104,052 research outputs found
THE PURSUIT OF HOLINESS IN MODERNITY: THERESE OF LISIEUX AND WILLIAM J. SEYMOUR COMPARED.
No full textAll about 4H in school club program
No full textyouth met monthly for 6 session through out the school year completing their STEM project
Don't Play With That Girl
No full textStrangers Within is an anthology exploring the idea of documentary as encounter through essays, stories, interviews and other creative responses by filmmakers, artists, and writers. The texts engage with the risks of encounter, unsettling assumptions about the distinctions between host and guest; stranger and friend; self and other; documentarian and protagonist. Opening up a series of questions about the mystery of another person, whose difference and unknowability is already a part of one’s self, the anthology offers a multidisciplinary approach to understanding the convergences between encounter, hospitality and autobiography.
with Khalik Allah, Ruth Beckermann, Jon Bang Carlsen, Adam Christensen, Annie Ernaux, Gareth Evans, Jane Fawcett, Xiaolu Guo, Umama Hamido, Therese Henningsen, Marc Isaacs, Mary Jiménez Freeman-Morris, Juliette Joffé, Andrew and Eden Kötting, David MacDougall, Trinh T. Minh-ha, Toni Morrison, Bruno de Wachter and Andrea Luka Zimmerman.
My contribution 'Don't Play With That Girl' (6500w) surveys the process foundational to my filmmaking practice. Through examples I explore radical possibilities emerging from a rigorous, collaborative, non extractive fimlmaking practice. Seeking ways of refusal in relation to persistent cultural tropes, such as the ways in which my and others’ pasts are so often represented as only realist, abject, in need of charitable support – that perpetuates a way of being visible based on erasure. Towards an otherwise to what writer and artist Morgan Quaintance calls a ‘marginal melancholy’, where structures demand an ongoing performance of lack, to enter visibility. To produce counter memories, and imagine otherwise
Letter, [Author unclear] to Paulina T. Merritt
No full textHandwritten letter to Paulina Merritt from an unknown author, October 1, 1876.
T-cadherin signaling in endothelial cells
No full textThe cadherin superfamily comprises transmembrane glycoproteins that mediate calciumdependent
homophilic cell-cell adhesion. In addition to their pivotal role in mechanical adhesion
between cells, cadherins have multiple functions in tissue morphogenesis, cell recognition and
sorting, regulated cell motility and the induction and maintenance of tissue/cell polarity.
T-cadherin (T-cad) is unusual member of cadherin superfamily; while possessing the Nterminal
tandem cadherin repeat structure (EC domain), it lacks both transmembrane and
cytoplasmic domains, and is bound to the plasma membrane via a glycosylphosphatidylinositol
(GPI) anchor. T-cad has five EC domains and a propeptide in its precursor form (130kDa),
which upon cleavage gets converted to mature form (105kDa). A role for T-cad in tissue
organization was first demonstrated in the avian embryonic nervous system where the protein
influenced the pattern of neural crest cell migration and maintained somite polarity. Many cancer
cell lines (e.g. breast, colon, lung, inter alia) display allelic loss of T-cad which is correlated
with tumor progression, and hence T-cad has been described as tumor suppressor gene.
T-cad is widely expressed in the vasculature and is upregulated in proliferative vascular
disorders such as atherosclerosis and restenosis. GPI-anchored T-cad is not localized at adherent
junctions but rather distributed globally over the cell surface. T-cad is localized within lipid
rafts. In vitro data supports participation of T-cad in many cellular processes such as vascular
differentiation, migration and proliferation of smooth muscle cells (SMC) and endothelial cells
(EC) and angiogenesis. Adenoviral mediated overexpression of T-cad in EC and SMC results in
cell cycle progression and a concomitant promotion of proliferation. T-cad exhibits deadhesive
functions upon homophilic ligation with antibody against T-cad or with immobilized
recombinant protein. Homophilic ligation of T-cad induces polarization and migration of
endothelial cells in a RhoA/ROCK and Rac dependent fashion. T-cad stimulates in-gel
outgrowth of endothelial sprouts in 3-dimensional EC-spheroid and heart tissue models of
angiogenesis. In vivo, myoblast-mediated delivery of recombinant soluble T-cad to mouse
skeletal muscle facilitates VEGF-induced angiogenesis, supporting a physiological role for Tcad
as a proangiogenic protein.
