| 1. |
- Thompson, Paul M., et al.
(författare)
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The ENIGMA Consortium : large-scale collaborative analyses of neuroimaging and genetic data
- 2014
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Ingår i: BRAIN IMAGING BEHAV. - : Springer Science and Business Media LLC. - 1931-7557 .- 1931-7565. ; 8:2, s. 153-182
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Tidskriftsartikel (refereegranskat)abstract
- The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA's first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way.
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| 2. |
- Wanschers, Bas F. J., et al.
(författare)
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A mutation in the human CBP4 ortholog UQCC3 impairs complex III assembly, activity and cytochrome b stability
- 2014
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:23, s. 6356-6365
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Tidskriftsartikel (refereegranskat)abstract
- Complex III (cytochrome bc(1)) is a protein complex of the mitochondrial inner membrane that transfers electrons from ubiquinol to cytochrome c. Its assembly requires the coordinated expression of mitochondrial-encoded cytochrome b and nuclear-encoded subunits and assembly factors. Complex III deficiency is a severe multisystem disorder caused by mutations in subunit genes or assembly factors. Sequence-profile-based orthology predicts C11orf83, hereafter named UQCC3, to be the ortholog of the fungal complex III assembly factor CBP4. We describe a homozygous c.59T > A missense mutation in UQCC3 from a consanguineous patient diagnosed with isolated complex III deficiency, displaying lactic acidosis, hypoglycemia, hypotonia and delayed development without dysmorphic features. Patient fibroblasts have reduced complex III activity and lower levels of the holocomplex and its subunits than controls. They have no detectable UQCC3 protein and have lower levels of cytochrome b protein. Furthermore, in patient cells, cytochrome b is absent from a high-molecular-weight complex III. UQCC3 is reduced in cells depleted for the complex III assembly factors UQCC1 and UQCC2. Conversely, absence of UQCC3 in patient cells does not affect UQCC1 and UQCC2. This suggests that UQCC3 functions in the complex III assembly pathway downstream of UQCC1 and UQCC2 and is consistent with what is known about the function of Cbp4 and of the fungal orthologs of UQCC1 and UQCC2, Cbp3 and Cbp6. We conclude that UQCC3 functions in complex III assembly and that the c.59T > A mutation has a causal role in complex III deficiency.
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| 3. |
- van den Heuvel, Martijn, et al.
(författare)
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Towards Verification-based Development of In-Vehicle Safety Critical Software : A Case Study
- 2010
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Ingår i: ACM International Conference Proceeding Series. - New York, New York, USA : ACM Press. - 9781605589152 ; , s. 35-38
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Konferensbidrag (refereegranskat)abstract
- The ever increasing software complexity in the safety critical automotive domain induces new challenges in ensuring a fault-free system design. In this paper we propose a novel approach using Analytical Software Design (ASD). The ASD toolsuite provides means to develop software that is robust by construction. We show the integration of the ASD approach in the commonly used development workflow using Matlab/Simulink by means of a case study.
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| 4. |
- Bril, Reinder J., et al.
(författare)
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Generalized fixed-priority scheduling with limited preemptions
- 2012
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Ingår i: Proceedings - Euromicro Conference on Real-Time Systems, 2012. - 9780769547398 ; , s. 209-220
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Konferensbidrag (refereegranskat)abstract
- Fixed-priority scheduling with deferred preemption(FPDS) and fixed-priority scheduling with preemption thresholds(FPTS) have been proposed in the literature as viable alternatives to fixed-priority preemptive scheduling (FPPS), that reduce memory requirements, reduce the cost of arbitrary preemptions, and may improve the feasibility of a task set even when preemption overheads are neglected. This paper aims at advancing the relative strength of limited preemptive schedulers by combining FPDS and FPTS. In particular, we present a refinement of FPDS with preemption thresholds for both jobs and sub-jobs, termed FPGS. We provide an exact schedulability analysis for FPGS, and show how to maximize the feasibility of a set of sporadic tasks under FPGS for given priorities, computation times, periods, and deadlines of tasks. We evaluate the effectiveness of FPGS by comparing the feasibility of task sets under FPGS with other fixed-priority scheduling algorithms by means of a simulation. Our experiments show that FPGS allows an increase of the number of task sets that are schedulable under fixed-priority scheduling.
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| 5. |
- Bril, Reinder J., et al.
