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See detailFunctional approximations with Stein's method of exchangeable pairs
Kasprzak, Mikolaj UL

in Annales Henri Poincare (2020), 56(4), 2540-564

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See detailThe functional Breuer-Major theorem
Nourdin, Ivan UL; Nualart, David

in Probability Theory and Related Fields (2020), 176

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See detailFunctional calculus in weighted group algebras
Dziubanski, Jacek; Ludwig, Jean; Molitor-Braun, Carine UL

in Revista Matemática Complutense (2004), 17(2), 321-357

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See detailFUNCTIONAL CHARACTERISATION OF THE A30P MUTATION IN ALPHA-SYNUCLEIN GENE IN A PATIENT-DERIVED CELLULAR MODEL OF PARKINSON’S DISEASE
Rodrigues Dos Santos, Bruno Filipe UL

Doctoral thesis (2019)

Our study aims to perform detailed phenotyping of the A30P alpha-synuclein familial case of PD, allowing to identify underlying mechanisms of the disease that may translate into novel therapies ... [more ▼]

Our study aims to perform detailed phenotyping of the A30P alpha-synuclein familial case of PD, allowing to identify underlying mechanisms of the disease that may translate into novel therapies. Parkinson’s disease (PD) is the second most common neurodegenerative disease. Approximately 20% of PD cases are known to have a genetic cause. From these, mutations in SNCA, the gene encoding alpha-synuclein, are linked to an autosomal dominant inheritance of the disease. In 1998, our group discovered the second known point mutation within the SNCA gene, causing an A30P exchange of the peptide sequence. We generated first patient-derived cellular model of the A30P alpha-synuclein mutation carrier, by obtaining fibroblasts from an affected sibling of the index patient, an unaffected sibling of the patient, and an age-matched gender-matched non-PD control. We reprogrammed these fibroblasts into induced pluripotent stem cells (iPSCs), and differentiated them into midbrain dopaminergic neurons. We obtained enriched cultures of 80% midbrain neurons (FoxA2+/Tuj1+), with approximately 12 % dopaminergic (TH+), for which we observed electrophysiological activity and dopamine release. We detected a significant reduction of the protein level of mitochondria complexes II, IV, and V in the patient lines compared with the controls, additionally we found a significant impairment of mitochondrial respiration and an increased susceptibility of the cells to oxidative stress. Gene-edited isogenic controls were generated to dissect mutation-specific effects. Furthermore, we investigated mitochondrial morphology and dynamics, and how these processes contribute to the dopaminergic neurodegeneration. Additionally, we were implementing previously established readouts on our high-throughput automated screening platform that will allow us to identify FDA approved compounds with potential to be re-purposed and used as PD treatment. We believe that detailed phenotyping of the A30P alpha-synuclein monogenic case may help to identify underlying mechanisms of the disease that may translate into novel therapies, which would also apply to the more common sporadic forms of PD. [less ▲]

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See detailFunctional characteristics of primary afferents innervating normal and inflamed knee joints of the rat
Schmidt, Robert; Pawlak, Matthias; Heppelmann, Bernd et al

in European Journal of Physiology (2000), 439

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See detailFunctional characterization of alternate optimal solutions of Escherichia coli's transcriptional and translational machinery.
Thiele, Ines UL; Fleming, Ronan MT UL; Bordbar, Aarash et al

in Biophysical Journal (2010), 98(10), 2072-81

The constraint-based reconstruction and analysis approach has recently been extended to describe Escherichia coli's transcriptional and translational machinery. Here, we introduce the concept of reaction ... [more ▼]

