Bulky DNA lesions in transcribed strands block RNA polymerase II (RNAPII) elongation and induce a genome-wide transcriptional arrest. The transcription-coupled repair (TCR) pathway efficiently... Show moreBulky DNA lesions in transcribed strands block RNA polymerase II (RNAPII) elongation and induce a genome-wide transcriptional arrest. The transcription-coupled repair (TCR) pathway efficiently removes transcription-blocking DNA lesions, but how transcription is restored in the genome following DNA repair remains unresolved. Here, we find that the TCR-specific CSB protein loads the PAF1 complex (PAF1C) onto RNAPII in promoter-proximal regions in response to DNA damage. Although dispensable for TCR-mediated repair, PAF1C is essential for transcription recovery after UV irradiation. We find that PAF1C promotes RNAPII pause release in promoter-proximal regions and subsequently acts as a processivity factor that stimulates transcription elongation throughout genes. Our findings expose the molecular basis for a non-canonical PAF1C-dependent pathway that restores transcription throughout the human genome after genotoxic stress. The transcription-coupled repair pathway removes transcription-blocking DNA lesions, but how transcription is restored following DNA repair is not clear. Here the authors reveal that the PAF1 complex, while dispensable for the repair process, restores transcription after DNA damage. Show less
Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown... Show moreDelineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large-scale studies. In response, we used cross-sectional data from 17,075 individuals aged 3-90 years from the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to infer age-related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta-analysis and one-way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes. Show less
Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown... Show moreDelineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large-scale studies. In response, we used cross-sectional data from 17,075 individuals aged 3-90 years from the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to infer age-related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta-analysis and one-way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes. Show less
Dima, D.; Modabbernia, A.; Papachristou, E.; Doucet, G.E.; Agartz, I.; Aghajani, M.; ... ; Frangou, S. 2021
Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These... Show moreAge has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to examine age-related trajectories inferred from cross-sectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3-90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter-individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age-related morphometric patterns. Show less
Dima, D.; Modabbernia, A.; Papachristou, E.; Doucet, G.E.; Agartz, I.; Aghajani, M.; ... ; Karolinska Schizophrenia Project K 2021
Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These... Show moreAge has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to examine age-related trajectories inferred from cross-sectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3-90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter-individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age-related morphometric patterns. Show less
Importance Large-scale neuroimaging studies have revealed group differences in cortical thickness across many psychiatric disorders. The underlying neurobiology behind these differences is not well... Show moreImportance Large-scale neuroimaging studies have revealed group differences in cortical thickness across many psychiatric disorders. The underlying neurobiology behind these differences is not well understood. Objective To determine neurobiologic correlates of group differences in cortical thickness between cases and controls in 6 disorders: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and schizophrenia. Design, Setting, and Participants Profiles of group differences in cortical thickness between cases and controls were generated using T1-weighted magnetic resonance images. Similarity between interregional profiles of cell-specific gene expression and those in the group differences in cortical thickness were investigated in each disorder. Next, principal component analysis was used to reveal a shared profile of group difference in thickness across the disorders. Analysis for gene coexpression, clustering, and enrichment for genes associated with these disorders were conducted. Data analysis was conducted between June and December 2019. The analysis included 145 cohorts across 6 psychiatric disorders drawn from the ENIGMA consortium. The numbers of cases and controls in each of the 6 disorders were as follows: ADHD: 1814 and 1602; ASD: 1748 and 1770; BD: 1547 and 3405; MDD: 2658 and 3572; OCD: 2266 and 2007; and schizophrenia: 2688 and 3244. Main Outcomes and Measures Interregional profiles of group difference in cortical thickness between cases and controls. Results A total of 12 721 cases and 15 600 controls, ranging from ages 2 to 89 years, were included