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See detailEvaluation of the Molecular Pathogenesis of Adrenocortical Tumors by Whole-Genome Sequencing
Neininger, Kerstin UL; May, Patrick UL; Altieri, Barbara et al

in Journal of the Endocrine Society (2021, May 03), 5(Issue Supplement_1), 68

Pathogenesis of autonomous steroid secretion and adrenocortical tumorigenesis remains partially obscure. Our aim was to identify novel genetic alterations in adrenocortical adenomas (ACA) without somatic ... [more ▼]

Pathogenesis of autonomous steroid secretion and adrenocortical tumorigenesis remains partially obscure. Our aim was to identify novel genetic alterations in adrenocortical adenomas (ACA) without somatic mutations in known driver genes. Whole-genome sequencing was performed on 26 ACA/blood-derived DNA pairs without driver mutations in PRKACA, GNAS and CTNNB1 genes at previous WES (ENSAT study JCEM 2016). These included 12 cortisol-producing adenomas with Cushing syndrome (CS-CPAs), 7 with mild autonomous cortisol secretion (MACS-CPAs), and 7 endocrine-inactive ACAs (EIAs). Seven adrenocortical carcinomas (ACC) were added to the cohort. We developed a bioinformatics pipeline for a comprehensive genome analysis and to reveal differences in variant distribution. Strelka, VarScan2 and ANNOVAR software and an in-house confidence score were used for variant calling and functional annotation. Combined Annotation-Dependent-Depletion (CADD) values were used to prioritize pathogenic variants. Additional focus relied on variants in pathogenically known pathways (Wnt/β-catenin, cAMP/PKA pathway). NovoBreak algorithm was applied to discover structural variations. Two hypermutated CS-CPA samples were excluded from further analysis. Using different filters, we detected variants in driver genes not observed at WES (one p.S45P in CTNNB1 and one p.R206L in PRKACA in two different CS-CPAs). In total, we report 179,830 variations (179,598 SNVs; 232 indels) throughout all samples, being more abundant in ACC (88,954) compared to ACA (CS-CPAs: 31,821; MACS-CPAs: 35,008; EIAs: 29,963). Most alterations were in intergenic (>50%), followed by intronic and ncRNA intronic regions. A total of 32 predicted pathogenic variants were found in both coding (CADD values ≥ 15) and non-coding (CADD values ≥ 5) regions. We found 3,301 possibly damaging and recurrent variants (intergenic mutations removed) (CS-CPAs: 1,463; MACS-CPAs: 1,549; EIAs: 1,268; ACC: 1,660), mostly accumulated in intronic regions. Some of these were detected in members of the Wnt/β-catenin (CS-CPAs: 6; MACS-CPAs: 2; EIA: 1) and cAMP/PKA (CS-CPAs: 6; MACS-CPAs: 7; EIA: 4) pathways (e.g. ADCY1, ADCY2, GNA13, PDE11A). We also found a slightly higher number of structural variations in EIA (3,620) and ACC (3,486) compared to CS-CPAs (977) and MACS-CPAs (2,119). In conclusion, still unrevealed genetic alterations, especially in intronic regions, may accompany early adrenal tumorigenesis and/or autonomous cortisol secretion. [less ▲]

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See detailDegree Adjusted Large-Scale Network Analysis Reveals Novel Putative Metabolic Disease Genes.
Badkas, Apurva UL; Nguyen, Thanh-Phuong UL; Caberlotto, Laura et al

in Biology (2021), 10(2),

A large percentage of the global population is currently afflicted by metabolic diseases (MD), and the incidence is likely to double in the next decades. MD associated co-morbidities such as non-alcoholic ... [more ▼]