The constraint-based reconstruction and analysis approach has recently been extended to describe Escherichia coli's transcriptional and translational machinery. Here, we introduce the concept of reaction coupling to represent the dependency between protein synthesis and utilization. These coupling constraints lead to a significant contraction of the feasible set of steady-state fluxes. The subset of alternate optimal solutions (AOS) consistent with maximal ribosome production was calculated. The majority of transcriptional and translational reactions were active for all of these AOS, showing that the network has a low degree of redundancy. Furthermore, all calculated AOS contained the qualitative expression of at least 92% of the known essential genes. Principal component analysis of AOS demonstrated that energy currencies (ATP, GTP, and phosphate) dominate the network's capability to produce ribosomes. Additionally, we identified regulatory control points of the network, which include the transcription reactions of sigma70 (RpoD) as well as that of a degradosome component (Rne) and of tRNA charging (ValS). These reactions contribute significant variance among AOS. These results show that constraint-based modeling can be applied to gain insight into the systemic properties of E. coli's transcriptional and translational machinery. [less ▲]

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See detailFunctional characterization of novel RhoT1 variants, which are associated with Parkinson's disease.
Grossmann, Dajana UL

Doctoral thesis (2016)

Parkinson’s disease (PD) is a common neurodegenerative disease affecting up to 2 % of the population older than 65 years. Most PD cases are sporadic with unknown cause, and about 10 % are familial ... [more ▼]

Parkinson’s disease (PD) is a common neurodegenerative disease affecting up to 2 % of the population older than 65 years. Most PD cases are sporadic with unknown cause, and about 10 % are familial inherited. PD is a progressive neurodegenerative disease characterized by loss of predominantly dopaminergic neurons, leading to typical symptoms like rigidity and tremor. Commonly involved pathogenic pathways are linked to mitochondrial dysfunction, e.g. increased oxidative stress, disruption of calcium homeostasis, decreased energy supply and mitochondrial-controlled apoptosis. The mitochondrial outer membrane protein Miro1 is important for mitochondrial distribution, quality control and maintenance. To date Miro1 is not established as risk factor for PD. Using a comprehensive mutation screening of RhoT1 in German PD patients we dissected the role of the first PD-associated mutations in RhoT1, the gene encoding for Miro1. Three mutations in RhoT1 have been identified in three PD patients with positive family history for PD. For analysis of mitochondrial phenotypes patient-derived fibroblasts from two of the three patients were available. As independent cell model served the neuroblastoma cell line M17 with stable knockdown of endogenous RhoT1 and transiently overexpression of the RhoT1 mutant variants. Investigation of yeast with knockout of endogenous Gem1 (the yeast orthologue of Miro1) and overexpression of mutant Gem1 revealed that growth on non-fermentable carbon source was impaired. These findings suggest that Miro1-mutant1 is a loss of function mutation. Interestingly, the Miro1 protein amount was significantly reduced in Miro1-mutant1 and Miro1-mutant2 fibroblast lines compared to controls. Functional analysis revealed that mitochondrial mass was decreased in Miro1-mutant2, but not in Miro1-mutant1 fibroblasts, whereas mitochondrial biogenesis was increased in Miro1-mutant2 fibroblasts, as indicated by elevation of PGC1α. A similar phenotype with reduction of mitochondrial mass was also observed in M17 cells overexpressing Miro1-mutant1 or Miro1-mutant2. Additionally, spare respiratory capacity was reduced in Miro1-mutant1 fibroblasts compared to Ctrl 1 fibroblasts. In contrast, Miro1-mutant2 fibroblasts showed increased respiratory activity compared to Ctrl 1, despite citrate synthase activity was significantly reduced. Both alterations of respiratory activity lead to mitochondrial membrane hyperpolarization in Miro1-mutant1 and Miro1-mutant2 fibroblasts, a phenotype which was also found in M17 cells with knockdown of RhoT1. Both Miro1 mutant fibroblasts lines displayed different problems with cytosolic calcium buffering: in Miro1-mutant1 fibroblasts histamine treatment increased cytosolic calcium concentration significantly compared to Ctrl 1 fibroblasts, indicating that calcium homeostasis was impaired, whereas in Miro1-mutant2 fibroblasts the buffering capacity for cytosolic calcium was impaired. The results indicate that mutations in Miro1 cause significant mitochondrial dysfunction, which are likely contributing to neurodegeneration in PD and underline the importance of Miro1 for mitochondrial maintenance. [less ▲]