The present thesis is focused on the regulation of T-cad expression and the signaling
mechanisms whereby T-cad affects vascular cell behavior. The conditions of proliferative
vascular cell disorders in which T-cad is upregulated are associated with oxidative stress and cell
survival/cell death. We observed an elevation in T-cad levels under condition of oxidative stress
induced by serum-deprivation and H2O2; this response was normalized upon inclusion of an
antioxidant, N-acetyl cysteine or NADPH oxidase inhibitor diphenyleneiodonium, suggesting T-
cad induction by reactive oxygen species is NADPH oxidase dependent. Adenoviral mediated
overexpression of T-cad in EC facilitated EC survival upon induction of apoptosis by serumdeprivation
and various apoptosis-inducing pharmacologicals. Western blot analysis of lysates
infected with Empty –adenovirus (E-EC) and T-cad adenovirus (T-cad+-EC) resulted in
hyperactivity of anti-apoptotic proteins (Akt and mTOR target p70S6 kinase) and diminished
activity of pro-apoptotic proteins (p38MAPK and active caspase3). PI3 kinase inhibitor,
wortmannin, and mTOR inhibitor, rapamycin, normalized anti-apoptotic effects of T-cad; these
data suggest that upregulation of T-cad in response to oxidative stress functions to protect EC by
concomitant induction of PI3K/Akt/mTOR pathway and suppression of p38/caspase3 pathways.
Subsequently we focused on identifying downstream targets of Akt and candidate
proximal molecular mediators for T-cad. T-cad+-EC exhibited hyperphosphorylation of glycogen
synthase kinase β (GSK3β) and concomitant nuclear accumulation of active β-catenin, a
transcription factor regulating cell cycle proteins. Using various GSK3β-carrying adenovectors
(kinase mutant, dominant negative or wild type) we demonstrated that T-cad induced nuclear
accumulation of β-catenin is GSK3β-dependent. siRNA mediated knockdown of T-cad resulted
in decreased phosphorylation of Akt and GSK3β and also in reduced nuclear accumulation of β-
catenin. T cell factor (TCF) and Leukocyte enhancer factor (LEF) are co-factors for β-catenin;
we found that luciferase (reporter) activity of TCF/LEF elements in T-cad+-EC was markedly
increased as compared to E-EC. Cyclin D1, one of the important regulators of the cell cycle is a
target of β-catenin/TCF/LEF transcription machinery; T-cad+-EC showed increased mRNA and
protein levels of cyclin D1 and increased cell proliferation. In searching for molecular mediators
of T-cad we considered Integrin linked kinase (ILK) as a putative candidate because both the
proteins are located in rafts and ILK acts upstream of Akt and GSK3β in a PI3K-dependent
fashion. T-cad+-EC exhibited increased ILK “kinase” activity in a pull-down assay. RNAimediated
knockdown of ILK abrogated effects of T-cad on both phosphorylation of Akt and
GSK3β and the nuclear accumulation β-catenin, suggesting involvement of ILK in T-cad
signaling. Confocal microscopy studies revealed colocalisation of T-cad and ILK in EC which
was most prominent within leading edges of migratory cells and at focal adhesions. Anti-ILK
immunoprecipitates contained T-cad indicating the existence of T-cad/ILK complexes, and
supporting our hypothesis that ILK can function as a proximal molecular mediator for T-cadelicited
PI3K/Akt/GSK3β signaling.
Transcriptional regulation of T-cad in endothelial cells is poorly understood. To
characterize the minimal promoter region of T-cad, we cloned serially deleted fragments of Tcad
promoter stretches into luciferase reporter vector (pGL3). Reporter gene analysis exhibited
basal levels of luciferase activity within -285bps suggesting existence of minimal promoter
region within -285bps from translational start site. Oxidative stress elevated reporter activity of
-285 bps construct, suggesting the minimal promoter region might be responsible for the redox
sensitivity of T-cad expression. To identify regulatory elements (transcription factors)
responsible for T-cad regulation gel shift assays were performed using nuclear extracts of EC
and various oligos designed from T-cad promoter region from -1 to -284 bps We identified
specific binding of regulatory protein(s) between -156 to -203 bps. Nuclear extracts from serumdeprived
EC exhibited increased binding to -156 to -203 bps oligo, suggesting that the identified
nucleoprotein complex could function to induce T-cad expression under conditions of oxidative
stress. To identify transcription factor(s) within the identified nucleoprotein complex we
performed pull-down assay using nuclear extracts of EC, biotinylated -156 to -203 bps and
streptavidin agarose beads. Proteins pulled down were subjected to microsequencing by mass
spectrometry. Interestingly thioredoxin (TRX1) was found to be present. TRX1 is a 12kDa
protein induced by NADPH oxidase under stress and it acts as an antioxidant by facilitating the
reduction of other proteins by cysteine thiol-disulfide exchange. Following its translocation to
the nucleus TRX1 reduces transcription factors, enabling their binding to regulatory elements.