in this study. Interregional profiles of group differences in cortical thickness for each of the 6 psychiatric disorders were associated with profiles of gene expression specific to pyramidal (CA1) cells, astrocytes (except for BD), and microglia (except for OCD); collectively, gene-expression profiles of the 3 cell types explain between 25% and 54% of variance in interregional profiles of group differences in cortical thickness. Principal component analysis revealed a shared profile of difference in cortical thickness across the 6 disorders (48% variance explained); interregional profile of this principal component 1 was associated with that of the pyramidal-cell gene expression (explaining 56% of interregional variation). Coexpression analyses of these genes revealed 2 clusters: (1) a prenatal cluster enriched with genes involved in neurodevelopmental (axon guidance) processes and (2) a postnatal cluster enriched with genes involved in synaptic activity and plasticity-related processes. These clusters were enriched with genes associated with all 6 psychiatric disorders. Conclusions and Relevance In this study, shared neurobiologic processes were associated with differences in cortical thickness across multiple psychiatric disorders. These processes implicate a common role of prenatal development and postnatal functioning of the cerebral cortex in these disorders.Question What are the neurobiologic underpinnings of group differences in cortical thickness in various psychiatric disorders? Findings In this consortium analysis of data from 145 cohorts, regions of the cerebral cortex with greater expression of genes specific to pyramidal (CA1) cells were also regions with greater case-control group differences in cortical thickness in all 6 disorders: attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depressive disorder, obsessive-compulsive disorder, and schizophrenia. There was a common profile of group differences in cortical thickness shared among these disorders, which was associated with the expression of genes involved in neurodevelopmental processes (prenatally) and processes underlying synaptic activity and plasticity (postnatally). Meaning There are shared neurobiologic and cellular mechanisms associated with differences in cortical thickness across multiple psychiatric disorders, implicating a common role of prenatal development and postnatal functioning of the cerebral cortex.This study evaluates neurobiologic correlates of group differences in cortical thickness between cases and controls in 6 psychiatric disorders. Show less
Bayesian Global Optimization (BGO) is a very efficient technique to optimize expensive evaluation problems. However, the application domain is limited to continuous search spaces when using a BGO... Show moreBayesian Global Optimization (BGO) is a very efficient technique to optimize expensive evaluation problems. However, the application domain is limited to continuous search spaces when using a BGO algorithm. To solve mixed integer problems with a BGO algorithm, this paper adapts the heterogeneous distance function to construct the Kriging models and applies these new Kriging models in Multi-objective Bayesian Global Optimization (MOBGO). The proposed mixed integer MOBGO algorithm and the traditional MOBGO algorithm are compared on three mixed integer multi-objective optimization problems (MOP), w.r.t. the mean value of the hypervolume (HV) and the related standard deviation. Show less
Blom, K. van der; Yang, K.; Bäck, T.; Emmerich, M.T.M. 2019
Many problems are of a mixed integer nature, rather than being restricted to a single variable type. Although mixed integer algorithms exist for the single-objective case, work on the multi... Show moreMany problems are of a mixed integer nature, rather than being restricted to a single variable type. Although mixed integer algorithms exist for the single-objective case, work on the multi-objective case remains limited. Evolution strategies are stochastic optimisation algorithms that feature step size adaptation mechanisms and are typically used in continuous domains. More recently they were generalised to mixed integer problems. In this work, first steps are taken towards extending the single-objective mixed integer evolution strategy for the multi-objective case. First results are promising, but step size adaptation for the multi-objective case can likely be improved. Show less