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See detailFunctional connectivity and structural analyses in the bilingual brain: implications for arithmetic.
Van Rinsveld, Amandine UL; Dricot, Laurence; Guillaume, Mathieu UL et al

Poster (2015, June)

Do bilinguals use the same brain networks than monolinguals when they solve arithmetic problems? We investigated this question by using resting-state functional connectivity and cortical thickness ... [more ▼]

Do bilinguals use the same brain networks than monolinguals when they solve arithmetic problems? We investigated this question by using resting-state functional connectivity and cortical thickness measurements. Recent studies highlighted differences of functional connectivity (e.g. Grady et al., 2015) and of brain structure (e.g. Klein et al., 2014) between bilinguals and monolinguals. However, no study so far has linked these differences to arithmetic problem solving, a cognitive skill that may at least partially rely on language processing. Our study population was composed of carefully selected German-French bilinguals (N = 20) who acquired each language at the same age, leading to high proficiency levels in both languages. These bilinguals all attended university in their second language at the time of the experiment, namely French. Therefore we selected a control group of French-speaking monolinguals (N = 12). Structural and functional images of brain activity were collected using a 3T MRI scanner. Functional scans of resting-state were acquired during a 6-minute session, with eyes closed. A 3D T1-weighted data set encompassing the whole brain was acquired to provide detailed anatomy (1 mm3), which was used both for the co-registration of functional data and for morphometric analyses. Prior to the scanning session, all participants took a behavioral test measuring their arithmetic skill. For the resting-state part of the study, we generated spheres based on ROIs reported in the literature as magnitude manipulation- and language-related areas during arithmetic problem solving (Klein et al. 2013), and addition-related areas reported in a recent meta-analysis (Arsalidou & Tayor, 2011). We used these spheres as seed regions for the analyses. We correlated resting activations between these regions and compared these correlations in bilinguals versus monolinguals. Results showed significantly higher correlations between the three seed regions in monolinguals than in bilinguals (all ts > 2.306; ps < .05), suggesting that regions used to solve arithmetic problems form a different network in bilinguals than in monolinguals. To control for general differences between both populations, we also created two spheres in areas not specifically related to neither arithmetic nor language regions. There were no significant differences between groups in terms of correlations of these regions with resting-state activations. These results suggest that the differences observed in arithmetic problem solving regions could not account for by general differences between groups. In the second part of the study, we aimed at verifying whether the differences in functional connectivity we observed between bilinguals and monolinguals coincide with structural brain differences. We measured and compared cortical thickness in both groups. Then we compared the correlations between cortical thickness and arithmetic skill in both groups (considering differences with corrected p < .001). Cortical thickness of areas commonly associated to language or number processing correlated differently with arithmetic skill as a function of the group: Higher cortical thickness of left pars triangularis, bilateral superior parietal gyri and precuneus positively correlated with arithmetic skill in monolinguals but negatively correlated with arithmetic skill in bilinguals. These results highlight that there are different relations between brain structure and arithmetic skills in bilinguals and monolinguals. In conclusion the current study provides new evidence for differences between bilinguals’ and monolinguals’ brain networks engaged in arithmetic problem solving, even without any arithmetic task during the data acquisition. These findings based on functional connectivity and brain structure analyses also reveal the general involvement of language in arithmetic problem solving in bilingual as well as non-bilingual individuals. [less ▲]

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See detailFunctional Convergence of U-processes with Size-Dependent Kernels
Döbler, Christian UL; Kasprzak, Mikolaj UL; Peccati, Giovanni UL

in Annals of Applied Probability (in press)

