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Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/108083/1/hep26952.pd

A disease- and phosphorylation-related nonmechanical function for keratin 8

Keratin 8 (K8) variants predispose to human liver injury via poorly understood mechanisms. We generated transgenic mice that overexpress the human disease-associated K8 Gly61-to-Cys (G61C) variant and showed that G61C predisposes to liver injury and apoptosis and dramatically inhibits K8 phosphorylation at serine 73 (S73) via stress-activated kinases. This led us to generate mice that overexpress K8 S73-to-Ala (S73A), which mimicked the susceptibility of K8 G61C mice to injury, thereby providing a molecular link between K8 phosphorylation and disease-associated mutation. Upon apoptotic stimulation, G61C and S73A hepatocytes have persistent and increased nonkeratin proapoptotic substrate phosphorylation by stress-activated kinases, compared with wild-type hepatocytes, in association with an inability to phosphorylate K8 S73. Our findings provide the first direct link between patient-related human keratin variants and liver disease predisposition. The highly abundant cytoskeletal protein K8, and possibly other keratins with the conserved S73-containing phosphoepitope, can protect tissue from injury by serving as a phosphate “sponge” for stress-activated kinases and thereby provide a novel nonmechanical function for intermediate filament proteins

Trust & reputation models for human sensor observations

Diese Arbeit befasst sich mit dem Problem die Qualität von Nutzer-generierten Inhalten zu bemessen. Zuerst werden, basierend auf vorherigen Arbeiten zu einer funktionalen Ontologie von Beobachtungen und Messungen, die Begriffe Vertrauen und Reputation als Maße für die Qualität von Nutzer-generierten Inhalten ontologisch beschrieben. Die besagte Ontologie wird um die Begriffe Vertrauen und Reputation erweitert. Die Ontologie ist als algebraische Spezifikation entwickelt. Als Zweites wird der Begriff des Vertrauens in Information, das das zwischenmenschliche Vertrauen kapselt, entwickelt. Danach werden zwei räumliche und zeitliche Modelle für Vertrauen und Reputation entwickelt um die Qualität menschlicher Beobachtungen zu bemessen. Analysen zeigen, dass die entwickelten Modelle effektive Werkzeuge zur Sichtung, Filterung und Bemessung der Qualität von menschlichen Beobachtungen sind. Weiterhin hat der Einbezug von Raum und Zeit einen positiven Einfluss auf die Leistung des Modells. This thesis deals with the problem of quality of user-generated content. First, we provide an ontological account of trust and reputation as measures for quality of user generated content based on earlier work on a functional ontology for observation and measurement. We extend the ontology with trust and reputation. The ontological account is developed as an algebraic specification. Second, we develop the notion of informational trust mediated by interpersonal trust to enable trusting information. We then develop two spatial and temporal computational trust and reputations models for quality assessment human observations. Our analysis shows that the developed models are effective tools for triage, filtering and quality assessment of human sensor observations. Furthermore, the integration of space and time in our trust and reputation models has a positive impact on the models' performance

Two strikes: limited NIH R55 and R56 retooling funds and abolishment of the A2 grant mechanism

The U.S. National Institutes of Health (NIH) are facing significant budgetary challenges as a result of the current economic climate. The recent sunset of investigator‐initiated R01‐type research grants after one revised submission, coupled with the present lack of an NIH retooling funding mechanism for such grant applicants, creates a concerning risk that talented and well‐trained investigators may be forced to give up their research careers. Existing NIH retooling mechanisms include the R55 Shannon Award, which was established in 1991 and was essentially replaced in 2005 by the R56 award. There is an urgent need to either significantly expand the R55/R56 mechanisms and definition of NIH grant bridging/retooling support for unfunded meritorious proposals or introduce a new mechanism that provides specific support to investigators with competitive but unfunded R01 revised grants. An expanded retooling funding mechanism deserves implementation during continuing assessment of whether allowance of only one revision of research proposals has achieved its initial intended goals. Omary, M. B., Offhaus, H., Kunkel, S. L. Two strikes: limited NIH R55 and R56 retooling funds and abolishment of the A2 grant mechanism. FASEB J. 25, 4108–4110 (2011). www.fasebj.orgPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154267/1/fsb2fj11188052.pd

