| 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. |
- Broman, David, et al.
(författare)
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Determinate Composition of FMUs for Co-Simulation
- 2013
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Ingår i: Proceedings of the International Conference on Embedded Software (EMSOFT 2013). - : IEEE conference proceedings. ; , s. 1-12
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Konferensbidrag (refereegranskat)abstract
- In this paper, we explain how to achieve deterministic execution of FMUs (Functional Mockup Units) under the FMI (Functional Mockup Interface) standard. In particular, we focus on co-simulation, where an FMU either contains its own internal simulation algorithm or serves as a gateway to a simulation tool. We give conditions on the design of FMUs and master algorithms (which orchestrate the execution of FMUs) to achieve deterministic co-simulation. We show that with the current version of the standard, these conditions demand capabilities from FMUs that are optional in the standard and rarely provided by an FMU in practice. When FMUs lacking these required capabilities are used to compose a model, many basic modeling capabilities become unachievable, including simple discrete-event simulation and variable-step-size numerical integration algorithms. We propose a small extension to the standard and a policy for designing FMUs that enables deterministic execution for a much broader class of models. The extension enables a master algorithm to query an FMU for the time of events that are expected in the future. We show that a model can be executed deterministically if all FMUs in the model are either memoryless or implement one of rollback or step-size prediction. We show further that such a model can contain at most one “legacy” FMU that is not memoryless and provides neither rollback nor step-size prediction.
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| 3. |
- Broman, David, 1977-, et al.
(författare)
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Requirements for Hybrid Cosimulation Standards
- 2015
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Ingår i: Proceedings of 18th ACM International Conference on Hybrid Systems: Computation and Control (HSCC). - New York, NY, USA : ACM Digital Library. - 9781450334334 ; , s. 179-188
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Konferensbidrag (refereegranskat)abstract
- This paper defines a suite of requirements for future hybrid cosimulation standards, and specifically provides guidance for development of a hybrid cosimulation version of the Functional Mockup Interface (FMI). A cosimulation standard defines interfaces that enable diverse simulation tools to interoperate. Specifically, one tool defines a component that forms part of a simulation model in another tool. We focus on components with inputs and outputs that are functions of time, and specifically on mixtures of discrete events and continuous time signals. This hybrid mixture is not well supported by existing cosimulation standards, and specifically not by FMI 2.0, for reasons that are explained in this paper. The paper defines a suite of test components, giving a mathematical model of an ideal behavior, plus a discussion of practical implementation considerations. The discussion includes acceptance criteria by which we can determine whether a standard supports definition of each component. In addition, we define a set of test compositions that define requirements for coordination between components, including consistent handling of timed events.
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| 4. |
- Atefi, Seyed Reza, et al.
(författare)
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Intracranial haemorrhage alters scalp potential distributions in bioimpedance cerebral monitoring applications : preliminary results from FEM simulation on a realistic head model and human subjects
- 2016
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Ingår i: Medical Physics. - : American Association of Physicists in Medicine. - 2473-4209 .- 0094-2405. ; 43:2, s. 675-686
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Current diagnostic neuroimaging for detection of intracranial hemorrhage (ICH) is limited to fixed scanners requiring patient transport and extensive infrastructure support. ICH diagnosis would therefore benefit from a portable diagnostic technology, such as electrical bioimpedance (EBI). Through simulations and patient observation, the authors assessed the influence of unilateral ICH hematomas on quasisymmetric scalp potential distributions in order to establish the feasibility of EBI technology as a potential tool for early diagnosis. Methods: Finite element method (FEM) simulations and experimental leftright hemispheric scalp potential differences of healthy and damaged brains were compared with respect to the asymmetry caused by ICH lesions on quasisymmetric scalp potential distributions. In numerical simulations, this asymmetry was measured at 25 kHz and visualized on the scalp as the normalized potential difference between the healthy and ICH damaged models. Proof-of-concept simulations were extended in a pilot study of experimental scalp potential measurements recorded between 0 and 50 kHz with the authors custom-made bioimpedance spectrometer. Mean leftright scalp potential differences recorded from the frontal, central, and parietal brain regions of ten healthy control and six patients suffering from acute/subacute ICH were compared. The observed differences were measured at the 5% level of significance using the two-sample Welch ttest. Results: The 3D-anatomically accurate FEM simulations showed that the normalized scalp potential difference between the damaged and healthy brain models is zero everywhere on the head surface, except in the vicinity of the lesion, where it can vary up to 5%. The authors preliminary experimental results also confirmed that the leftright scalp potential difference in patients with ICH (e.g., 64 mV) is significantly larger than in healthy subjects (e.g., 20.8 mV; P < 0.05). Conclusions: Realistic, proof-of-concept simulations confirmed that ICH affects quasisymmetric scalp potential distributions. Pilot clinical observations with the authors custom-made bioimpedance spectrometer also showed higher leftright potential differences in the presence of ICH, similar to those of their simulations, that may help to distinguish healthy subjects from ICH patients. Although these pilot clinical observations are in agreement with the computer simulations, the small sample size of this study lacks statistical power to exclude the influence of other possible confounders such as age, ex, and electrode positioning. The agreement with previously published simulation-based and clinical results, however, suggests that EBI technology may be potentially useful for ICH detection.