A large percentage of the global population is currently afflicted by metabolic diseases (MD), and the incidence is likely to double in the next decades. MD associated co-morbidities such as non-alcoholic fatty liver disease (NAFLD) and cardiomyopathy contribute significantly to impaired health. MD are complex, polygenic, with many genes involved in its aetiology. A popular approach to investigate genetic contributions to disease aetiology is biological network analysis. However, data dependence introduces a bias (noise, false positives, over-publication) in the outcome. While several approaches have been proposed to overcome these biases, many of them have constraints, including data integration issues, dependence on arbitrary parameters, database dependent outcomes, and computational complexity. Network topology is also a critical factor affecting the outcomes. Here, we propose a simple, parameter-free method, that takes into account database dependence and network topology, to identify central genes in the MD network. Among them, we infer novel candidates that have not yet been annotated as MD genes and show their relevance by highlighting their differential expression in public datasets and carefully examining the literature. The method contributes to uncovering connections in the MD mechanisms and highlights several candidates for in-depth study of their contribution to MD and its co-morbidities. [less ▲]

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See detailGene expression profile of CD14+ blood monocytes following lifestyle-induced weight loss in individuals with metabolic syndrome.
Noor, Fozia UL; Biemann, Ronald; Roomp, Kirsten UL et al

in Scientific Reports (2020), 10(1), 17855

Lifestyle-induced weight loss is regarded as an efficient therapy to reverse metabolic syndrome (MetS) and to prevent disease progression. The objective of this study was to investigate whether lifestyle ... [more ▼]

Lifestyle-induced weight loss is regarded as an efficient therapy to reverse metabolic syndrome (MetS) and to prevent disease progression. The objective of this study was to investigate whether lifestyle-induced weight loss modulates gene expression in circulating monocytes. We analyzed and compared gene expression in monocytes (CD14+ cells) and subcutaneous adipose tissue biopsies by unbiased mRNA profiling. Samples were obtained before and after diet-induced weight loss in well-defined male individuals in a prospective controlled clinical trial (ICTRP Trial Number: U1111-1158-3672). The BMI declined significantly (- 12.6%) in the treatment arm (N = 39) during the 6-month weight loss intervention. This was associated with a significant reduction in hsCRP (- 45.84%) and circulating CD14+ cells (- 21.0%). Four genes were differentially expressed (DEG's) in CD14+ cells following weight loss (ZRANB1, RNF25, RB1CC1 and KMT2C). Comparative analyses of paired CD14+ monocytes and subcutaneous adipose tissue samples before and after weight loss did not identify common genes differentially regulated in both sample types. Lifestyle-induced weight loss is associated with specific changes in gene expression in circulating CD14+ monocytes, which may affect ubiquitination, histone methylation and autophagy [less ▲]

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See detailA rare loss-of function variant of ADAM17 is associated with late-onset familial Alzheimer disease
Hartl, Daniela; May, Patrick UL; Gu, Wei UL et al

in Molecular Psychiatry (2020), 25(3), 629-639

Common variants of about 20 genes contributing to AD risk have so far been identified through genome-wide association studies (GWAS). However, there is still a large proportion of heritability that might ... [more ▼]

Common variants of about 20 genes contributing to AD risk have so far been identified through genome-wide association studies (GWAS). However, there is still a large proportion of heritability that might be explained by rare but functionally important variants. One of the so far identified genes with rare AD causing variants is ADAM10. Using whole-genome sequencing we now identified a single rare nonsynonymous variant (SNV) rs142946965 [p.R215I] in ADAM17 co-segregating with an autosomal-dominant pattern of late-onset AD in one family. Subsequent genotyping and analysis of available whole-exome sequencing data of additional case/control samples from Germany, the UK and the USA identified five variant carriers among AD patients only. The mutation inhibits pro-protein cleavage and the formation of the active enzyme, thus leading to loss-of-function of ADAM17 α-secretase. Further, we identified a strong negative correlation between ADAM17 and APP gene expression in human brain and present in vitro evidence that ADAM17 negatively controls the expression of APP. As a consequence, p.R215I mutation of ADAM17 leads to elevated Aß formation in vitro. Together our data supports a causative association of the identified ADAM17 variant in the pathogenesis of AD. [less ▲]

