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Marc Kirschner

Axel Neulen, Tobias Pantel, Michael Kosterhon, Stefanie Kirschner, Marc A Brockmann, Sven R Kantelhardt, Alf Giese, Serge C Thal
INTRODUCTION: Quantification of cerebral vasospasm after subarachnoid hemorrhage (SAH) is crucial in animal studies as well as clinical routine. We have developed a method for computer-based volumetric assessment of intracranial blood vessels from cross-sectional imaging data. Here we demonstrate the quantification of vasospasm from micro computed tomography (micro-CT) data in a rodent SAH model and the transferability of the volumetric approach to clinical data. METHODS: We obtained rodent data by performing an ex vivo micro-CT of murine brains after sham surgery or SAH by endovascular filament perforation on day 3 post hemorrhage...
2017: PloS One
Lixin Wan, Ming Chen, Juxiang Cao, Xiangpeng Dai, Qing Yin, Jinfang Zhang, Su-Jung Song, Ying Lu, Jing Liu, Hiroyuki Inuzuka, Jesse M Katon, Kelsey Berry, Jacqueline Fung, Christopher Ng, Pengda Liu, Min Sup Song, Lian Xue, Roderick T Bronson, Marc W Kirschner, Rutao Cui, Pier Paolo Pandolfi, Wenyi Wei
BRAF drives tumorigenesis by coordinating the activation of RAS/RAF/MEK/ERK oncogenic signaling cascade. However, upstream pathway(s) governing BRAF kinase activity and protein stability remains undefined. Here, we report that in primary cells with active APCFZR1, APCFZR1 earmarks BRAF for ubiquitination-mediated proteolysis, while in cancer cells with APC-free FZR1, FZR1 suppresses BRAF through disrupting BRAF dimerization. Moreover, we identified FZR1 as a direct target of ERK and CYCLIN D1/CDK4 kinases. Phosphorylation of FZR1 inhibits APCFZR1, leading to elevation of a cohort of oncogenic APCFZR1 substrates to facilitate melanomagenesis...
February 7, 2017: Cancer Discovery
Stefanie Kirschner, Bettina Mürle, Manuela Felix, Anna Arns, Christoph Groden, Frederik Wenz, Andreas Hug, Gerhard Glatting, Martin Kramer, Frank A Giordano, Marc A Brockmann
PURPOSE: There is an increasing need for small animal in vivo imaging in murine orthotopic glioma models. Because dedicated small animal scanners are not available ubiquitously, the applicability of a clinical CT scanner for visualization and measurement of intracerebrally growing glioma xenografts in living mice was validated. MATERIALS AND METHODS: 2.5x106 U87MG cells were orthotopically implanted in NOD/SCID/ᵞc-/- mice (n = 9). Mice underwent contrast-enhanced (300 μl Iomeprol i...
2016: PloS One
Shuobing Chen, Jiayi Wu, Ying Lu, Yong-Bei Ma, Byung-Hoon Lee, Zhou Yu, Qi Ouyang, Daniel J Finley, Marc W Kirschner, Youdong Mao
The proteasome is the major engine of protein degradation in all eukaryotic cells. At the heart of this machine is a heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitylated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides. Using cryoelectron microscopy, we determined a near-atomic-resolution structure of the 2.5-MDa human proteasome in its ground state, as well as subnanometer-resolution structures of the holoenzyme in three alternative conformational states...
November 15, 2016: Proceedings of the National Academy of Sciences of the United States of America
Jens Kübler, Stefanie Kirschner, Linda Hartmann, Grit Welzel, Maren Engelhardt, Carsten Herskind, Marlon R Veldwijk, Christian Schultz, Manuela Felix, Gerhard Glatting, Patrick Maier, Frederik Wenz, Marc A Brockmann, Frank A Giordano
Patients with actively replicating human immunodeficiency virus (HIV) exhibit adverse reactions even to low irradiation doses. High levels of the virus-encoded viral protein R (Vpr) are believed to be one of the major underlying causes for increased radiosensitivity. As Vpr efficiently crosses the blood-brain barrier and accumulates in astrocytes, we examined its efficacy as a drug for treatment of glioblastoma multiforme (GBM).In vitro, four glioblastoma-derived cell lines with and without methylguanine-DNA methyltransferase (MGMT) overexpression (U251, U87, U251-MGMT, U87-MGMT) were exposed to Vpr, temozolomide (TMZ), conventional photon irradiation (2 to 6 Gy) or to combinations thereof...