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| 5. |
- Clark, Kristen D., et al.
(författare)
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State-Level Policy Environments, Discrimination, and Victimization among Sexual and Gender Minority People
- 2022
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Ingår i: International Journal of Environmental Research and Public Health. - : MDPI. - 1661-7827 .- 1660-4601. ; 19:16
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Tidskriftsartikel (refereegranskat)abstract
- Legislation has been passed in some states to reduce discrimination and victimization toward sexual and gender minority people (SGM; people who are not solely heterosexual and/or whose gender identity is not equal to what is socially associated with sex assigned at birth). The purpose of these analyses is to test whether state-level policy environments are associated with past-year discrimination and victimization among SGM people. Cross-sectional data from The Population Research in Identity and Disparities for Equality (PRIDE) Study annual questionnaire (collected 2018–2019), a national study of the health of SGM adults in the USA, were used for these analyses. Measures included related to discrimination, victimization, and demographic characteristics. State-level policy environments were measured using data from the Movement Advancement Project. Logistic regression analyses evaluated state-level policy environment scores and past-year discrimination and victimization among gender identity categories. In this sample, 7044 people (gender minority n = 2530) were included. Cisgender sexual minority (odds ratio [OR] = 1.007, p = 0.041) and the gender expansive subgroup of gender minority people (OR = 1.010, p = 0.047) in states with more protective policy environments had greater odds of discrimination. The gender expansive subgroup was found to have greater odds of victimization in states with more protective policy environments (OR = 1.003, p < 0.05). There was no relationship between state-level policy environments and victimization among any other study groups. SGM people may experience increased risk for discrimination and victimization despite legislative protections, posing continued risks for poor health outcomes and marginalization. Evaluation of factors (e.g., implementation strategies, systems of accountability) that influence the effectiveness of state-level polices on the reported experiences of discrimination and victimization among SGM people is needed.
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| 6. |
- Dai, Lei, et al.
(författare)
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AME : A Cross-Scale Constellation of CubeSats to Explore Magnetic Reconnection in the Solar-Terrestrial Relation
- 2020
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Ingår i: Frontiers in Physics. - : Frontiers Media SA. - 2296-424X. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- A major subset of solar-terrestrial relations, responsible, in particular, for the driver of space weather phenomena, is the interaction between the Earth's magnetosphere and the solar wind. As one of the most important modes of the solar-wind-magnetosphere interaction, magnetic reconnection regulates the energy transport and energy release in the solar-terrestrial relation. In situ measurements in the near-Earth space are crucial for understanding magnetic reconnection. Past and existing spacecraft constellation missions mainly focus on the measurement of reconnection on plasma kinetic-scales. Resolving the macro-scale and cross-scale aspects of magnetic reconnection is necessary for accurate assessment and predictions of its role in the context of space weather. Here, we propose the AME (self-Adaptive Magnetic reconnection Explorer) mission consisting of a cross-scale constellation of 12+ CubeSats and one mother satellite. Each CubeSat is equipped with instruments to measure magnetic fields and thermal plasma particles. With multiple CubeSats, the AME constellation is intended to make simultaneous measurements at multiple scales, capable of exploring cross-scale plasma processes ranging from kinetic scale to macro scale.
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| 7. |
- Heap, Graham A., et al.
