Effects Of An Intervention To Promote Stair Use In A University Building

Wellness programs have been implemented by companies and other organizations for various reasons since before the 1970s, and many have focused on the promotion of physical activity as a health-promoting behavior. Promoting physical activity via stairwell prompting at the workplace has become very popular in recent years. This study tested an intervention based upon motivational signage placed in the stairwells of a University administrative building, as well as daily emails sent to the employees in the building. Key concepts from Self-Determination Theory (SDT) and a sub-theory of SDT, Organismic Integration Theory (OIT) were integrated into the messages of the posters and emails encouraging stair use among employees of the building. Twelve motivational signs were placed in the stairwells and in front of elevator openings, and five motivational emails were sent out during the five-day intervention period. Automatic people counters were used to track use of the elevators and stairs. After the intervention, building employees were invited to complete a questionnaire designed to assess whether their SDT-related perceptions were influenced by the motivational e-mails and posters. Chi square analyses of the counter data showed that the motivational messages increased stair use by individuals using the building. The staircase mainly used by building employees showed the largest increase in use during the intervention. The questionnaire responses indicated that three out of the four SDT-related motivational perceptions were enhanced by the e-mail messages and stairwell posters

Investigation of Methods for the Generation of Selective Small-molecule Kinase Inhibitors.

Protein kinases have evolved as key players in the signaling processes that allow the mammalian cell to respond to environmental stimuli. Determination of the function of each the individual members of this large class of enzymes is aided by development of selective inhibitors. Most kinase inhibitors function through binding the highly conserved ATP-pocket and are often poorly selective as a result. This dissertation assesses two general strategies to improve kinase inhibitor selectivity. One strategy regards ATP-competitive inhibitors which target distinct kinase folds, and an orthogonal strategy regards targeting inhibitor binding sites outside of the highly conserved ATP-pocket. First, the drug dasatinib is rationally altered to provide two sets of inhibitors which respectively bind distinct “inactive” kinase folds (DFG-out and c-helix out). Large scale selectivity profiling reveals that most of dasatinib’s kinase targets can adopt the DFG-out conformation, while the c-helix out conformation appears less conserved. These results imply that targeting inactive conformations does not necessarily entail higher kinase inhibitor selectivity. Second, inhibitors that target regions outside of the ATP-pocket are developed using a bivalent approach. A fragment intended to target a region outside of the ATP-pocket is covalently tethered to an ATP-competitive inhibitor. Application of this strategy demonstrates the amount of selectivity that can be gained from targeting alternate pockets. In one example, we show that the site at which kinases bind their protein target can be modularly targeted for highly selective inhibition. In another example, the development of a highly selective c-Src inhibitor is achieved through targeting the phosphate binding-loop region. In an application of our c-Src selective inhibitor, it is shown that selective inhibition is more effective than multi-kinase inhibition in the treatment of several cancer cell lines. Altogether this dissertation provides insight regarding the design of selective kinase inhibitors. One study reveals that ATP-competitive inhibitors that bind “inactive” kinase folds appear to be much less selective than previously suggested. A second study demonstrates that targeting sites outside of the ATP-pocket can provide very highly selective kinase inhibitors.PHDMedicinal ChemistryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/108801/1/kristofb_1.pd

Myc regulates VEGF production in B cells by stimulating initiation of VEGF mRNA translation.

