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Ulf klein

William C Adams, Yen-Hua Chen, Radomir Kratchmarov, Bonnie Yen, Simone A Nish, Wen-Hsuan W Lin, Nyanza J Rothman, Larry L Luchsinger, Ulf Klein, Meinrad Busslinger, Jeffrey C Rathmell, Hans-Willem Snoeck, Steven L Reiner
Regeneration requires related cells to diverge in fate. We show that activated lymphocytes yield sibling cells with unequal elimination of aged mitochondria. Disparate mitochondrial clearance impacts cell fate and reflects larger constellations of opposing metabolic states. Differentiation driven by an anabolic constellation of PI3K/mTOR activation, aerobic glycolysis, inhibited autophagy, mitochondrial stasis, and ROS production is balanced with self-renewal maintained by a catabolic constellation of AMPK activation, mitochondrial elimination, oxidative metabolism, and maintenance of FoxO1 activity...
December 20, 2016: Cell Reports
Serdar Elhatisari, Ning Li, Alexander Rokash, Jose Manuel Alarcón, Dechuan Du, Nico Klein, Bing-Nan Lu, Ulf-G Meißner, Evgeny Epelbaum, Hermann Krebs, Timo A Lähde, Dean Lee, Gautam Rupak
How do protons and neutrons bind to form nuclei? This is the central question of ab initio nuclear structure theory. While the answer may seem as simple as the fact that nuclear forces are attractive, the full story is more complex and interesting. In this work we present numerical evidence from ab initio lattice simulations showing that nature is near a quantum phase transition, a zero-temperature transition driven by quantum fluctuations. Using lattice effective field theory, we perform Monte Carlo simulations for systems with up to twenty nucleons...
September 23, 2016: Physical Review Letters
Julia Hoefele, Markus J Kemper, Ulf Schoenermarck, Susanna Mueller, Hanns-Georg Klein, Anja Lemke
About 30% of children with nephrotic syndrome (NS) have inherited forms. Among them, mutations in Wilms tumor suppressor gene 1 (WT1) are a well characterized cause associated with steroid-resistant NS, Wilms tumor, and urogenital malformation in males. However, the role of WT1 mutations in adult-onset focal segmental glomerulosclerosis (FSGS) is unclear. We report the case of a 38-year-old female with FSGS. She had been diagnosed with streak ovaries during diagnostic workup for infertility. Mutational analysis identified the heterozygous mutation c...
2017: Nephron
Maja Milanovic, Nicole Heise, Nilushi S De Silva, Michael M Anderson, Kathryn Silva, Amanda Carette, Fabiano Orelli, Govind Bhagat, Ulf Klein
Signaling through the canonical nuclear factor-κB (NF-κB) pathway is critical for the generation and maintenance of mature B cells and for antigen-dependent B-cell activation. c-REL (rel) and RELA (rela) are the downstream transcriptional activators of the canonical NF-κB pathway. Studies of B cells derived from constitutional rel knockout mice and chimeric mice repopulated with rela(-/-) fetal liver cells provided evidence that the subunits can have distinct roles during B-cell development. However, the B cell-intrinsic functions of c-REL and RELA during B-cell generation and antigen-dependent B-cell activation have not been determined in vivo...
October 18, 2016: Immunology and Cell Biology
Takatoshi Chinen, Arun K Kannan, Andrew G Levine, Xiying Fan, Ulf Klein, Ye Zheng, Georg Gasteiger, Yongqiang Feng, Jason D Fontenot, Alexander Y Rudensky
Regulatory T cells (Treg cells), which have abundant expression of the interleukin 2 receptor (IL-2R), are reliant on IL-2 produced by activated T cells. This feature indicates a key role for a simple network based on the consumption of IL-2 by Treg cells in their suppressor function. However, congenital deficiency in IL-2R results in reduced expression of the Treg cell lineage-specification factor Foxp3, which has confounded experimental efforts to understand the role of IL-2R expression and signaling in the suppressor function of Treg cells...
November 2016: Nature Immunology
Nilushi S De Silva, Michael M Anderson, Amanda Carette, Kathryn Silva, Nicole Heise, Govind Bhagat, Ulf Klein
The NF-κB signaling cascade relays external signals essential for B-cell growth and survival. This cascade is frequently hijacked by cancers that arise from the malignant transformation of germinal center (GC) B cells, underscoring the importance of deciphering the function of NF-κB in these cells. The NF-κB signaling cascade is comprised of two branches, the canonical and alternative NF-κB pathways, mediated by distinct transcription factors. The expression and function of the transcription factors of the alternative pathway, RELB and NF-κB2, in late B-cell development is incompletely understood...