July 19, 2016: Oncotarget
Nicholas G Brown, Ryan VanderLinden, Edmond R Watson, Florian Weissmann, Alban Ordureau, Kuen-Phon Wu, Wei Zhang, Shanshan Yu, Peter Y Mercredi, Joseph S Harrison, Iain F Davidson, Renping Qiao, Ying Lu, Prakash Dube, Michael R Brunner, Christy R R Grace, Darcie J Miller, David Haselbach, Marc A Jarvis, Masaya Yamaguchi, David Yanishevski, Georg Petzold, Sachdev S Sidhu, Brian Kuhlman, Marc W Kirschner, J Wade Harper, Jan-Michael Peters, Holger Stark, Brenda A Schulman
Protein ubiquitination involves E1, E2, and E3 trienzyme cascades. E2 and RING E3 enzymes often collaborate to first prime a substrate with a single ubiquitin (UB) and then achieve different forms of polyubiquitination: multiubiquitination of several sites and elongation of linkage-specific UB chains. Here, cryo-EM and biochemistry show that the human E3 anaphase-promoting complex/cyclosome (APC/C) and its two partner E2s, UBE2C (aka UBCH10) and UBE2S, adopt specialized catalytic architectures for these two distinct forms of polyubiquitination...
June 2, 2016: Cell
Jeremy M Berg, Needhi Bhalla, Philip E Bourne, Martin Chalfie, David G Drubin, James S Fraser, Carol W Greider, Michael Hendricks, Chonnettia Jones, Robert Kiley, Susan King, Marc W Kirschner, Harlan M Krumholz, Ruth Lehmann, Maria Leptin, Bernd Pulverer, Brooke Rosenzweig, John E Spiro, Michael Stebbins, Carly Strasser, Sowmya Swaminathan, Paul Turner, Ronald D Vale, K VijayRaghavan, Cynthia Wolberger
No abstract text is available yet for this article.
May 20, 2016: Science
Erik R Hanschen, Tara N Marriage, Patrick J Ferris, Takashi Hamaji, Atsushi Toyoda, Asao Fujiyama, Rafik Neme, Hideki Noguchi, Yohei Minakuchi, Masahiro Suzuki, Hiroko Kawai-Toyooka, David R Smith, Halle Sparks, Jaden Anderson, Robert Bakarić, Victor Luria, Amir Karger, Marc W Kirschner, Pierre M Durand, Richard E Michod, Hisayoshi Nozaki, Bradley J S C Olson
The transition to multicellularity has occurred numerous times in all domains of life, yet its initial steps are poorly understood. The volvocine green algae are a tractable system for understanding the genetic basis of multicellularity including the initial formation of cooperative cell groups. Here we report the genome sequence of the undifferentiated colonial alga, Gonium pectorale, where group formation evolved by co-option of the retinoblastoma cell cycle regulatory pathway. Significantly, expression of the Gonium retinoblastoma cell cycle regulator in unicellular Chlamydomonas causes it to become colonial...
2016: Nature Communications
Christopher J Lowe, Mark Terasaki, Michael Wu, Robert M Freeman, Linda Runft, Kristen Kwan, Saori Haigo, Jochanan Aronowicz, Eric Lander, Chris Gruber, Mark Smith, Marc Kirschner, John Gerhart
No abstract text is available yet for this article.
December 2015: PLoS Biology
Marc Kirschner
To understand the meaning of the term Systems Medicine and to distinguish it from seemingly related other expressions currently in use, such as precision, personalized, -omics, or big data medicine, its underlying history and development into present time needs to be highlighted. Having this development in mind, it becomes evident that Systems Medicine is a genuine concept as well as a novel way of tackling the manifold complexity that occurs in nowadays clinical medicine-and not just a rebranding of what has previously been done in the past...
