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251 Publications visible to you, out of a total of 251
Alu elements in ANRIL non-coding RNA at chromosome 9p21 modulate atherogenic cell functions through trans-regulation of gene networks
Genetical Statistics and Systems Biology

Abstract (Expand)

The chromosome 9p21 (Chr9p21) locus of coronary artery disease has been identified in the first surge of genome-wide association and is the strongest genetic factor of atherosclerosis known today. … Chr9p21 encodes the long non-coding RNA (ncRNA) antisense non-coding RNA in the INK4 locus (ANRIL). ANRIL expression is associated with the Chr9p21 genotype and correlated with atherosclerosis severity. Here, we report on the molecular mechanisms through which ANRIL regulates target-genes in trans, leading to increased cell proliferation, increased cell adhesion and decreased apoptosis, which are all essential mechanisms of atherogenesis. Importantly, trans-regulation was dependent on Alu motifs, which marked the promoters of ANRIL target genes and were mirrored in ANRIL RNA transcripts. ANRIL bound Polycomb group proteins that were highly enriched in the proximity of Alu motifs across the genome and were recruited to promoters of target genes upon ANRIL over-expression. The functional relevance of Alu motifs in ANRIL was confirmed by deletion and mutagenesis, reversing trans-regulation and atherogenic cell functions. ANRIL-regulated networks were confirmed in 2280 individuals with and without coronary artery disease and functionally validated in primary cells from patients carrying the Chr9p21 risk allele. Our study provides a molecular mechanism for pro-atherogenic effects of ANRIL at Chr9p21 and suggests a novel role for Alu elements in epigenetic gene regulation by long ncRNAs.

Authors: Lesca Miriam Holdt, Steve Hoffmann, Kristina Sass, David Langenberger, Markus Scholz, Knut Krohn, Knut Finstermeier, Anika Stahringer, Wolfgang Wilfert, Frank Beutner, Stephan Gielen, Gerhard Schuler, Gábor Gäbel, Hendrik Bergert, Ingo Bechmann, Peter F. Stadler, Joachim Thiery, Daniel Teupser

Date Published: 4th Jul 2013

Publication Type: Journal article

Risk of tumorigenicity in mesenchymal stromal cell-based therapies–bridging scientific observations and regulatory viewpoints
Genetical Statistics and Systems Biology

Abstract (Expand)

In the past decade, the therapeutic value of mesenchymal stromal cells (MSCs) has been studied in various indications, thereby taking advantage of their immunosuppressive properties. Easy procurement … from bone marrow, adipose tissue or other sources and conventional in vitro expansion culture have made their clinical use attractive. Bridging the gap between current scientific knowledge and regulatory prospects on the transformation potential and possible tumorigenicity of MSCs, the Cell Products Working Party and the Committee for Advanced Therapies organized a meeting with leading European experts in the field of MSCs. This meeting elucidated the risk of potential tumorigenicity related to MSC-based therapies from two angles: the scientific perspective and the regulatory point of view. The conclusions of this meeting, including the current regulatory thinking on quality, nonclinical and clinical aspects for MSCs, are presented in this review, leading to a clearer way forward for the development of such products.

Authors: Lisbeth Barkholt, Egbert Flory, Veronika Jekerle, Sophie Lucas-Samuel, Peter Ahnert, Louise Bisset, Dirk Büscher, Willem Fibbe, Arnaud Foussat, Marcel Kwa, Olivier Lantz, Romaldas Mačiulaitis, Tiina Palomäki, Christian K. Schneider, Luc Sensebé, Gérard Tachdjian, Karin Tarte, Lucie Tosca, Paula Salmikangas

Date Published: 1st Jul 2013

Publication Type: Journal article

A Genome-Wide Association Study Suggests Novel Loci Associated with a Schizophrenia-Related Brain-Based Phenotype
Genetical Statistics and Systems Biology

Abstract (Expand)

