University of Marburg

About: University of Marburg is a education organization based out in Marburg, Germany. It is known for research contribution in the topics: Population & Gene. The organization has 23195 authors who have published 42907 publications receiving 1506069 citations. The organization is also known as: Philipps University of Marburg & Philipps-Universität.

Genome-wide analysis of copy number variants in attention deficit hyperactivity disorder: the role of rare variants and duplications at 15q13.3

Abstract: OBJECTIVE: Attention deficit hyperactivity disorder (ADHD) is a common, highly heritable psychiatric disorder. Because of its multifactorial etiology, however, identifying the genes involved has been difficult. The authors followed up on recent findings suggesting that rare copy number variants (CNVs) may be important for ADHD etiology. METHOD: The authors performed a genome-wide analysis of large, rare CNVs (<1% population frequency) in children with ADHD (N=896) and comparison subjects (N=2,455) from the IMAGE II Consortium. RESULTS: The authors observed 1,562 individually rare CNVs >100 kb in size, which segregated into 912 independent loci. Overall, the rate of rare CNVs >100 kb was 1.15 times higher in ADHD case subjects relative to comparison subjects, with duplications spanning known genes showing a 1.2-fold enrichment. In accordance with a previous study, rare CNVs >500 kb showed the greatest enrichment (1.28-fold). CNVs identified in ADHD case subjects were significantly enriched for loci implicated in autism and in schizophrenia. Duplications spanning the CHRNA7 gene at chromosome 15q13.3 were associated with ADHD in single-locus analysis. This finding was consistently replicated in an additional 2,242 ADHD case subjects and 8,552 comparison subjects from four independent cohorts from the United Kingdom, the United States, and Canada. Presence of the duplication at 15q13.3 appeared to be associated with comorbid conduct disorder. CONCLUSIONS: These findings support the enrichment of large, rare CNVs in ADHD and implicate duplications at 15q13.3 as a novel risk factor for ADHD. With a frequency of 0.6% in the populations investigated and a relatively large effect size (odds ratio=2.22, 95% confidence interval=1.5–3.6), this locus could be an important contributor to ADHD etiology.

Neuraminidase Inhibitor-Resistant Influenza Viruses May Differ Substantially in Fitness and Transmissibility

Abstract: Mutations of the conserved residues of influenza virus neuraminidase (NA) that are associated with NA inhibitor (NAI) resistance decrease the sialidase activity and/or stability of the NA, thus compromising viral fitness. In fact, clinically derived NAI-resistant variants with different NA mutations have shown different transmissibilities in ferrets (M. L. Herlocher, R. Truscon, S. Elias, H. Yen, N. A. Roberts, S. E. Ohmit, and A. S. Monto, J. Infect. Dis. 190:1627-1630, 2004). Molecular characterization of mutant viruses that have a homogeneous genetic background is required to determine the effect of single mutations at conserved NA residues. We generated recombinant viruses containing either the wild-type NA (RG WT virus) or a single amino acid change at NA residue 119 (RG E119V-NA virus) or 292 (RG R292K-NA virus) in the A/Wuhan/359/95 (H3N2) influenza virus background by reverse genetics. Both mutants showed decreased sensitivity to oseltamivir carboxylate, and the RG R292K-NA virus showed cross-resistance to zanamivir. We also observed differences between the two mutants in NA enzymatic activity and thermostability. The R292K mutation caused greater reduction of sialidase activity and thermostability than the E119V mutation. The NA defect caused by the R292K mutation was associated with compromised growth and transmissibility, whereas the growth and transmissibility of the RG E119V-NA virus were comparable to those of RG WT virus. Our results suggest that NAI-resistant influenza virus variants may differ substantially in fitness and transmissibility, depending on different levels of NA functional loss.

The pRb/E2F cell-cycle pathway mediates cell death in Parkinson's disease

Abstract: The mechanisms leading to degeneration of dopaminergic neurons (DNs) in the substantia nigra of patients with Parkinson's disease (PD) are not completely understood. Here, we show, in the postmortem human tissue, that these neurons aberrantly express mitosis-associated proteins, including the E2F-1 transcription factor, and appear to duplicate their nuclear DNA. We further demonstrate that the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injected into mice and application of its active metabolite 1-methyl-4-phenylpyridinium to mesencephalic cultures activate the retinoblastoma–E2F pathway in postmitotic DNs. We also find that cell death rather than mitotic division followed the toxin-induced replication of DNA, as determined by BrdU incorporation in DNs. In addition, blocking E2F-1 transcription protected cultured DNs against 1-methyl-4-phenylpyridinium toxicity. Finally, E2F-1-deficient mice were significantly more resistant to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic cell death than their wild-type littermates. Altogether, BrdU incorporation in mature neurons and lack of evidence for newborn neurons argue against neuronal turnover in normal conditions or during pathological states in the substantia nigra. Instead, our results demonstrate that mitosis-like signals are activated in mature DNs in patients with PD and mediate neuronal death in experimental models of the disease. Inhibition of mitosis-like signals may therefore provide strategies for neuroprotection in PD.

Tumor promotion in the liver.

Abstract: Intensive research during recent years has made the rodent liver one of the best model systems to study chemical carcinogenesis and tumor promotion in vivo. As will be shown in the present paper current knowledge mainly rests on the results of histological and histochemical studies but has reached a state where broader application of the techniques of biochemistry and molecular biology is both possible and necessary for further progress. Such progress will have important implications for the design of future cancer therapies and for the toxicological evaluation of potentially carcinogenic compounds.

Optical spectroscopy of field-induced charge in self-organized high mobility poly(3-hexylthiophene)

Abstract: Charge modulation spectroscopy (CMS) is an electro-optical spectroscopic technique that allows the charge carriers present in the conducting channels of field-effect transistors (FET's) to be studied in situ. We use this technique to study the charge carriers present in regio-regular poly(3-hexylthiophene) P3HT that has been shown to exhibit high field-effect mobilities of up to 0.1 ${\mathrm{cm}}^{2}$/Vs, similar to that observed for amorphous silicon. We demonstrate that the CMS spectra of charge carriers in high-mobility regio-regular P3HT FET's are independent of charge density, modulation frequency, and temperature. This is evidence for the presence of a single, intrinsic charge carrier that we identify as a singly charged polaronic species. The spectral features attributed to the charged species show a lack of vibronic structure that is in contrast to the vibronic structure present in the bleaching of the main $\ensuremath{\pi}\ensuremath{-}{\ensuremath{\pi}}^{*}$ absorption of the neutral chains. The transition energies observed in regio-regular P3HT cannot be understood as an extrapolation of charge-induced transitions in isolated short-chain oligomers to long conjugation lengths. Our results give evidence that interchain coupling in highly ordered P3HT is sufficiently strong so that the charge carriers cannot be considered to be confined to a single chain, rather, they now exhibit quasi-two-dimensional characteristics.