally distributed at the Cretaceous-Paleogene boundary. The temporal match between the ejecta layer and the onset of the extinctions and the agreement of ecological patterns in the fossil record with modeled environmental perturbations (for example, darkness and cooling) lead us to conclude that the Chicxulub impact triggered the mass extinction.
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| 6. |
- Schulte, Robin, et al.
(författare)
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Gradient-enhanced modelling of damage for rate-dependent material behaviour-a parameter identification framework
- 2020
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Ingår i: Materials. - : MDPI AG. - 1996-1944. ; 13:14
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Tidskriftsartikel (refereegranskat)abstract
- The simulation of complex engineering components and structures under loads requires the formulation and adequate calibration of appropriate material models. This work introduces an optimisation-based scheme for the calibration of viscoelastic material models that are coupled to gradient-enhanced damage in a finite strain setting. The parameter identification scheme is applied to a self-diagnostic poly(dimethylsiloxane) (PDMS) elastomer, where so-called mechanophore units are incorporated within the polymeric microstructure. The present contribution, however, focuses on the purely mechanical response of the material, combining experiments with homogeneous and inhomogeneous states of deformation. In effect, the results provided lay the groundwork for a future extension of the proposed parameter identification framework, where additional field-data provided by the self-diagnostic capabilities can be incorporated into the optimisation scheme.
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| 7. |
- Schulte, Robin, et al.
(författare)
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Machine learning-assisted parameter identification for constitutive models based on concatenated loading path sequences
- 2023
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Ingår i: European Journal of Mechanics, A/Solids. - : Elsevier BV. - 0997-7538. ; 98
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Tidskriftsartikel (refereegranskat)abstract
- A hybrid strategy for the identification of material parameters of constitutive models is presented. One main challenge in the context of classic optimisation-based parameter identification schemes is the generation of adequate starting values for the multi-objective optimisation procedure. We address this issue by employing an artificial neural network that is trained with data obtained from the material model, more precisely speaking, from different solutions of the direct problem for homogeneous states of deformation. As a result, a solution of the inverse problem of parameter identification can be approximated with the help of a neural network processing experimental data. This approximate solution is used as a starting value for a subsequent, classic optimisation-based parameter identification approach. One key advantage of this strategy is that a network only has to be trained once per material model and can subsequently be applied for different materials. A rather sophisticated material model, incorporating gradient-enhanced damage coupled to plasticity in a geometrically non-linear setting, is used to demonstrate the capabilities of this approach. Two different strategies for the generation of training data are investigated and compared, and the neural network's hyperparameters are optimised for improved prediction capabilities. In view of the calibration of material parameters related to the non-locality of the model, the obtained set of parameters is again considered as a starting value for a final optimisation step, where we consider inhomogeneous states of deformation and digital image correlation data.
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| 8. |
- van Es, Michael A, et al.
(författare)
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Angiogenin variants in Parkinson disease and amyotrophic lateral sclerosis
- 2011
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Ingår i: Annals of Neurology. - : Wiley-Blackwell. - 0364-5134 .- 1531-8249. ; 70:6, s. 964-973
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Several studies have suggested an increased frequency of variants in the gene encoding angiogenin (ANG) in patients with amyotrophic lateral sclerosis (ALS). Interestingly, a few ALS patients carrying ANG variants also showed signs of Parkinson disease (PD). Furthermore, relatives of ALS patients have an increased risk to develop PD, and the prevalence of concomitant motor neuron disease in PD is higher than expected based on chance occurrence. We therefore investigated whether ANG variants could predispose to both ALS and PD.METHODS: We reviewed all previous studies on ANG in ALS and performed sequence experiments on additional samples, which allowed us to analyze data from 6,471 ALS patients and 7,668 controls from 15 centers (13 from Europe and 2 from the USA). We sequenced DNA samples from 3,146 PD patients from 6 centers (5 from Europe and 1 from the USA). Statistical analysis was performed using the variable threshold test, and the Mantel-Haenszel procedure was used to estimate odds ratios.RESULTS: Analysis of sequence data from 17,258 individuals demonstrated a significantly higher frequency of ANG variants in both ALS and PD patients compared to control subjects (p = 9.3 × 10(-6) for ALS and p = 4.3 × 10(-5) for PD). The odds ratio for any ANG variant in patients versus controls was 9.2 for ALS and 6.7 for PD.INTERPRETATION: The data from this multicenter study demonstrate that there is a strong association between PD, ALS, and ANG variants. ANG is a genetic link between ALS and PD.
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| 9. |
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- 2019
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Tidskriftsartikel (refereegranskat)
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