Raf-1 activation disrupts its binding to keratins during cell stress

Keratins 8 and 18 (K8/18) heteropolymers may regulate cell signaling via the known K18 association with 14-3-3 proteins and 14-3-3 association with Raf-1 kinase. We characterized Raf–keratin–14-3-3 associations and show that Raf associates directly with K8, independent of Raf kinase activity or Ras–Raf interaction, and that K18 is a Raf physiologic substrate. Raf activation during oxidative and toxin exposure in cultured cells and animals disrupt keratin–Raf association in a phosphorylation-dependent manner. Mutational analysis showed that 14-3-3 residues that are essential for Raf binding also regulate 14-3-3–keratin association. Similarly, Raf phosphorylation sites that are important for binding to 14-3-3 are also essential for Raf binding to K8/18. Therefore, keratins may modulate some aspects of Raf signaling under basal conditions via sequestration by K8, akin to Raf–14-3-3 binding. Keratin-bound Raf kinase is released upon Raf hyperphosphorylation and activation during oxidative and other stresses

Increased co‐first authorships in biomedical and clinical publications: a call for recognition

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154532/1/fsb2027010039.pd

Személyre szabott kezelés szinkrón, nyirokcsomó-pozitív petefészek- és vastagbéldaganatban

Absztrakt A 71 éves nőbetegnél jobb alhasi fájdalom és láz miatt sürgősségi laparotomiára került sor. Makroszkóposan duplex coecum és colon transversum, továbbá szigma/bal petefészek daganatának gyanúja merült fel. A szövettani vizsgálat szinkrón bal petefészek- (papillaris adenocarcinoma) és colon transversum (tubularis adenocarcinoma) daganatot mutatott. Mind a két primer daganat a regionális nyirokcsomóikba adott áttétet, továbbá a petefészek-daganat infiltrálta a szigmabelet és távoli áttétet képzett a coecum területére. Immunhisztokémiával a nyirokcsomóáttétek egyértelműen elkülöníthetők voltak: petefészek-eredetű CK7-pozitív, coloneredetű CK20- és CEA-pozitív. A szikrón primer daganatokat kombinált kemoterápiával kezeltük (FOLFOX-4 és heti paclitaxel). A kombinált kezelést a beteg jól tolerálta. A ritka eset hangsúlyozza annak jelentőségét, hogy a többszörös primer daganatok egyénre szabott kemoterápiás sémával kezelhetők jó hatásfokkal és enyhe mellékhatásokkal. Orv. Hetil., 2015, 156(23), 939–943

Fibrinogen-γ proteolysis and solubility dynamics during apoptotic mouse liver injury: Heparin prevents and treats liver damage

Fas ligand (FasL)-mediated hepatocyte apoptosis occurs in the context of acute liver injury that can be accompanied by intravascular coagulation (IC). We tested the hypothesis that analysis of selected protein fractions from livers undergoing apoptosis will shed light on mechanisms that are involved in liver injury that might be amenable to intervention. Proteomic analysis of the major insoluble liver proteins after FasL exposure for 4-5 hours identified fibrinogen-γ (FIB-γ) dimers and FIB-γ–containing high molecular mass complexes among the major insoluble proteins visible via Coomassie blue staining. Presence of the FIB-γ–containing products was confirmed using FIB-γ–specific antibodies. The FIB-γ–containing products partition selectively and quantitatively into the liver parenchyma after inducing apoptosis. Similar formation of FIB-γ products occurs after acetaminophen administration. The observed intrahepatic IC raised the possibility that heparin therapy may ameliorate FasL-mediated liver injury. Notably, heparin administration in mice 4 hours before or up to 2 hours after FasL injection resulted in a dramatic reduction of liver injury—including liver hemorrhage, serum alanine aminotransferase, caspase activation, and liver apoptosis—compared with heparin-untreated mice. Heparin did not directly interfere with FasL-induced apoptosis in isolated hepatocytes, and heparin-treated mice survived the FasL-induced liver injury longer compared with heparin-untreated animals. There was a sharp, near-simultaneous rise in FasL-induced intrahepatic apoptosis and coagulation, with IC remaining stable while apoptosis continued to increase. Conclusion: Formation of FIB-γ dimers and their high molecular mass products are readily detectable within the liver during mouse apoptotic liver injury. Heparin provides a potential therapeutic modality, because it not only prevents extensive FasL-related liver injury but also limits the extent of injury if given at early stages of injury exposure. (H EPATOLOGY 2011;)Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/83742/1/24203_ftp.pd

Keratin 8 phosphorylation regulates its transamidation and hepatocyte Mallory‐Denk body formation

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154269/1/fsb2026006010.pd