(författare)
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HLA-DQA1-HLA-DRB1 variants confer susceptibility to pancreatitis induced by thiopurine immunosuppressants
- 2014
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 46:10, s. 1131-1134
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Tidskriftsartikel (refereegranskat)abstract
- Pancreatitis occurs in approximately 4% of patients treated with the thiopurines azathioprine or mercaptopurine. Its development is unpredictable and almost always leads to drug withdrawal. We identified patients with inflammatory bowel disease (IBD) who had developed pancreatitis within 3 months of starting these drugs from 168 sites around the world. After detailed case adjudication, we performed a genome-wide association study on 172 cases and 2,035 controls with IBD. We identified strong evidence of association within the class II HLA region, with the most significant association identified at rs2647087 (odds ratio 2.59, 95% confidence interval 2.07-3.26, P = 2 x 10(-16)). We replicated these findings in an independent set of 78 cases and 472 controls with IBD matched for drug exposure. Fine mapping of the H LA region identified association with the HLA-DQA1*02:01-HLA-DRB1*07:01 haplotype. Patients heterozygous at rs2647087 have a 9% risk of developing pancreatitis after administration of a thiopurine, whereas homozygotes have a 17% risk.
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| 8. |
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| 9. |
- Kliest, Tessa, et al.
(författare)
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Clinical trials in pediatric ALS: a TRICALS feasibility study
- 2022
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Ingår i: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. - : Taylor & Francis Group. - 2167-8421 .- 2167-9223. ; 23:7-8, s. 481-488
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Tidskriftsartikel (refereegranskat)abstract
- Background: Pediatric investigation plans (PIPs) describe how adult drugs can be studied in children. In 2015, PIPs for Amyotrophic Lateral Sclerosis (ALS) became mandatory for European marketing-authorization of adult treatments, unless a waiver is granted by the European Medicines Agency (EMA).Objective: To assess the feasibility of clinical studies on the effect of therapy in children (<18 years) with ALS in Europe.Methods: The EMA database was searched for submitted PIPs in ALS. A questionnaire was sent to 58 European ALS centers to collect the prevalence of pediatric ALS during the past ten years, the recruitment potential for future pediatric trials, and opinions of ALS experts concerning a waiver for ALS.Results: Four PIPs were identified; two were waived and two are planned for the future. In total, 49 (84.5%) centers responded to the questionnaire. The diagnosis of 44,858 patients with ALS was reported by 46 sites; 39 of the patients had an onset < 18 years (prevalence of 0.008 cases per 100,000 or 0.087% of all diagnosed patients). The estimated recruitment potential (47 sites) was 26 pediatric patients within five years. A majority of ALS experts (75.5%) recommend a waiver should apply for ALS due to the low prevalence of pediatric ALS.Conclusions: ALS with an onset before 18 years is extremely rare and may be a distinct entity from adult ALS. Conducting studies on the effect of disease-modifying therapy in pediatric ALS may involve lengthy recruitment periods, high costs, ethical/legal implications, challenges in trial design and limited information.
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| 10. |
- Novikova, Liudmila N., et al.
(författare)
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Trimethylene carbonate-caprolactone conduit with poly-p-dioxanone microfilaments to promote regeneration after spinal cord injury
- 2018
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Ingår i: Acta Biomaterialia. - : Elsevier. - 1742-7061 .- 1878-7568. ; 66, s. 177-191
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Tidskriftsartikel (refereegranskat)abstract
- Spinal cord injury (SCI) is often associated with scarring and cavity formation and therefore bridging strategies are essential to provide a physical substrate for axonal regeneration. In this study we investigated the effects of a biodegradable conduit made from trimethylene carbonate and c-caprolactone (TC) containing poly-p-dioxanone microfilaments (PDO) with longitudinal grooves on regeneration after SCI in adult rats. In vitro studies demonstrated that different cell types including astrocytes, meningeal fibroblasts, Schwann cells and adult sensory dorsal root ganglia neurons can grow on the TC and PDO material. For in vivo experiments, the TC/PDO conduit was implanted into a small 2-3 mm long cavity in the C3-C4 cervical segments immediately after injury (acute SCI) or at 2-5 months after initial surgery (chronic SCI). At 8 weeks after implantation into acute SCI, numerous 5HT-positive descending raphaespinal axons and sensory CGRP-positive axons regenerated across the conduit and were often associated with PDO microfilaments and migrated host cells. Implantation into chronically injured SCI induced regeneration mainly of the sensory CGRP-positive axons. Although the conduit had no effect on the density of OX42-positive microglial cells when compared with SCI control, the activity of GFAP-positive astrocytes was reduced. The results suggest that a TC/PDO conduit can support axonal regeneration after acute and chronic SCI even without addition of exogenous glial or stem cells.
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