Deregulated c-myc gene expression is associated with many human and animal cancers. Myc overexpression promotes the growth of blood and lymphatic vessels, which is due in part to induction of growth factors including vascular endothelial growth factor (VEGF). We determined that the P493-6 human B-cell line increases VEGF production 10-fold upon Myc overexpression. Myc overexpression in avian B cells similarly resulted in high level VEGF production. Real-time RT-PCR analyses showed that Myc did not alter the VEGF mRNA content of these cell lines, indicating that a post-transcriptional mechanism regulates VEGF production. VEGF mRNA translation was examined by RT-PCR analysis of monosome and polysome sucrose gradient fractions from Myc-on and Myc-off P493-6 cells. Myc increased VEGF mRNA translation initiation, as VEGF mRNA loading onto polysomes increased 14-fold in Myc-on cells, and the number of ribosomes loaded per VEGF mRNA increased threefold. This translational regulation is specific to VEGF mRNA, as total polysomes show the same sucrose gradient profile in Myc-on and Myc-off cells, with no change in the percent ribosomes in polysomes, or in the number of ribosomes per polysomal mRNA. Myc stimulates VEGF production by a rapamycin- and LY294002-sensitive pathway, which does not involve alteration of eIF4E activity

"Den tar jo tid, men jeg ville ikke vært den foruten". Evalueringsboka, et redskap for formativ vurdering?

Forskning fastslår at vurderingspraksis som setter elevene i sentrum har stor læringseffekt. Elevene bør i samråd med lærer vurdere egen læringsprosess, og på sikt være i stand til egenhendig å endre kurs og vurdere egne læringsmål. Disse prinsippene faller innenfor formativ vurdering. I forskning og politiske dokumenter blir formativ vurdering ofte omtalt i abstrakte ordelag, og det kan virke utfordrende å omsette prinsippene til praksis. Vårt formål har vært å bidra til konkret innsikt i et vurderingsredskap som fremmer formativ vurdering. For å nærme oss fagfeltet på en realistisk måte, valgte vi å studere en skole som har hatt formativ vurdering som utviklingsarbeid gjennom flere år. Skolen bruker aktivt en evalueringsbok i sin vurderingspraksis, og vi ønsket å undersøke muligheter og utfordringer i anvendelsen av denne boka. For å innhente nødvendig datamateriale, gjennomførte vi tre semistrukturerte intervjuer, observasjon av informantenes muntlige vurdering og dokumentanalyse av elevenes individuelle evalueringsbok. Datamaterialet ble analysert med en temasentrert tilnærming. I analyseprosessen fant vi flere muligheter og utfordringer tilknyttet evalueringsboka. Et sentralt funn var at evalueringsboka bidro til aktive elever som i stor grad kunne overvåke egen læringsprosess. På den andre siden havnet lærerne ofte i tidsklemma som følge av ambisiøse læringsmål og lite tid til gjennomgang

TORC1-mediated sensing of chaperone activity alters glucose metabolism and extends lifespan

Protein quality control mechanisms, required for normal cellular functioning, encompass multiple functions related to protein production and maintenance. However, the existence of communication between proteostasis and metabolic networks and its underlying mechanisms remain elusive. Here, we report that enhanced chaperone activity and consequent improved proteostasis are sensed by TORC1 via the activity of Hsp82. Chaperone enrichment decreases the level of Hsp82, which deactivates TORC1 and leads to activation of Snf1/AMPK, regardless of glucose availability. This mechanism culminates in the extension of yeast replicative lifespan (RLS) that is fully reliant on both TORC1 deactivation and Snf1/AMPK activation. Specifically, we identify oxygen consumption increase as the downstream effect of Snf1 activation responsible for the entire RLS extension. Our results set a novel paradigm for the role of proteostasis in aging: modulation of the misfolded protein level can affect cellular metabolic features as well as mitochondrial activityand consequently modify lifespan. The described mechanism is expected to open new avenues for research of aging and age-related diseases

Supplementary materials - Analysis of gene expression during myc oncogene-induced lymphomagenesis in the bursa of Fabricius.

