Connectivity mapping (ssCMap) to predict A20-inducing drugs and their antiinflammatory action in cystic fibrosis

Cystic fibrosis (CF) lung disease is characterized by chronic and exaggerated inflammation in the airways. Despite recent developments to therapeutically overcome the underlying functional defect in the cystic fibrosis transmembrane conductance regulator, there is still an unmet need to also normalize the inflammatory response. The prolonged and heightened inflammatory response in CF is, in part, mediated by a lack of intrinsic down-regulation of the proinflammatory NF-κB pathway. We have previously identified reduced expression of the NF-κB down-regulator A20 in CF as a key target to normalize the inflammatory response. Here, we have used publicly available gene array expression data together with a statistically significant connections’ map (sscMap) to successfully predict drugs already licensed for the use in humans to induce A20 mRNA and protein expression and thereby reduce inflammation. The effect of the predicted drugs on A20 and NF-κB(p65) expression (mRNA) as well as proinflammatory cytokine release (IL-8) in the presence and absence of bacterial LPS was shown in bronchial epithelial cells lines (16HBE14o−, CFBE41o−) and in primary nasal epithelial cells from patients with CF (Phe508del homozygous) and non-CF controls. Additionally, the specificity of the drug action on A20 was confirmed using cell lines with tnfαip3 (A20) knockdown (siRNA). We also show that the A20-inducing effect of ikarugamycin and quercetin is lower in CF-derived airway epithelial cells than in non-CF cells

Hymyä ja ehkä vähän kyyneliä : Traagiset elementit komediaelokuvassa

Tämän opinnäytetyön tavoite on selvittää, miten komediaelokuvaan kirjoitetaan traagisia elementtejä. Aihetta lähestytään analysoimalla komediaelokuvia, joissa on mukana traagisia elementtejä. Elokuvat on luokiteltu tragikomedioiksi ja tragedian määrä vaihtelee elokuvissa. Työn alussa selvennetään käsitteitä kuten, komedia, tragedia, draama ja tragikomedia. Seuraavaksi pohditaan miksi tragikomediaa kannattaa kirjoittaa, ja miten tragikomedia eroaa muista genreistä merkitykseltään. Elokuvien analyyseissa pohditaan ensin komedian tyylilajia ja käydään läpi henkilöiden komediallisia ja traagisia piirteitä. Tämän jälkeen analysoidaan mitä traagisia elementtejä elokuvista on havaittavissa. Tragikomedian kirjoittamiseen perehdytään lähteiden ja esimerkkielokuvien avulla. Esiin nostetaan tragikomedian rakenne, henkilöt, maailman merkitys ja kulttuurikonteksti. Myös käsikirjoittajan työprosessia ja omakohtaisten kokemusten käyttöä pohditaan. Lopuksi pohditaan, millainen tarina sopii kerrottavaksi tragikomedian keinoin ja mikä yhteiskunnallinen ja taiteellinen merkitys tragikomedialla on. Johtopäätöksenä todetaan, että päällimmäisenä tarkoituksena tragikomedian kirjoittamiselle on, että tragikomedian avulla voidaan katsoja saada kokemaan, sekä komediaan että tragediaan liittyviä tunnetiloja, kuten pelkoa, sääliä ja iloa. Tragikomediassa henkilögallerian merkitys on suuri, koska henkilöissä on havaittavissa sekä komedian että draaman roolifunktioita. Tragikomedian rakenne noudattaa usein draaman rakennetta ja komedia syntyy henkilöiden kautta. Esimerkkielokuvissa yhteiskunta toimii pääosin antagonistina ja teemana käsitellään lähimmäisen rakkautta, koska se näyttää sopivan tragikomedian tyylilajiin. Opinnäytetyön toivotaan saavan käsikirjoittajien innostumaan tragikomedian kirjoittamisesta.The purpose of this work is to explain how to write tragical elements into a comedy movie. The approach of this thesis is analysing comedy movies which have tragic elements. Movies are considered tragicomedies and the amount of tragic elements vary between the movies. In the beginning of the thesis, subjects such as comedy, tragedy, drama and tragicomedy are explained. Next, the question arises why tragicomedy is written and how it differs from other genres by its meaning. In the analyses, example movies are considered by their genre and the character´s comic and tragic characteristics are analyzed. Subsequently, tragic elements in the movies are analyzed. Writing tragicomedy is familiarized with sources and for example movies. The structure of tragicomedy, characters, surroundings and cultural context are highlighted. The writer´s workprocess and personal experiences are pondered. Finally the thesis considers what kind of a story is suitable to be told with tragicomic ways and which social and artistic meaning tragicomedy has. As a conclusion, the topmost purpose of writing tragicomedy is to make the viewer feel moods like in comedy and tragedy as fear, pity and joy. In tragicomedy, the meaning of the character gallery is significant because in the characters, there are noticeable role functions from both comedy and drama. The structure of tragicomedy obeys mostly composition of drama and comedy born out of the characters. In the example movies society works mostly as antagonist and as a theme is considered brotherly love, because it appears to fit in the tragicomic genre. Hoped effect of the thesis is to inspire writers to write tragicomedy