Terrestrial plants may experience nutrient and oxygen stress when they are submerged, and increases in flooding are anticipated with climate change. It has been well reported that plants usually... Show moreTerrestrial plants may experience nutrient and oxygen stress when they are submerged, and increases in flooding are anticipated with climate change. It has been well reported that plants usually shift biomass allocation and produce more roots in response to nutrient deficiency. However, it is unclear whether plants experiencing oxygen deficiency stimulate biomass allocation to roots to enhance nutrient absorption, similar to how plants experiencing nutrient deficiency behave. We investigated the responses of the terrestrial species Alternanthera philoxeroides, upon root flooding, to nutrient versus dissolved oxygen deficiency in terms of plant growth, biomass allocation, root production, root efficiency (plant growth sustained per unit root surface area), and root aerenchyma formation. Both nutrient and dissolved oxygen deficiency hampered the growth of root-flooded plants. As expected, plants experiencing nutrient deficiency increased biomass allocation to roots and exhibited lower root efficiency; in contrast, plants experiencing dissolved oxygen deficiency decreased biomass allocation to roots but achieved higher root efficiency. The diameter of aerenchyma channels in roots were enlarged in plants experiencing dissolved oxygen deficiency but did not change in plants experiencing nutrient deficiency. The widening of aerenchyma channels in roots could have improved the oxygen status and thereby the nutrient absorption capability of roots in low oxygen environments, which might benefit the plants to tolerate flooding. Show less
Prognostics and Health Management (PHM) attracts increasing interest of many researchers due to its potentially important applications in diverse disciplines and industries. In general, PHM systems... Show morePrognostics and Health Management (PHM) attracts increasing interest of many researchers due to its potentially important applications in diverse disciplines and industries. In general, PHM systems use real-time and historical state information of subsystems and components of the operating systems to provide actionable information, enabling intelligent decision-making for improved performance, safety, reliability, and maintainability. Every year, a substantial number of papers in this area including theory and practical applications, appear in academic journals, conference proceedings and technical reports. This paper aims to summarize and review researches, developments and recent contributions in PHM for automotive- and aerospace industries. It can also be considered as the starting point for researchers and practitioners in general to assist them through PHM implementation and help them to accomplish their work more easily. Show less
The Expected Hypervolume Improvement (EHVI) is a frequently used infill criterion in Multi-Objective Bayesian Global Optimization (MOBGO), due to its good ability to lead the exploration. Recently,... Show moreThe Expected Hypervolume Improvement (EHVI) is a frequently used infill criterion in Multi-Objective Bayesian Global Optimization (MOBGO), due to its good ability to lead the exploration. Recently, the computational complexity of EHVI calculation is reduced to O(n log n) for both 2-D and 3-D cases. However, the optimizer in MOBGO still requires a significant amount of time, because the calculation of EHVI is carried out in each iteration and usually tens of thousands of the EHVI calculations are required. This paper derives a formula for the Expected Hypervolume Improvement Gradient (EHVIG) and proposes an efficient algorithm to calculate EHVIG. The new criterion (EHVIG) is utilized by two different strategies to improve the efficiency of the optimizer discussed in this paper. Firstly, it enables gradient ascent methods to be used in MOBGO. Moreover, since the EHVIG of an optimal solution should be a zero vector, it can be regarded as a stopping criterion in global optimization, e.g., in Evolution Strategies. Empirical experiments are performed on seven benchmark problems. The experimental results show that the second proposed strategy, using EHVIG as a stopping criterion for local search, can outperform the normal MOBGO on problems where the optimal solutions are located in the interior of the search space. For the ZDT series test problems, EHVIG still can perform better when gradient projection is applied. Show less
A common method to solve expensive function evaluation problem is using Bayesian Global Optimization, instead of Evolutionary Algorithms. However, the execution time of multi-objective... Show moreA common method to solve expensive function evaluation problem is using Bayesian Global Optimization, instead of Evolutionary Algorithms. However, the execution time of multi-objective Bayesian Global Optimization (MOBGO) itself is still too long, even though it only requires a few function evaluations. The reason for the high cost of MOBGO is two-fold: on the one hand, MOBGO requires an infill criterion to be calculated many times, but the computational complexity of an infill criterion has so far been very high. Another reason is that the optimizer, which aims at searching for an optimal solution according to the surrogate models, is not sufficiently efficient. The main contributions of this thesis consist of 1. Decreased the computational complexity of a well-known infill criteria, Expected Hypervolume Improvement, into $n log (n)$ both in 2-D and 3-D cases; 2. Proposed a new criterion, Truncated Expected Hypervolume Improvement, to make full use of a-priori knowledge of objective functions, whenever it is available; 3. Proposed another infill criterion, Expected Hypervolume Improvement Gradient, to improve the convergence of the optimizer in MOBGO. Show less