The transcriptional effects of deregulated myc gene overexpression are implicated in tumorigenesis in a spectrum of experimental and naturally occurring neoplasms. In follicles of the chicken bursa of Fabricius, myc induction of B-cell neoplasia requires a target cell population present during early bursal development and progresses through preneoplastic transformed follicles to metastatic lymphomas. We developed a chicken immune system cDNA microarray to analyze broad changes in gene expression that occur during normal embryonic B-cell development and during myc-induced neoplastic transformation in the bursa. The number of mRNAs showing at least 3-fold change was greater during myc-induced lymphomagenesis than during normal development, and hierarchical cluster analysis of expression patterns revealed that levels of several hundred mRNAs varied in concert with levels of myc overexpression. A set of 41 mRNAs were most consistently elevated in myc-overexpressing preneoplastic and neoplastic cells, most involved in processes thought to be subject to regulation by Myc. The mRNAs for another cluster of genes were overexpressed in neoplasia independent of myc expression level, including a small subset with the expression signature of embryonic bursal lymphocytes. Overexpression of myc, and some of the genes overexpressed with myc, may be important for generation of preneoplastic transformed follicles. However, expression profiles of late metastatic tumors showed a large variation in concert with myc expression levels, and some showed minimal myc overexpression. Therefore, high-level myc overexpression may be more important in the early induction of these lymphomas than in maintenance of late-stage metastases

Interleukin-34 promotes tumor progression and metastatic process in osteosarcoma through induction of angiogenesis and macrophage recruitment

International audienceInterleukin-34 (IL-34) was recently characterized as the M-CSF "twin" cytokine, regulating the proliferation/differentiation/survival of myeloid cells. The implication of M-CSF in oncology was initially suspected by the reduced metastatic dissemination in knock-out mice, due to angiogenesis impairment. Based on this observation, our work studied the involvement of IL-34 in the pathogenesis of osteosarcoma. The in vivo effects of IL-34 were assessed on tissue vasculature and macrophage infiltration in a murine preclinical model based on a paratibial inoculation of human osteosarcoma cells overexpressing or not IL-34 or M-CSF. In vitro investigations using endothelial cell precursors and mature HUVEC cells were performed to analyse the involvement of IL-34 in angiogenesis and myeloid cell adhesion. The data revealed that IL-34 overexpression was associated with the progression of osteosarcoma (tumor growth, lung metastases) and an increase of neo-angiogenesis. In vitro analyses demonstrated that IL-34 stimulated endothelial cell proliferation and vascular cord formation. Pre-treatment of endothelial cells by chondroitinases/heparinases reduced the formation of vascular tubes and abolished the associated cell signalling. In addition, IL-34 increased the in vivo recruitment of M2 tumor-associated macrophages into the tumor tissue. IL-34 increased in vitro monocyte/CD34(+) cell adhesion to activated HUVEC monolayers under physiological shear stress conditions. This work also demonstrates that IL-34 is expressed by osteosarcoma cells, is regulated by TNF-α, IL-1β, and contributes to osteosarcoma growth by increasing the neo-angiogenesis and the recruitment of M2 macrophages. By promoting new vessel formation and extravasation of immune cells, IL-34 may play a key role in tumor development and inflammatory diseases

Substrate Activity Screening with Kinases: Discovery of Small‐Molecule Substrate‐Competitive c‐Src Inhibitors

Substrate‐competitive kinase inhibitors represent a promising class of kinase inhibitors, however, there is no methodology to selectively identify this type of inhibitor. Substrate activity screening was applied to tyrosine kinases. By using this methodology, the first small‐molecule substrates for any protein kinase were discovered, as well as the first substrate‐competitive inhibitors of c‐Src with activity in both biochemical and cellular assays. Characterization of the lead inhibitor demonstrates that substrate‐competitive kinase inhibitors possess unique properties, including cellular efficacy that matches biochemical potency and synergy with ATP‐competitive inhibitors. SASsy inhibitors : Small‐molecule substrate‐competitive inhibitors of the tyrosine kinase c‐Src were discovered through the application of substrate activity screening (SAS). Characterization of the lead inhibitor demonstrates that substrate‐competitive kinase inhibitors possess unique properties, including cellular efficacy that matches biochemical potency and synergy with ATP‐competitive inhibitors.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/107499/1/7010_ftp.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/107499/2/anie_201311096_sm_miscellaneous_information.pd