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See detailFunctional differences between L- and T-plastin isoforms.
Arpin, M.; Friederich, Evelyne UL; Algrain, M. et al

in The Journal of cell biology (1994), 127(6 Pt 2), 1995-2008

Fimbrins/plastins are a family of highly conserved actin-bundling proteins. They are present in all eukaryotic cells including yeast, but each isoform displays a remarkable tissue specificity. T-plastin ... [more ▼]

Fimbrins/plastins are a family of highly conserved actin-bundling proteins. They are present in all eukaryotic cells including yeast, but each isoform displays a remarkable tissue specificity. T-plastin is normally found in epithelial and mesenchymal cells while L-plastin is present in hematopoietic cells. However, L-plastin has been also found in tumor cells of non-hematopoietic origin (Lin, C.-S., R. H. Aebersold, S. B. Kent, M. Varma, and J. Leavitt. 1988. Mol. Cell. Biol. 8:4659-4668; Lin, C.-S., R. H. Aebersold, and J. Leavitt. 1990. Mol. Cell. Biol. 10: 1818-1821). To learn more about the biological significance of their tissue specificity, we have overproduced the T- and L-plastin isoforms in a fibroblast-like cell line, CV-1, and in a polarized epithelial cell line, LLC-PK1. In CV-1 cells, overproduction of T- and L-plastins induces cell rounding and a concomitant reorganization of actin stress fibers into geodesic structures. L-plastin remains associated with microfilaments while T-plastin is almost completely extracted after treatment of the cells with non-ionic detergent. In LLC-PK1 cells, T-plastin induces shape changes in microvilli and remains associated with microvillar actin filaments after detergent extraction while L-plastin has no effect on these structures and is completely extracted. The effect of T-plastin on the organization of microvilli differs from that of villin, another actin-bundling protein. Our experiments indicate that these two isoforms play differing roles in actin filament organization, and do so in a cell type-specific fashion. Thus it is likely that these plastin isoforms play fundamentally different roles in cell function. [less ▲]

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See detailFunctional effects and molecular mechanisms of subtype-selective ERalpha and ERbeta agonists in the cardiovascular system.
Arias-Loza, P. A.; Jazbutyte, V.; Fritzemeier, K. H. et al

in Ernst Schering Foundation symposium proceedings (2006), (1), 87-106

Gender differences in the development of cardiovascular disease suggested for a protective function of estrogens in heart disease. The negative or neutral outcome of clinical trials on hormone replacement ... [more ▼]

Gender differences in the development of cardiovascular disease suggested for a protective function of estrogens in heart disease. The negative or neutral outcome of clinical trials on hormone replacement therapy provides clear evidence that the role of female sex hormones in the cardiovascular system is more complex than previously thought. In particular, the function of estrogens can not be understood without detailed knowledge on the specific function of both estrogen receptor subtypes in the heart and in the vasculature. In here, we review recent studies on subtype selective ERalpha and ERbeta agonists in different animal models of hypertension, cardiac hypertrophy and vascular inflammation. The results indicate that the activation of specific ER subtypes confers specific as well as redundant protective effects in hypertensive heart disease that might ultimately translate into novel treatment options for hypertensive heart disease. [less ▲]

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See detailFunctional equation that characterize higher order derivations
Kiss, Gergely UL

Scientific Conference (2018, June)

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See detailFunctional Genome Analysis
Schneider, Reinhard UL

in Proceedings zur Tagung Hoechstleistungsrechnen in der Chemie. Tagung fuer industrielle Anwender (1998)

Scientific history is made in sequencing complete genomes. Two challenges loom large: decipher the function of all genes and describe the workings of the eukaryotic cell in full molecular detail ! A ... [more ▼]

Scientific history is made in sequencing complete genomes. Two challenges loom large: decipher the function of all genes and describe the workings of the eukaryotic cell in full molecular detail ! A combination of experimental and theoretical approaches will be brought to bear on these challenges. What's next in genome analysis from the point of view of bioinformatics ? [less ▲]