August 9, 2016: Proceedings of the National Academy of Sciences of the United States of America
Sarah C Reitz, Stephanie-Michelle Hof, Vinzenz Fleischer, Alla Brodski, Adriane Gröger, René-Maxime Gracien, Amgad Droby, Helmuth Steinmetz, Ulf Ziemann, Frauke Zipp, Ralf Deichmann, Johannes C Klein
White matter (WM) lesions with a distinct lesion-tissue contrast are the main radiological hallmark of multiple sclerosis (MS) in standard magnetic resonance imaging (MRI). Pathological WM changes beyond lesion development lack suitable contrasts, rendering the investigation of normal appearing WM (NAWM) more challenging. In this study, repeat quantitative MRI (qMRI) was collected in 9 relapsing remitting MS patients with mild disease over nine months. The relaxation times T1 and T2, the proton density (PD), and the magnetization transfer ratio (MTR) were analysed in the NAWM...
May 2, 2016: Brain Imaging and Behavior
Haiying Sun, Linh M Van, David Floch, Xuemin Jiang, Ulf R Klein, Ken Abrams, Gangadhar Sunkara
The characterization of the pharmacokinetic (PK) and pharmacodynamic (PD) properties in pediatric patients is essential in supporting the recommended dosage of canakinumab in the relevant population. Here the PK and PD properties of canakinumab-a monoclonal antibody-in pediatric patients with systemic juvenile idiopathic arthritis (SJIA) are presented. Blood samples were obtained from 4 phase 2/3 clinical studies in patients with SJIA. Canakinumab PK properties and total interleukin (IL)-1β kinetic properties were characterized by a population-based PK-binding model...
December 2016: Journal of Clinical Pharmacology
Katerina Vlantis, Andy Wullaert, Apostolos Polykratis, Vangelis Kondylis, Marius Dannappel, Robin Schwarzer, Patrick Welz, Teresa Corona, Henning Walczak, Falk Weih, Ulf Klein, Michelle Kelliher, Manolis Pasparakis
Intestinal epithelial cells (IECs) regulate gut immune homeostasis, and impaired epithelial responses are implicated in the pathogenesis of inflammatory bowel diseases (IBD). IEC-specific ablation of nuclear factor κB (NF-κB) essential modulator (NEMO) caused Paneth cell apoptosis and impaired antimicrobial factor expression in the ileum, as well as colonocyte apoptosis and microbiota-driven chronic inflammation in the colon. Combined RelA, c-Rel, and RelB deficiency in IECs caused Paneth cell apoptosis but not colitis, suggesting that NEMO prevents colon inflammation by NF-κB-independent functions...
March 15, 2016: Immunity
Roman Maresch, Sebastian Mueller, Christian Veltkamp, Rupert Öllinger, Mathias Friedrich, Irina Heid, Katja Steiger, Julia Weber, Thomas Engleitner, Maxim Barenboim, Sabine Klein, Sandra Louzada, Ruby Banerjee, Alexander Strong, Teresa Stauber, Nina Gross, Ulf Geumann, Sebastian Lange, Marc Ringelhan, Ignacio Varela, Kristian Unger, Fengtang Yang, Roland M Schmid, George S Vassiliou, Rickmer Braren, Günter Schneider, Mathias Heikenwalder, Allan Bradley, Dieter Saur, Roland Rad
Mouse transgenesis has provided fundamental insights into pancreatic cancer, but is limited by the long duration of allele/model generation. Here we show transfection-based multiplexed delivery of CRISPR/Cas9 to the pancreas of adult mice, allowing simultaneous editing of multiple gene sets in individual cells. We use the method to induce pancreatic cancer and exploit CRISPR/Cas9 mutational signatures for phylogenetic tracking of metastatic disease. Our results demonstrate that CRISPR/Cas9-multiplexing enables key applications, such as combinatorial gene-network analysis, in vivo synthetic lethality screening and chromosome engineering...