Preliminary data using RNAi-mediated knockdown of TRX1 abrogates oxidative stress-induced
upregulation of T-cad in EC, suggesting that NADPH dependent-induction of T-cad involves
nuclear translocation of TRX1. These data may explain the observations of upregulation of Tcad
on vascular cells in atherosclerotic lesions where oxidative stress plays a key pathogenic
role
Modulatory effects of T-cadherin on cell behavior and growth factor receptor activity in carcinoma cells
No full textCancer is a major health problem. Epidermal growth factor receptor (EGFR) pathway plays an important role in cancer progression. EGFR-targeted anti-cancer drugs are being developed to improve anti-cancer therapy. These drugs can give good results especially when a disease is driven by a dominant oncogene. However, the malignant process is generally supported by multiple genetic alterations and a complex signaling network that can compensate for deactivation of signaling targets by increasing activity of other pathways. Deeper understanding of molecular mechanisms of growth factor signaling regulation in cancer will improve anti-cancer therapy and increase clinical benefits.
Classical cadherins are well recognized to be involved in cancer progression and regulation of receptor tyrosine kinase (RTK) signaling. Implication of T-cadherin, an atypical member of cadherin superfamily, in cancer progression has been documented in many cancers but mostly on genetic and epigenetic levels. Few studies have examined functional effects of T-cadherin in cancer, the molecular mechanisms of its effects are poorly understood, and whether T-cadherin regulates RTK signaling in tumor cells is unknown.
This thesis aimed at delineation of the functions of T-cadherin and molecular mechanisms of action in cutaneous squamous cell carcinoma (SCC). We found that T-cadherin loss promotes cell elongation, cell cluster disorganization, cell motility and invasive potential, while T-cadherin upregulation reduces malignant behavior of cells. T-cadherin loss increases, while T-cadherin upregulation blunts sensitivity to stimulation by EGF, manifest at the levels of ligand-induced EGFR phosphorylation/internalization, signal transduction, cell retraction and motility. Molecular mechanisms underlying functional effects of T-cadherin involve ?1 integrin activation status and the Rho family of small GTPases. Effects of T-cadherin on EGFR activity are due to altered accumulation of EGFR within lipid raft domains; T-cadherin upregulation retains, while T-cadherin loss releases EGFR from these domains. Thus, T-cadherin acts as a negative auxiliary regulator of EGFR. EGFR activation in SCC promotes T-cadherin redistribution to intercellular contacts, supporting a reciprocal nature of cross-talk between EGFR and T-cadherin. We postulated that modulation of EGFR activity by T-cadherin could be a regulatory mechanism common to other RTKs. Using prostate cancer cells DU145 (which express comparable levels of EGFR and IGF-1R) we found that T-cadherin regulates activity of both EGFR and IGF-1R and their cross talk. Therefore modulation of growth factor receptor tyrosine kinase activity and cross-talk may be a common mechanistic principle underlying T-cad-dependent control of carcinoma cell behavior. In summary, the findings of this thesis have advanced knowledge on the functional role of T-cadherin in cancer and the participating molecular mechanisms
Il-forma ortografika u t-tifsira semantika fl-għażla tal-lessiku Malti fl-oqsma tat-traduzzjoni u tat-terminoloġija
No full textDin l-analiżi turi kif is-Semitiku, ir-Rumanz u l-Ingliż li minnhom magħmul il-Malti
jippermettu dinamiżmu u flessibilità kbira fil-qasam tat-traduzzjoni kemm letterarja kif
ukoll nonletterarja. Il-forma ortografika u t-tifsira semantika tal-kliem Malti-Rumanz huma
ħafna drabi l-istess bħal dawk tal-kliem Malti-Ingliż u dan għax kemm l-Ingliż kif ukoll
it-Taljan għandhom fil-lessiku għadd ta’ għeruq komuni li etimoloġikament imorru lura
għal-Latin Medjevali. Ir-rwol tat-traduzzjoni hu li jwassal it-test sors b’mod awtentiku lillqarrej
tat-test mira u mhux li jippreserva l-element Semitiku fil-Malti. Għalhekk għandha
ssir distinzjoni bejn lingwa u traduzzjoni sabiex jiġi osservat id-determiniżmu lingwisitku
stabbilit mill-awtur tal-lingwa sors fl-għażla tal-lessiku li twassal għar-replika vera tat-test
oriġinali fil-lingwa mira tat-traduttur.peer-reviewe
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