2016: Methods in Molecular Biology
Beatrice Andres, Marc Christ, Cornelius Gahl, Marko Wietstruk, Martin Weinelt, Jürgen Kirschner
Employing spin-, time-, and energy-resolved photoemission spectroscopy, we present the first study on the spin polarization of a single electronic state after ultrafast optical excitation. Our investigation concentrates on the majority-spin component of the d-band-derived Gd(0001) surface state d(z(2))(↑). While its binding energy shows a rapid Stoner-like shift by 90 meV with an exponential time constant of τ(E)=0.6±0.1 ps, the d(z(2))(↑) spin polarization remains nearly constant within the first picoseconds and decays with τ(S)=15±8  ps...
November 13, 2015: Physical Review Letters
Sungmin Son, Joon Ho Kang, Seungeun Oh, Marc W Kirschner, T J Mitchison, Scott Manalis
Osmotic regulation of intracellular water during mitosis is poorly understood because methods for monitoring relevant cellular physical properties with sufficient precision have been limited. Here we use a suspended microchannel resonator to monitor the volume and density of single cells in suspension with a precision of 1% and 0.03%, respectively. We find that for transformed murine lymphocytic leukemia and mouse pro-B cell lymphoid cell lines, mitotic cells reversibly increase their volume by more than 10% and decrease their density by 0...
November 23, 2015: Journal of Cell Biology
Oleg Simakov, Takeshi Kawashima, Ferdinand Marlétaz, Jerry Jenkins, Ryo Koyanagi, Therese Mitros, Kanako Hisata, Jessen Bredeson, Eiichi Shoguchi, Fuki Gyoja, Jia-Xing Yue, Yi-Chih Chen, Robert M Freeman, Akane Sasaki, Tomoe Hikosaka-Katayama, Atsuko Sato, Manabu Fujie, Kenneth W Baughman, Judith Levine, Paul Gonzalez, Christopher Cameron, Jens H Fritzenwanker, Ariel M Pani, Hiroki Goto, Miyuki Kanda, Nana Arakaki, Shinichi Yamasaki, Jiaxin Qu, Andrew Cree, Yan Ding, Huyen H Dinh, Shannon Dugan, Michael Holder, Shalini N Jhangiani, Christie L Kovar, Sandra L Lee, Lora R Lewis, Donna Morton, Lynne V Nazareth, Geoffrey Okwuonu, Jireh Santibanez, Rui Chen, Stephen Richards, Donna M Muzny, Andrew Gillis, Leonid Peshkin, Michael Wu, Tom Humphreys, Yi-Hsien Su, Nicholas H Putnam, Jeremy Schmutz, Asao Fujiyama, Jr-Kai Yu, Kunifumi Tagawa, Kim C Worley, Richard A Gibbs, Marc W Kirschner, Christopher J Lowe, Noriyuki Satoh, Daniel S Rokhsar, John Gerhart
Acorn worms, also known as enteropneust (literally, 'gut-breathing') hemichordates, are marine invertebrates that share features with echinoderms and chordates. Together, these three phyla comprise the deuterostomes. Here we report the draft genome sequences of two acorn worms, Saccoglossus kowalevskii and Ptychodera flava. By comparing them with diverse bilaterian genomes, we identify shared traits that were probably inherited from the last common deuterostome ancestor, and then explore evolutionary trajectories leading from this ancestor to hemichordates, echinoderms and chordates...
November 26, 2015: Nature
Leonid Peshkin, Martin Wühr, Esther Pearl, Wilhelm Haas, Robert M Freeman, John C Gerhart, Allon M Klein, Marko Horb, Steven P Gygi, Marc W Kirschner
A biochemical explanation of development from the fertilized egg to the adult requires an understanding of the proteins and RNAs expressed over time during embryogenesis. We present a comprehensive characterization of protein and mRNA dynamics across early development in Xenopus. Surprisingly, we find that most protein levels change little and duplicated genes are expressed similarly. While the correlation between protein and mRNA levels is poor, a mass action kinetics model parameterized using protein synthesis and degradation rates regresses protein dynamics to RNA dynamics, corrected for initial protein concentration...