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See detailMeasuring mode I fracture properties of thick-layered structural silicone sealants
Rosendahl, P. L.; Staudt, Y.; Odenbreit, Christoph UL et al

in International Journal of Adhesion and Adhesives (2019), 91

The failure hyperelastic structural sealant joints is a fracture mechanics problem. Its modeling requires knowledge of the material property fracture toughness. The present work describes a methodology ... [more ▼]

The failure hyperelastic structural sealant joints is a fracture mechanics problem. Its modeling requires knowledge of the material property fracture toughness. The present work describes a methodology for determining the mode I bulk material fracture toughness of structural silicone sealants. The concept is demonstrated using DOWSIL™ 993 as an example. In total we manufactured, tested and evaluated 13 DCB specimens of 6mm and 12mm adhesive thickness. The fracture toughness is identified from J-integral measurements. The theory for determining the J-integral at finite deformations is laid out and an automated data analysis procedure is suggested. The presented approach further allows... [less ▲]

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See detailIncreased Circulating VAP-1 Levels Are Associated with Liver Fibrosis in Chronic Hepatitis C Infection.
Kraemer, Marcel; Krawczyk, Marcin; Noor, Fozia UL et al

in Journal of clinical medicine (2019), 8(1),

Vascular adhesion protein-1 (VAP-1) is a multifunction protein. While membrane-bound VAP-1 is an adhesion protein, soluble VAP-1 catalyzes the deamination of primary amines through its semicarbazide ... [more ▼]

Vascular adhesion protein-1 (VAP-1) is a multifunction protein. While membrane-bound VAP-1 is an adhesion protein, soluble VAP-1 catalyzes the deamination of primary amines through its semicarbazide-sensitive amino oxidase (SSAO) activity. VAP-1 supports the transmigration of leukocytes and increases oxidative stress. In chronic liver diseases, it plays a role in leukocyte infiltration and fibrogenesis. Here, we measured VAP-1 plasma concentration and its SSAO activity in 322 patients with chronic hepatitis C infection and evaluated the association of VAP-1 with fibrosis stages. VAP-1 concentration strongly correlated with liver stiffness and was the second strongest influencing variable after gamma-glutamytransferase (GGT) for liver stiffness in regression analysis. The VAP-1 concentration increased with advancing fibrosis stages and the highest concentrations were found in patients with cirrhosis. According to the receiver operating characteristic (ROC) analysis, a VAP-1 cut-off value of 541 ng/mL predicted histologically confirmed cirrhosis (sensitivity 74%; specificity 72%). SSAO activity correlated only moderately with liver stiffness, showing a relatively small increase in advanced fibrosis. To our knowledge, this is the first study on VAP-1 in chronic hepatitis C infection showing its association with progressive fibrosis. In conclusion, VAP-1 plasma concentration, rather than its SSAO activity, may represent a non-invasive biomarker for monitoring fibrogenesis in patients with chronic hepatitis C infection. [less ▲]

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See detailRare ABCA7 variants in 2 German families with Alzheimer disease
May, Patrick UL; Pichler, Sabrina; Hartl, Daniela et al

in Neurology Genetics (2018), 4(2),

Objective The aim of this study was to identify variants associated with familial late-onset Alzheimer disease (AD) using whole-genome sequencing. Methods Several families with an autosomal dominant ... [more ▼]