Patients with schizophrenia and their siblings typically show subtle changes of brain structures, such as a reduction of hippocampal volume. Hippocampal volume is heritable, may explain a variety of … cognitive symptoms of schizophrenia and is thus considered an intermediate phenotype for this mental illness. The aim of our analyses was to identify single-nucleotide polymorphisms (SNP) related to hippocampal volume without making prior assumptions about possible candidate genes. In this study, we combined genetics, imaging and neuropsychological data obtained from the Mind Clinical Imaging Consortium study of schizophrenia (n = 328). A total of 743,591 SNPs were tested for association with hippocampal volume in a genome-wide association study. Gene expression profiles of human hippocampal tissue were investigated for gene regions of significantly associated SNPs. None of the genetic markers reached genome-wide significance. However, six highly correlated SNPs (rs4808611, rs35686037, rs12982178, rs1042178, rs10406920, rs8170) on chromosome 19p13.11, located within or in close proximity to the genes NR2F6, USHBP1, and BABAM1, as well as four SNPs in three other genomic regions (chromosome 1, 2 and 10) had p-values between 6.75\times10(-6) and 8.3\times10(-7). Using existing data of a very recently published GWAS of hippocampal volume and additional data of a multicentre study in a large cohort of adolescents of European ancestry, we found supporting evidence for our results. Furthermore, allelic differences in rs4808611 and rs8170 were highly associated with differential mRNA expression in the cis-acting region. Associations with memory functioning indicate a possible functional importance of the identified risk variants. Our findings provide new insights into the genetic architecture of a brain structure closely linked to schizophrenia. In silico replication, mRNA expression and cognitive data provide additional support for the relevance of our findings. Identification of causal variants and their functional effects may unveil yet unknown players in the neurodevelopment and the pathogenesis of neuropsychiatric disorders.

Authors: Johanna Hass, Esther Walton, Holger Kirsten, Jingyu Liu, Lutz Priebe, Christiane Wolf, Nazanin Karbalai, Randy Gollub, Tonya White, Veit Roessner, Kathrin U. Müller, Tomas Paus, Michael N. Smolka, Gunter Schumann, Markus Scholz, Sven Cichon, Vince D. Calhoun, Stefan Ehrlich

Date Published: 21st Jun 2013

Publication Type: Journal article

The vacuum phenomenon in intervertebral disc disease of dogs based on computed tomography images
Genetical Statistics and Systems Biology

Abstract (Expand)

OBJECTIVES\backslashr\backslashnVacuum phenomenon is suspected to be indicative of disc degeneration and subsequent herniation. The objective of this study was to assess the reliability of vacuum … phenomenon for identification of herniated discs causing neurological signs. Prevalence of vacuum phenomenon and influencing factors in dogs with disc herniation were determined.\backslashr\backslashnMETHODS\backslashr\backslashnRetrospective review of computed tomography scans from dogs with suspected disc herniation for the presence of gas within intervertebral disc space with subsequent comparison of vacuum phenomenon and herniated disc as confirmed by surgery. Subgroups were created (chondrodystrophic, non-chondrodystrophic and unknown classification) to analyse prevalence and influencing factors (age, breed and gender) for vacuum phenomenon and agreement with herniated disc.\backslashr\backslashnRESULTS\backslashr\backslashnPrevalence of vacuum phenomenon in all dogs, chondrodystrophic, non-chondrodystrophic dogs and those with unknown classification was 19·8, 14·9, 35·7 and 24·5%, respectively. Corresponding correlation rate between vacuum phenomenon and herniated disc was 64, 67, 40 and 82%. Prevalence of vacuum phenomenon was significantly higher in nonchondrodystrophic dogs (P=0·04). Age was the only factor influencing prevalence of vacuum phenomenon (P=0·04).\backslashr\backslashnCLINICAL SIGNIFICANCE\backslashr\backslashnIn dogs with intervertebral disc disease, vacuum phenomenon is a frequent but inconsistent finding. Although helpful to identify degenerated discs, it is not suitable to identify currently herniated disc with sufficient accuracy.