2016: Nature Communications
Nilushi S De Silva, Kathryn Silva, Michael M Anderson, Govind Bhagat, Ulf Klein
BAFF is critical for the survival and maturation of mature B cells. BAFF, via BAFFR, activates multiple signaling pathways in B cells, including the alternative NF-κB pathway. The transcription factors RELB and NF-κB2 (p100/p52) are the downstream mediators of the alternative pathway; however, the B cell-intrinsic functions of these NF-κB subunits have not been studied in vivo using conditional alleles, either individually or in combination. We in this study report that B cell-specific deletion of relb led to only a slight decrease in the fraction of mature splenic B cells, whereas deletion of nfkb2 caused a marked reduction...
March 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Sonja Zweegman, Bronno van der Holt, Ulf-Henrik Mellqvist, Morten Salomo, Gerard M J Bos, Mark-David Levin, Heleen Visser-Wisselaar, Markus Hansson, Annette W G van der Velden, Wendy Deenik, Astrid Gruber, Juleon L L M Coenen, Torben Plesner, Saskia K Klein, Bea C Tanis, Damian L Szatkowski, Rolf E Brouwer, Matthijs Westerman, M Rineke B L Leys, Harm A M Sinnige, Einar Haukås, Klaas G van der Hem, Marc F Durian, E Vera J M Mattijssen, Niels W C J van de Donk, Marian J P L Stevens-Kroef, Pieter Sonneveld, Anders Waage
The combination of melphalan, prednisone, and thalidomide (MPT) is considered standard therapy for newly diagnosed patients with multiple myeloma who are ineligible for stem cell transplantation. Long-term treatment with thalidomide is hampered by neurotoxicity. Melphalan, prednisone, and lenalidomide, followed by lenalidomide maintenance therapy, showed promising results without severe neuropathy emerging. We randomly assigned 668 patients between nine 4-week cycles of MPT followed by thalidomide maintenance until disease progression or unacceptable toxicity (MPT-T) and the same MP regimen with thalidomide being replaced by lenalidomide (MPR-R)...
March 3, 2016: Blood
Wen-Hsuan W Lin, William C Adams, Simone A Nish, Yen-Hua Chen, Bonnie Yen, Nyanza J Rothman, Radomir Kratchmarov, Takaharu Okada, Ulf Klein, Steven L Reiner
Metazoan sibling cells often diverge in activity and identity, suggesting links between growth signals and cell fate. We show that unequal transduction of nutrient-sensitive PI3K/AKT/mTOR signaling during cell division bifurcates transcriptional networks and fates of kindred cells. A sibling B lymphocyte with stronger signaling, indexed by FoxO1 inactivation and IRF4 induction, undergoes PI3K-driven Pax5 repression and plasma cell determination, while its sibling with weaker PI3K activity renews a memory or germinal center B cell fate...
December 15, 2015: Cell Reports
Vangelis Kondylis, Apostolos Polykratis, Hanno Ehlken, Laura Ochoa-Callejero, Beate Katharina Straub, Santosh Krishna-Subramanian, Trieu-My Van, Harald-Morten Curth, Nicole Heise, Falk Weih, Ulf Klein, Peter Schirmacher, Michelle Kelliher, Manolis Pasparakis
IκB kinase/nuclear [corrected] factor κB (IKK/NF-κB) signaling exhibits important yet opposing functions in hepatocarcinogenesis. Mice lacking NEMO in liver parenchymal cells (LPC) spontaneously develop steatohepatitis and hepatocellular carcinoma (HCC) suggesting that NF-κB prevents liver disease and cancer. Here, we show that complete NF-κB inhibition by combined LPC-specific ablation of RelA, c-Rel, and RelB did not phenocopy NEMO deficiency, but constitutively active IKK2-mediated NF-κB activation prevented hepatocellular damage and HCC in NEMO(LPC-KO) mice...
November 9, 2015: Cancer Cell
Amgad Droby, Kenneth S L Yuen, Muthuraman Muthuraman, Sarah-Christina Reitz, Vinzenz Fleischer, Johannes Klein, René-Maxime Gracien, Ulf Ziemann, Ralf Deichmann, Frauke Zipp, Sergiu Groppa
Diffuse inflammation in multiple sclerosis (MS) extends beyond focal lesion sites, affecting interconnected regions; however, little is known about the impact of an individual lesion affecting major white matter (WM) pathways on brain functional connectivity (FC). Here, we longitudinally assessed the effects of acute and chronic lesions on FC in relapsing-remitting MS (RRMS) patients using resting-state fMRI. 45 MRI data sets from 9 RRMS patients were recorded using 3T MR scanner over 5 time points at 8 week intervals...