Objective The aim of this study was to identify variants associated with familial late-onset Alzheimer disease (AD) using whole-genome sequencing. Methods Several families with an autosomal dominant inheritance pattern of AD were analyzed by whole-genome sequencing. Variants were prioritized for rare, likely pathogenic variants in genes already known to be associated with AD and confirmed by Sanger sequencing using standard protocols. Results We identified 2 rare ABCA7 variants (rs143718918 and rs538591288) with varying penetrance in 2 independent German AD families, respectively. The single nucleotide variant (SNV) rs143718918 causes a missense mutation, and the deletion rs538591288 causes a frameshift mutation of ABCA7. Both variants have previously been reported in larger cohorts but with incomplete segregation information. ABCA7 is one of more than 20 AD risk loci that have so far been identified by genome-wide association studies, and both common and rare variants of ABCA7 have previously been described in different populations with higher frequencies in AD cases than in controls and varying penetrance. Furthermore, ABCA7 is known to be involved in several AD-relevant pathways. Conclusions We conclude that both SNVs might contribute to the development of AD in the examined family members. Together with previous findings, our data confirm ABCA7 as one of the most relevant AD risk genes. [less ▲]

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See detailThe Gut Microbiota and Hematopoietic Stem Cell Transplantation: Challenges and Potentials.
Noor, Fozia UL; Kaysen, Anne UL; Wilmes, Paul UL et al

in Journal of innate immunity (2018)

The human gut microbiota gained tremendous importance in the last decade as next-generation technologies of sequencing and multiomics analyses linked the role of the microbial communities to host ... [more ▼]

The human gut microbiota gained tremendous importance in the last decade as next-generation technologies of sequencing and multiomics analyses linked the role of the microbial communities to host physiology and pathophysiology. A growing number of human pathologies and diseases are linked to the gut microbiota. One of the main mechanisms by which the microbiota influences the host is through its interactions with the host immune system. These interactions with both innate and adaptive host intestinal and extraintestinal immunity, although usually commensalistic even mutualistic with the host, in some cases lead to serious health effects. In the case of allogenic hematopoietic stem cell transplantation (allo-HSCT), the disruption of the intestinal microbiota diversity is associated with acute graft-versus-host disease (GvHD). Causing inflammation of the liver, skin, lungs, and the intestine, GvHD occurs in 40-50% of patients undergoing allo-HSCT and results in significant posttransplantation mortality. In this review, we highlight the impact of the gut microbiota on the host immunity in GvHD and the potential of microbiota in alleviation or even prevention of GvHD. [less ▲]

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See detailItaconic acid indicates cellular but not systemic immune system activation
Meiser, Johannes; Kraemer, Lisa; Jäger, Christian UL et al

in Oncotarget (2018), 9(63),

Itaconic acid is produced by mammalian leukocytes upon pro-inflammatory activation. It appears to inhibit bacterial growth and to rewire the metabolism of the host cell by inhibiting succinate ... [more ▼]

Itaconic acid is produced by mammalian leukocytes upon pro-inflammatory activation. It appears to inhibit bacterial growth and to rewire the metabolism of the host cell by inhibiting succinate dehydrogenase. Yet, it is unknown whether itaconic acid acts only intracellularly, locally in a paracrine fashion, or whether it is even secreted from the inflammatory cells at meaningful levels in peripheral blood of patients with severe inflammation or sepsis. The aim of this study was to determine the release rate of itaconic acid from pro-inflammatory activated macrophages in vitro and to test for the abundance of itaconic acid in bodyfluids of patients suffering from acute inflammation. We demonstrate that excretion of itaconic acid happens at a low rate and that it cannot be detected in significant amounts in plasma or urine of septic patients or in liquid from bronchial lavage of patients with pulmonary inflammation. We conclude that itaconic acid may serve as a pro-inflammatory marker in immune cells but that it does not qualify as a biomarker in the tested body fluids. [less ▲]

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See detailIDENTIFICATION OF A RARE GENE VARIANT THAT IS ASSOCIATED WITH FAMILIAL ALZHEIMER DISEASE AND REGULATES APP EXPRESSION
Hartl, Daniela; May, Patrick UL; Gu, Wei UL et al

in Alzheimer's and Dementia: the Journal of the Alzheimer's Association (2017), 13(7, Supplement), 648