Authors: M. K. Müller, E. Ludewig, G. Oechtering, Markus Scholz, T. Flegel

Date Published: 1st May 2013

Publication Type: Journal article

Seminal plasma adipokine levels are correlated with functional characteristics of spermatozoa
Genetical Statistics and Systems Biology

Abstract (Expand)

OBJECTIVE\backslashr\backslashnTo study adipokines as a potential link between obesity and male subfertility.\backslashr\backslashnDESIGN\backslashr\backslashnCross-sectional study of subjects stratified … into subgroups according to body mass index (BMI): normal-weight (18.50-24.99 kg/m(2)), overweight (25-29.99 kg/m(2)), and obese (\textgreater30 kg/m(2)).\backslashr\backslashnSETTING\backslashr\backslashnLeipzig, Germany from 2007 to 2011.\backslashr\backslashnPATIENT(S)\backslashr\backslashnNinety-six male volunteers without spermatogenesis-associated diseases.\backslashr\backslashnINTERVENTION(S)\backslashr\backslashnNone.\backslashr\backslashnMAIN OUTCOME MEASURE(S)\backslashr\backslashnSemen parameters, reproductive hormones in serum, and leptin, adiponectin, resistin, chemerin, progranulin, vaspin, and visfatin concentrations in serum and seminal plasma.\backslashr\backslashnRESULT(S)\backslashr\backslashnAll measured adipokines were detectable in human seminal plasma. The levels of progranulin, visfatin, and vaspin were statistically significantly higher in seminal plasma than in serum. An increase in body weight was associated with decreased levels of seminal plasma progranulin. Additionally, overweight/obese men had statistically significantly lower progranulin levels in seminal plasma than normal weight men. Adiponectin and progranulin concentrations in seminal plasma statistically significantly positively correlated with sperm concentration, sperm count, and total normomorphic spermatozoa.\backslashr\backslashnCONCLUSION(S)\backslashr\backslashnAdipokines are differently regulated in human male reproductive tract compared with the peripheral blood, and they could influence sperm functionality.

Authors: Stephanie Thomas, Dorothea Kratzsch, Michael Schaab, Markus Scholz, Sonja Grunewald, Joachim Thiery, Uwe Paasch, Jürgen Kratzsch

Date Published: 1st Apr 2013

Publication Type: Journal article

Comparing measures of association in 2x2 probability tables
Genetical Statistics and Systems Biology

Abstract

Not specified

Authors: Dirk Hasenclever, Markus Scholz

Date Published: 2013

Publication Type: Journal article

Merging concepts - coupling an agent-based model of hematopoietic stem cells with an ODE model of granulopoiesis
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND\backslashr\backslashnHematopoiesis is a complex process involving different cell types and feedback mechanisms mediated by cytokines. This complexity stimulated various models with different … scopes and applications. A combination of complementary models promises to provide their mutual confirmation and to explain a broader range of scenarios. Here we propose a combination of an ordinary differential equation (ODE) model of human granulopoiesis and an agent-based model (ABM) of hematopoietic stem cell (HSC) organization. The first describes the dynamics of bone marrow cell stages and circulating cells under various perturbations such as G-CSF treatment or chemotherapy. In contrast to the ODE model describing cell numbers, our ABM focuses on the organization of individual cells in the stem population.\backslashr\backslashnRESULTS\backslashr\backslashnWe combined the two models by replacing the HSC compartment of the ODE model by a difference equation formulation of the ABM. In this hybrid model, regulatory mechanisms and parameters of the original models were kept unchanged except for a few specific improvements: (i) Effect of chemotherapy was restricted to proliferating HSC and (ii) HSC regulation in the ODE model was replaced by the intrinsic regulation of the ABM. Model simulations of bleeding, chronic irradiation and stem cell transplantation revealed that the dynamics of hybrid and ODE model differ markedly in scenarios with stem cell damage. Despite these differences in response to stem cell damage, both models explain clinical data of leukocyte dynamics under four chemotherapy regimens.\backslashr\backslashnCONCLUSIONS\backslashr\backslashnABM and ODE model proved to be compatible and were combined without altering the structure of both models. The new hybrid model introduces model improvements by considering the proliferative state of stem cells and enabling a cell cycle-dependent effect of chemotherapy. We demonstrated that it is able to explain and predict granulopoietic dynamics for a large variety of scenarios such as irradiation, bone marrow transplantation, chemotherapy and growth factor applications. Therefore, it promises to serve as a valuable tool for studies in a broader range of clinical applications, in particular where stem cell activation and proliferation are involved.

Authors: Axel Krinner, Ingo Roeder, Markus Loeffler, Markus Scholz

Date Published: 2013

Publication Type: Journal article

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