November 9, 2015: Developmental Cell
Martin Wühr, Thomas Güttler, Leonid Peshkin, Graeme C McAlister, Matthew Sonnett, Keisuke Ishihara, Aaron C Groen, Marc Presler, Brian K Erickson, Timothy J Mitchison, Marc W Kirschner, Steven P Gygi
The composition of the nucleoplasm determines the behavior of key processes such as transcription, yet there is still no reliable and quantitative resource of nuclear proteins. Furthermore, it is still unclear how the distinct nuclear and cytoplasmic compositions are maintained. To describe the nuclear proteome quantitatively, we isolated the large nuclei of frog oocytes via microdissection and measured the nucleocytoplasmic partitioning of ∼9,000 proteins by mass spectrometry. Most proteins localize entirely to either nucleus or cytoplasm; only ∼17% partition equally...
October 19, 2015: Current Biology: CB
Marc Kirschner, Angela Bauch, Alvar Agusti, Sebastian Hilke, Sibylle Merk, Christophe Pison, Jim Roldan, Bernard Seidenath, Michael Wilken, Emiel F Wouters, Hans-Werner Mewes, Klaus Heumann, Dieter Maier
The cause of a complex disease cannot be pinpointed to a single origin; rather, a highly complex network of many factors that interact on different levels over time and space is disturbed. This complexity requires novel approaches to diagnosis, treatment, and prevention. To foster the necessary shift to a pro-active systems medicine, proof-of-concept studies are needed. Here, we highlight several systems approaches that have been shown to work within the field of respiratory medicine, and we propose the next steps for broader implementation...
2015: Genome Medicine
Giovanna Figueiredo, Teresa Fiebig, Stefanie Kirschner, Omid Nikoubashman, Lisa Kabelitz, Ahmed Othman, Andrea Nonn, Martin Kramer, Marc A Brockmann
BACKGROUND: Repetitive administration of medication or contrast agents is frequently performed in mice. The introduction of vascular access mini-ports (VAMP) for mice allows long-term vascular catheterization, hereby eliminating the need for repeated vessel puncture. With catheter occlusion being the most commonly reported complication of chronic jugular vein catheterization, we tested whether digital subtraction angiography (DSA) can be utilized to evaluate VAMP patency in mice. METHODS: Twenty-three mice underwent catheterization of the jugular vein and subcutaneous implantation of a VAMP...
2015: PloS One
Allon M Klein, Linas Mazutis, Ilke Akartuna, Naren Tallapragada, Adrian Veres, Victor Li, Leonid Peshkin, David A Weitz, Marc W Kirschner
It has long been the dream of biologists to map gene expression at the single-cell level. With such data one might track heterogeneous cell sub-populations, and infer regulatory relationships between genes and pathways. Recently, RNA sequencing has achieved single-cell resolution. What is limiting is an effective way to routinely isolate and process large numbers of individual cells for quantitative in-depth sequencing. We have developed a high-throughput droplet-microfluidic approach for barcoding the RNA from thousands of individual cells for subsequent analysis by next-generation sequencing...
May 21, 2015: Cell
Manuela C Felix, Jens Fleckenstein, Stefanie Kirschner, Linda Hartmann, Frederik Wenz, Marc A Brockmann, Gerhard Glatting, Frank A Giordano
PURPOSE/OBJECTIVE: Although radiotherapy is a key component of cancer treatment, its implementation into pre-clinical in vivo models with relatively small target volumes is frequently omitted either due to technical complexity or expected side effects hampering long-term observational studies. We here demonstrate how an affordable industrial micro-CT can be converted into a small animal IGRT device at very low costs. We also demonstrate the proof of principle for the case of partial brain irradiation of mice carrying orthotopic glioblastoma implants...
2015: PloS One
Miriam B Ginzberg, Ran Kafri, Marc Kirschner
Different animal cell types have distinctive and characteristic sizes. How a particular cell size is specified by differentiation programs and physiology remains one of the fundamental unknowns in cell biology. In this Review, we explore the evidence that individual cells autonomously sense and specify their own size. We discuss possible mechanisms by which size-sensing and size-specification may take place. Last, we explore the physiological implications of size control: Why is it important that particular cell types maintain a particular size? We develop these questions through examination of the current literature and pose the questions that we anticipate will guide this field in the upcoming years...
May 15, 2015: Science
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