Background Genetic mutations leading to familial forms of Alzheimer disease (AD) have so far been reported for a few genes including APP, PSEN1 and PSEN2, UNC5C, PLD3, ABCA7, TTC3, and possibly ADAM10 ... [more ▼]

Background Genetic mutations leading to familial forms of Alzheimer disease (AD) have so far been reported for a few genes including APP, PSEN1 and PSEN2, UNC5C, PLD3, ABCA7, TTC3, and possibly ADAM10. With the advent of whole exome and whole genome sequencing approaches new genes and mutations are likely to be identified. Methods We analyzed the genetic cause of AD in a large multiplex family with an autosomal-dominant pattern of inheritance with LOAD. The family lacked pathogenic mutations of known AD genes. We performed whole-genome sequencing (WGS) in six family members (two affected and four unaffected) and prioritized rare, potential damaging, variants that segregated with disease. Variants were further characterized by subsequent molecular analyzes in human brain and cell culture models. Results We identified a single rare nonsynonymous variant co-segregating with AD. The mutation inhibits pro-protein cleavage and the formation of the active enzyme, thus leading to a loss-of-function of the gene. We further found a strong negative correlation between the identified gene and APP gene expression in human brain and in cells over-expressing the gene. The negative regulation of APP expression was only observed for the wt gene, but not for mutated forms, thus causing beside the loss of enzyme function a decoupling of both APPexpression and subsequent beta-amyloid formation. The identity of the gene will be presented on the conference. Conclusions This novel pathway strongly supports a causative association of the identified gene with the pathogenesis of AD. [less ▲]

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See detailIntegrated meta-omic analyses of the gastrointestinal tract microbiome in patients undergoing allogeneic hematopoietic stem cell transplantation.
Kaysen, Anne UL; Heintz, Anna UL; Muller, Emilie UL et al

in Translational Research: the Journal of Laboratory and Clinical Medicine (2017)

In patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), treatment-induced changes to the gastrointestinal tract (GIT) microbiome have been linked to adverse outcomes, most ... [more ▼]

In patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), treatment-induced changes to the gastrointestinal tract (GIT) microbiome have been linked to adverse outcomes, most notably graft-versus-host disease (GvHD). However, it is presently unknown whether this relationship is causal or consequential. Here, we performed an integrated meta-omic analysis to probe deeper into the GIT microbiome changes during allo-HSCT and its accompanying treatments. We used 16S and 18S rRNA gene amplicon sequencing to resolve archaea, bacteria, and eukaryotes within the GIT microbiomes of 16 patients undergoing allo-HSCT for the treatment of hematologic malignancies. These results revealed a major shift in the GIT microbiome after allo-HSCT including a marked reduction in bacterial diversity, accompanied by only limited changes in eukaryotes and archaea. An integrated analysis of metagenomic and metatranscriptomic data was performed on samples collected from a patient before and after allo-HSCT for acute myeloid leukemia. This patient developed severe GvHD, leading to death 9 months after allo-HSCT. In addition to drastically decreased bacterial diversity, the post-treatment microbiome showed a higher overall number and higher expression levels of antibiotic resistance genes (ARGs). One specific Escherichia coli strain causing a paravertebral abscess was linked to GIT dysbiosis, suggesting loss of intestinal barrier integrity. The apparent selection for bacteria expressing ARGs suggests that prophylactic antibiotic administration may adversely affect the overall treatment outcome. We therefore assert that such analyses including information about the selection of pathogenic bacteria expressing ARGs may assist clinicians in "personalizing" regimens for individual patients to improve overall outcomes. [less ▲]