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See detailFunctional Genomics, Proteomics, Metabolomics and Bioinformatics for Systems Biology
Ballereau, S.; Glaab, Enrico UL; Kolodkin, Alexey UL et al

in Prokop, Ales; Csukás, Bela (Eds.) Systems Biology: Integrative Biology and Simulation Tools (2013)

This chapter introduces systems biology, its context, aims, concepts and strategies. It then describes approaches and methods used for collection of high-dimensional structural and functional genomics ... [more ▼]

This chapter introduces systems biology, its context, aims, concepts and strategies. It then describes approaches and methods used for collection of high-dimensional structural and functional genomics data, including epigenomics, transcriptomics, proteomics, metabolomics and lipidomics, and how recent technological advances in these fields have moved the bottleneck from data production to data analysis and bioinformatics. Finally, the most advanced mathematical and computational methods used for clustering, feature selection, prediction analysis, text mining and pathway analysis in functional genomics and systems biology are reviewed and discussed in the context of use cases. [less ▲]

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See detailFunctional impairment matters in the screening and diagnosis of gaming disorder
Billieux, Joël UL; King, Daniel Luke; Higuchi, Susumu et al

in Journal of Behavioral Addictions (2017), 6(3), 285-289

This commentary responds to Aarseth et al.’s (in press) criticisms that the ICD-11 Gaming Disorder proposal would result in “moral panics around the harm of video gaming” and “the treatment of abundant ... [more ▼]

This commentary responds to Aarseth et al.’s (in press) criticisms that the ICD-11 Gaming Disorder proposal would result in “moral panics around the harm of video gaming” and “the treatment of abundant false-positive cases.” The ICD-11 Gaming Disorder avoids potential “overpathologizing” with its explicit reference to functional impairment caused by gaming and therefore improves upon a number of flawed previous approaches to identifying cases with suspected gaming-related harms. We contend that moral panics are more likely to occur and be exacerbated by misinformation and lack of understanding, rather than proceed from having a clear diagnostic system [less ▲]

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See detailFunctional inequalities for Feynman-Kac semigroups
Thompson, James UL

in Journal of Theoretical Probability (2020)

Using stochastic analysis, we prove various gradient estimates and Harnack inequalities for Feynman-Kac semigroups with possibly unbounded potentials. One of the main results is a derivative formula which ... [more ▼]

Using stochastic analysis, we prove various gradient estimates and Harnack inequalities for Feynman-Kac semigroups with possibly unbounded potentials. One of the main results is a derivative formula which can be used to characterize a lower bound on Ricci curvature using a potential. [less ▲]

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See detailFunctional inequalities on manifolds with non-convex boundary
Cheng, Li Juan UL; Thalmaier, Anton UL; Thompson, James UL

in Science China Mathematics (2018), 61(8), 1421-1436

In this article, new curvature conditions are introduced to establish functional inequalities including gradient estimates, Harnack inequalities and transportation-cost inequalities on manifolds with non ... [more ▼]

In this article, new curvature conditions are introduced to establish functional inequalities including gradient estimates, Harnack inequalities and transportation-cost inequalities on manifolds with non-convex boundary. [less ▲]

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See detailFunctional inequalities on path space of sub-Riemannian manifolds and applications
Cheng, Li Juan UL; Grong, Erlend; Thalmaier, Anton UL

in Nonlinear Analysis (2021), 210(112387), 1-30

We consider the path space of a manifold with a measure induced by a stochastic flow with an infinitesimal generator that is hypoelliptic, but not elliptic. These generators can be seen as sub-Laplacians ... [more ▼]