(författare)
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Improved feasibility of fixed-priority scheduling with deferred preemption using preemption thresholds for preemption points
- 2013
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Ingår i: RTNS '13 Proceedings of the 21st International conference on Real-Time Networks and Systems. - New York, NY, USA : ACM. - 9781450320580 ; , s. 255-264
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Konferensbidrag (refereegranskat)abstract
- This paper aims at advancing the relative strength of limited-preemptive schedulers by improving the feasibility of a task set and simultaneously limiting, or even precluding, arbitrary preemptions. In particular, we present a refinement of existing limited-preemptive fixed-priority scheduling (FPS) schemes with preemption thresholds for preemption points next to preemption thresholds for sub-jobs, termed fixed-priority scheduling with varying preemption thresholds (FPVS). We derive exact schedulability analysis for FPVS and we develop algorithms to maximize the schedulability of a set of sporadic tasks for given priorities. Since FPVS generalizes existing FPS schemes, we apply our algorithms to those schemes to compare the ratio of schedulable systems. Our experiments show that FPVS can achieve the same schedulability ratio with limited-preemptive sub-jobs as with entirely non-preemptive sub-jobs.
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| 6. |
- Bril, Reinder J., et al.
(författare)
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Integrating Cache-Related Pre-emption Delays into Analysis of Fixed Priority Scheduling with Pre-emption Thresholds
- 2015
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Ingår i: Proceedings - Real-Time Systems Symposium. - 9781479972890 ; , s. 161-172
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Konferensbidrag (refereegranskat)abstract
- Cache-related pre-emption delays (CRPD) have been integrated into the schedulability analysis of sporadic tasks with constrained deadlines for fixed-priority pre-emptive scheduling (FPPS). This paper generalizes that work by integrating CRPD into the schedulability analysis of tasks with arbitrary deadlines for fixed-priority pre-emption threshold scheduling (FPTS). The analysis is complemented by an optimal threshold assignment algorithm that minimizes CRPD. The paper includes a comparative evaluation of the schedulability ratios of FPPS and FPTS, for constrained-deadline tasks, taking CRPD into account.
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| 7. |
- J. Bril, Reinder, et al.
(författare)
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Fixed priority scheduling with pre-emption thresholds and cache-related pre-emption delays : integrated analysis and evaluation
- 2017
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Ingår i: Real-time systems. - : Springer Science and Business Media LLC. - 0922-6443 .- 1573-1383. ; 53:4, s. 403-466
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Tidskriftsartikel (refereegranskat)abstract
- Commercial off-the-shelf programmable platforms for real-time systems typically contain a cache to bridge the gap between the processor speed and main memory speed. Because cache-related pre-emption delays (CRPD) can have a significant influence on the computation times of tasks, CRPD have been integrated in the response time analysis for fixed-priority pre-emptive scheduling (FPPS). This paper presents CRPD aware response-time analysis of sporadic tasks with arbitrary deadlines for fixed-priority pre-emption threshold scheduling (FPTS), generalizing earlier work. The analysis is complemented by an optimal (pre-emption) threshold assignment algorithm, assuming the priorities of tasks are given. We further improve upon these results by presenting an algorithm that searches for a layout of tasks in memory that makes a task set schedulable. The paper includes an extensive comparative evaluation of the schedulability ratios of FPPS and FPTS, taking CRPD into account. The practical relevance of our work stems from FPTS support in AUTOSAR, a standardized development model for the automotive industry. [(This paper forms an extended version of Bril et al. (in Proceedings of 35th IEEE real-time systems symposium (RTSS), 2014). The main extensions are described in Sect. 1.2.].
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| 8. |
- Kaboodvand, Neda, et al.
(författare)
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Macroscopic resting state model predicts theta burst stimulation response : A randomized trial
- 2023
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Ingår i: PloS Computational Biology. - : Public Library of Science (PLoS). - 1553-734X .- 1553-7358. ; 19:3
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Tidskriftsartikel (refereegranskat)abstract
- Repetitive transcranial magnetic stimulation (rTMS) is a promising alternative therapy for treatment-resistant depression, although its limited remission rate indicates room for improvement. As depression is a phenomenological construction, the biological heterogeneity within this syndrome needs to be considered to improve the existing therapies. Whole-brain modeling provides an integrative multi-modal framework for capturing disease heterogeneity in a holistic manner.Computational modelling combined with a probabilistic nonparametric fitting was applied to the resting-state fMRI data from 42 patients (21 women), to parametrize baseline brain dynamics in depression. All patients were randomly assigned to two treatment groups, namely active (i.e., rTMS, n = 22) or sham (n = 20). The active treatment group received rTMS treatment with an accelerated intermittent theta burst protocol over the dorsomedial prefrontal cortex. The sham treatment group underwent the identical procedure but with the magnetically shielded side of the coil.We stratified the depression sample into distinct covert subtypes based on their baseline attractor dynamics captured by different model parameters. Notably, the two detected depression subtypes exhibited different phenotypic behaviors at baseline. Our stratification could predict the diverse response to the active treatment that could not be explained by the sham treatment. Critically, we further found that one group exhibited more distinct improvement in certain affective and negative symptoms. The subgroup of patients with higher responsiveness to treatment exhibited blunted frequency dynamics for intrinsic activity at baseline, as indexed by lower global metastability and synchrony.Our findings suggested that whole-brain modeling of intrinsic dynamics may constitute a determinant for stratifying patients into treatment groups and bringing us closer towards precision medicine.