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See detailErratum: Integrated multi-omics of the human gut microbiome in a case study of familial type 1 diabetes.
Heintz, Anna UL; May, Patrick UL; Laczny, Cedric C. et al

in Nature microbiology (2016), 2

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See detailIntegrated multi-omics of the human gut microbiome in a case study of familial type 1 diabetes.
Heintz, Anna UL; May, Patrick UL; Laczny, Cedric C. et al

in Nature microbiology (2016), 2

The gastrointestinal microbiome is a complex ecosystem with functions that shape human health. Studying the relationship between taxonomic alterations and functional repercussions linked to disease ... [more ▼]

The gastrointestinal microbiome is a complex ecosystem with functions that shape human health. Studying the relationship between taxonomic alterations and functional repercussions linked to disease remains challenging. Here, we present an integrative approach to resolve the taxonomic and functional attributes of gastrointestinal microbiota at the metagenomic, metatranscriptomic and metaproteomic levels. We apply our methods to samples from four families with multiple cases of type 1 diabetes mellitus (T1DM). Analysis of intra- and inter-individual variation demonstrates that family membership has a pronounced effect on the structural and functional composition of the gastrointestinal microbiome. In the context of T1DM, consistent taxonomic differences were absent across families, but certain human exocrine pancreatic proteins were found at lower levels. The associated microbial functional signatures were linked to metabolic traits in distinct taxa. The methodologies and results provide a foundation for future large-scale integrated multi-omic analyses of the gastrointestinal microbiome in the context of host-microbe interactions in human health and disease. [less ▲]

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See detailStatic Output Feedback H-infinity Control for a Fractional-Order Glucose-Insulin System
N'Doye, Ibrahima; Voos, Holger UL; Darouach, Mohamed et al

in International Journal of Control, Automation, and Systems (2015), 13(4), 798-807

This paper presents the H∞ static output feedback control of nonlinear fractional-order systems. Based on the extended bounded real lemma, the H∞ control is formulated and sufficient conditions are ... [more ▼]

This paper presents the H∞ static output feedback control of nonlinear fractional-order systems. Based on the extended bounded real lemma, the H∞ control is formulated and sufficient conditions are derived in terms of linear matrix inequalities (LMIs) formulation by using the fractional Lyapunov direct method where the fractional-order α belongs to 0 < α < 1. The control approach is finally applied to the regulation of the glucose level in diabetes type 1 treatment. Therefore, it is attempted to incorporate fractional-order into the mathematical minimal model of glucose-insulin system dynamics and it is still an interesting challenge to show, how the order of a fractional differential system affects the dynamics of the system in the presence of meal disturbance. Numerical simulations are carried out to illustrate our proposed results and show that the nonlinear fractional-order glucose-insulin systems are, at least, as stable as their integer-order counterpart in the presence of exogenous glucose infusion or meal disturbance. [less ▲]

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See detailSuppression of beta3-integrin in mice triggers a neuropilin-1-dependent change in focal adhesion remodelling that can be targeted to block pathological angiogenesis.
Ellison, Tim S.; Atkinson, Samuel J.; Steri, Veronica et al

in Disease Models and Mechanisms (2015), 8(9), 1105-19

Anti-angiogenic treatments against alphavbeta3-integrin fail to block tumour growth in the long term, which suggests that the tumour vasculature escapes from angiogenesis inhibition through alphavbeta3 ... [more ▼]

Anti-angiogenic treatments against alphavbeta3-integrin fail to block tumour growth in the long term, which suggests that the tumour vasculature escapes from angiogenesis inhibition through alphavbeta3-integrin-independent mechanisms. Here, we show that suppression of beta3-integrin in mice leads to the activation of a neuropilin-1 (NRP1)-dependent cell migration pathway in endothelial cells via a mechanism that depends on NRP1's mobilisation away from mature focal adhesions following VEGF-stimulation. The simultaneous genetic targeting of both molecules significantly impairs paxillin-1 activation and focal adhesion remodelling in endothelial cells, and therefore inhibits tumour angiogenesis and the growth of already established tumours. These findings provide a firm foundation for testing drugs against these molecules in combination to treat patients with advanced cancers. [less ▲]

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