We consider the path space of a manifold with a measure induced by a stochastic flow with an infinitesimal generator that is hypoelliptic, but not elliptic. These generators can be seen as sub-Laplacians of a sub-Riemannian structure with a chosen complement. We introduce a concept of gradient for cylindrical functionals on path space in such a way that the gradient operators are closable in L^2. With this structure in place, we show that a bound on horizontal Ricci curvature is equivalent to several inequalities for functions on path space, such as a gradient inequality, log-Sobolev inequality and Poincaré inequality. As a consequence, we also obtain a bound for the spectral gap of the Ornstein-Uhlenbeck operator. [less ▲]

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See detailFunctional Interpretation of Single Amino Acid Substitutions in 1,330 Disease-Associated Genes
Iqbal, Sumaiya; Jespersen, Jakob Berg; Perez-Palma, Eduardo et al

in Biophysical Journal (2019, February 15), 116(3), 420-421

Elucidating molecular consequences of amino-acid-altering missense variants at scale is challenging. In this work, we explored whether features derived from three-dimensional (3D) protein structures can ... [more ▼]

Elucidating molecular consequences of amino-acid-altering missense variants at scale is challenging. In this work, we explored whether features derived from three-dimensional (3D) protein structures can characterize patient missense variants across different protein classes with similar molecular level activities. The identified disease-associated features can advance our understanding of how a single amino acid substitution can lead to the etiology of monogenic disorders. For 1,330 disease-associated genes (>80%, 1,077/1,330 implicated in Mendelian disorders), we collected missense variants from the general population (gnomAD database, N=164,915) and patients (ClinVar and HGMD databases, N=32,923). We in silico mapped the variant positions onto >14k human protein 3D structures. We annotated the protein positions of variants with 40 structural, physiochemical, and functional features. We then grouped the genes into 24 protein classes based on their molecular functions and performed statistical association analyses with the features of population and patient variants. We identified 18 (out of 40) features that are associated with patient variants in general. Specifically, patient variants are less exposed to solvent (p<1.0e-100), enriched on b-sheets (p<2.37e-39), frequently mutate aromatic residues (p<1.0e-100), occur in ligand binding sites (p<1.0e-100) and are spatially close to phosphorylation sites (p<1.0e-100). We also observed differential protein-class-specific features. For three protein classes (signaling molecules, proteases and hydrolases), patient variants significantly perturb the disulfide bonds (p<1.0e-100). Only in immunity proteins, patient variants are enriched in flexible coils (p<1.65e-06). Kinases and cell junction proteins exhibit enrichment of patient variants around SUMOylation (p<1.0e-100) and methylation sites (p<9.29e-11), respectively. In summary, we studied shared and unique features associated with patient variants on protein structure across 24 protein classes, providing novel mechanistic insights. We generated an online resource that contains amino-acid-wise feature annotation-track for 1,330 genes, summarizes the patient-variant-associated features on residue level, and can guide variant interpretation. [less ▲]

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See detailFunctional meta-omics provide critical insights into long- and short-read assemblies
Galata, Valentina UL; Busi, Susheel Bhanu UL; Kunath, Benoît UL et al

in Briefings in Bioinformatics (2021)

Real-world evaluations of metagenomic reconstructions are challenged by distinguishing reconstruction artifacts from genes and proteins present in situ. Here, we evaluate short-read-only, long-read-only ... [more ▼]

Real-world evaluations of metagenomic reconstructions are challenged by distinguishing reconstruction artifacts from genes and proteins present in situ. Here, we evaluate short-read-only, long-read-only and hybrid assembly approaches on four different metagenomic samples of varying complexity. We demonstrate how different assembly approaches affect gene and protein inference, which is particularly relevant for downstream functional analyses. For a human gut microbiome sample, we use complementary metatranscriptomic and metaproteomic data to assess the metagenomic data-based protein predictions. Our findings pave the way for critical assessments of metagenomic reconstructions. We propose a reference-independent solution, which exploits the synergistic effects of multi-omic data integration for the in situ study of microbiomes using long-read sequencing data. [less ▲]

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