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| 9. |
- Schophuizen, Carolien M. S., et al.
(författare)
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Cationic uremic toxins affect human renal proximal tubule cell functioning through interaction with the organic cation transporter
- 2013
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Ingår i: Pflügers Archiv. - : Springer Science and Business Media LLC. - 0031-6768. ; 465:12, s. 1701-1714
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Tidskriftsartikel (refereegranskat)abstract
- Several organic cations, such as guanidino compounds and polyamines, have been found to accumulate in plasma of patients with kidney failure due to inadequate renal clearance. Here, we studied the interaction of cationic uremic toxins with renal organic cation transport in a conditionally immortalized human proximal tubule epithelial cell line (ciPTEC). Transporter activity was measured and validated in cell suspensions by studying uptake of the fluorescent substrate 4-(4-(dimethylamino)styryl)-N-methylpyridinium-iodide (ASP(+)). Subsequently, the inhibitory potencies of the cationic uremic toxins, cadaverine, putrescine, spermine and spermidine (polyamines), acrolein (polyamine breakdown product), guanidine, and methylguanidine (guanidino compounds) were determined. Concentration-dependent inhibition of ASP(+) uptake by TPA, cimetidine, quinidine, and metformin confirmed functional endogenous organic cation transporter 2 (OCT2) expression in ciPTEC. All uremic toxins tested inhibited ASP(+) uptake, of which acrolein required the lowest concentration to provoke a half-maximal inhibition (IC50 = 44 +/- 2 mu M). A Dixon plot was constructed for acrolein using three independent inhibition curves with 10, 20, or 30 mu M ASP(+), which demonstrated competitive or mixed type of interaction (K (i) = 93 +/- 16 mu M). Exposing the cells to a mixture of cationic uremic toxins resulted in a more potent and biphasic inhibitory response curve, indicating complex interactions between the toxins and ASP(+) uptake. In conclusion, ciPTEC proves a suitable model to study cationic xenobiotic interactions. Inhibition of cellular uptake transport was demonstrated for several uremic toxins, which might indicate a possible role in kidney disease progression during uremia.
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| 10. |
- Smits, Paulien, et al.
(författare)
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Reconstructing the evolution of the mitochondrial ribosomal proteome
- 2007
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Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 35:14, s. 4686-4703
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Tidskriftsartikel (refereegranskat)abstract
- For production of proteins that are encoded by the mitochondrial genome, mitochondria rely on their own mitochondrial translation system, with the mitoribosome as its central component. Using extensive homology searches, we have reconstructed the evolutionary history of the mitoribosomal proteome that is encoded by a diverse subset of eukaryotic genomes, revealing an ancestral ribosome of alpha-proteobacterial descent that more than doubled its protein content in most eukaryotic lineages. We observe large variations in the protein content of mitoribosomes between different eukaryotes, with mammalian mitoribosomes sharing only 74 and 43% of its proteins with yeast and Leishmania mitoribosomes, respectively. We detected many previously unidentified mitochondrial ribosomal proteins (MRPs) and found that several have increased in size compared to their bacterial ancestral counterparts by addition of functional domains. Several new MRPs have originated via duplication of existing MRPs as well as by recruitment from outside of the mitoribosomal proteome. Using sensitive profile-profile homology searches, we found hitherto undetected homology between bacterial and eukaryotic ribosomal proteins, as well as between fungal and mammalian ribosomal proteins, detecting two novel human MRPs. These newly detected MRPs constitute, along with evolutionary conserved MRPs, excellent new screening targets for human patients with unresolved mitochondrial oxidative phosphorylation disorders.
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