December 2016: Brain Imaging and Behavior
Johanna Schröder, Leon Sautier, Levente Kriston, Thomas Berger, Björn Meyer, Christina Späth, Ulf Köther, Yvonne Nestoriuc, Jan Philipp Klein, Steffen Moritz
BACKGROUND: Only a minority of people suffering from depression receive adequate treatment. Psychological Online Interventions (POIs) could help bridge existing treatment gaps and augment the effectiveness of current treatments. Apart from effectiveness, user acceptance of POIs must be achieved if such interventions are to be broadly implemented in existing health-care. Valid measurement tools examining attitudes towards POIs are lacking. Therefore, we examined the dimensionality of attitudes towards POIs, developed a novel questionnaire, the Attitudes towards Psychological Online Interventions Questionnaire (APOI), and gathered data to examine its reliability...
November 15, 2015: Journal of Affective Disorders
Lars Franken, Marika Klein, Marina Spasova, Anna Elsukova, Ulf Wiedwald, Meike Welz, Percy Knolle, Michael Farle, Andreas Limmer, Christian Kurts
A main function of splenic red pulp macrophages is the degradation of damaged or aged erythrocytes. Here we show that these macrophages accumulate ferrimagnetic iron oxides that render them intrinsically superparamagnetic. Consequently, these cells routinely contaminate splenic cell isolates obtained with the use of MCS, a technique that has been widely used in immunological research for decades. These contaminations can profoundly alter experimental results. In mice deficient for the transcription factor SpiC, which lack red pulp macrophages, liver Kupffer cells take over the task of erythrocyte degradation and become superparamagnetic...
2015: Scientific Reports
Ulf Klein, Nicole Heise
PURPOSE OF REVIEW: B-cell tumors originating from the transformation of germinal center B cells frequently harbor genetic mutations, leading to constitutive activation of the nuclear factor-κB (NF-κB) signaling pathway. The present review highlights recent insights into the roles of separate NF-κB transcription factors in germinal center B-cell development and discusses implications of the results for germinal center lymphomagenesis. RECENT FINDINGS: Understanding how aberrant NF-κB activation promotes tumorigenesis requires the understanding of the role of NF-κB in the tumor-precursor cells...
July 2015: Current Opinion in Hematology
Dennis Lal, Ann-Kathrin Ruppert, Holger Trucks, Herbert Schulz, Carolien G de Kovel, Dorothée Kasteleijn-Nolst Trenité, Anja C M Sonsma, Bobby P Koeleman, Dick Lindhout, Yvonne G Weber, Holger Lerche, Claudia Kapser, Christoph J Schankin, Wolfram S Kunz, Rainer Surges, Christian E Elger, Verena Gaus, Bettina Schmitz, Ingo Helbig, Hiltrud Muhle, Ulrich Stephani, Karl M Klein, Felix Rosenow, Bernd A Neubauer, Eva M Reinthaler, Fritz Zimprich, Martha Feucht, Rikke S Møller, Helle Hjalgrim, Peter De Jonghe, Arvid Suls, Wolfgang Lieb, Andre Franke, Konstantin Strauch, Christian Gieger, Claudia Schurmann, Ulf Schminke, Peter Nürnberg, Thomas Sander
Genetic generalised epilepsy (GGE) is the most common form of genetic epilepsy, accounting for 20% of all epilepsies. Genomic copy number variations (CNVs) constitute important genetic risk factors of common GGE syndromes. In our present genome-wide burden analysis, large (≥ 400 kb) and rare (< 1%) autosomal microdeletions with high calling confidence (≥ 200 markers) were assessed by the Affymetrix SNP 6.0 array in European case-control cohorts of 1,366 GGE patients and 5,234 ancestry-matched controls...
May 2015: PLoS Genetics
Mari L Fischer, Axel Hochkirch, Mike Heddergott, Christoph Schulze, Helena E Anheyer-Behmenburg, Johannes Lang, Frank-Uwe Michler, Ulf Hohmann, Hermann Ansorge, Lothar Hoffmann, Roland Klein, Alain C Frantz
Biological invasions provide excellent study systems to understand evolutionary, genetic and ecological processes during range expansions. There is strong evidence for positive effects of high propagule pressure and the associated higher genetic diversity on invasion success, but some species have become invasive despite small founder numbers. The raccoon (Procyon lotor) is often considered as a typical example for such a successful invasion resulting from a small number of founders. The species' largest non-native population in Germany is commonly assumed to stem from a small number of founders and two separate founding events in the 1930s and 1940s...
2015: PloS One
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