Judging causal associations in observational research on caudal anesthesia and hypospadias repair

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140029/1/pan13260_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/140029/2/pan13260.pd

Caudal clonidine and apnea risk

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/110530/1/pan12605.pd

Harm attributable to research distraction? Challenging conclusions on caudal epinephrine

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109642/1/pan12563.pd

Reply

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

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

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

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