Le Courrier

08 janvier 18261826/01/08 (A0,N8)

An Alzheimer’s Disease Patient-Derived Olfactory Stem Cell Model Identifies Gene Expression Changes Associated with Cognition

An early symptom of Alzheimer’s disease (AD) is an impaired sense of smell, for which the molecular basis remains elusive. Here, we generated human olfactory neurosphere-derived (ONS) cells from people with AD and mild cognitive impairment (MCI), and performed global RNA sequencing to determine gene expression changes. ONS cells expressed markers of neuroglial differentiation, providing a unique cellular model to explore changes of early AD-associated pathways. Our transcriptomics data from ONS cells revealed differentially expressed genes (DEGs) associated with cognitive processes in AD cells compared to MCI, or matched healthy controls (HC). A-Kinase Anchoring Protein 6 (AKAP6) was the most significantly altered gene in AD compared to both MCI and HC, and has been linked to cognitive function. The greatest change in gene expression of all DEGs occurred between AD and MCI. Gene pathway analysis revealed defects in multiple cellular processes with aging, intellectual deficiency and alternative splicing being the most significantly dysregulated in AD ONS cells. Our results demonstrate that ONS cells can provide a cellular model for AD that recapitulates disease-associated differences. We have revealed potential novel genes, including AKAP6 that may have a role in AD, particularly MCI to AD transition, and should be further examined

LAG3: a novel immune checkpoint expressed by multiple lymphocyte subsets in diffuse large B-cell lymphoma

Blockade of\ua0the PD-1 axis has modest efficacy in diffuse large B-cell lymphoma (DLBCL), but data regarding LAG3 are sparse. The impact of LAG3 digital gene expression was tested in 309 patients with DLBCL treated with standard chemoimmunotherapy. Cellular distribution of LAG3 protein was determined by immunohistochemistry and flow cytometry. In tumor-infiltrating lymphocytes (TILs), LAG3 expression was highest on CD4+\ua0regulatory T cells (Tregs) and was also highly expressed on CD8+\ua0T cells compared with CD4+\ua0non-Tregs (both\ua0P\ua0= .008). LAG3high\ua0TILs were enriched in PD-1 and TIM-3. LAG3 was also expressed on a proportion of malignant B cells, and these patients had significantly higher LAG3 messenger RNA in their biopsies (P\ua0= .03). LAG3high\ua0gene expression was\ua0associated with inferior survival in discovery/validation cohorts, independent of cell of origin and the international prognostic index. Patients who were PD-L1high\ua0were fivefold more likely to be LAG3high\ua0(P\ua0< .0001). Patients who were LAG3high/PD-L1high\ua0had an inferior progression-free survival (P\ua0= .011) and overall survival (P\ua0= .005) compared with patients who were LAG3low/PD-L1high. Digital spatial protein analysis confirms LAG3 expression on T cells and, surprisingly, tumor-associated macrophages (TAMs) at higher levels than found on CD20+\ua0B cells in the tumor microenvironment. LAG3 is frequently expressed on CD4+\ua0Tregs and CD8+\ua0TILs, typically with other immune checkpoints, and is also present in a proportion of malignant B cells in DLBCL and in areas enriched for TAMs. LAG3high\ua0expression is associated with poor outcome independent of conventional prognosticators

An Alzheimer’s Disease Patient-Derived Olfactory Stem Cell Model Identifies Gene Expression Changes Associated with Cognition

An early symptom of Alzheimer’s disease (AD) is an impaired sense of smell, for which the molecular basis remains elusive. Here, we generated human olfactory neurosphere-derived (ONS) cells from people with AD and mild cognitive impairment (MCI), and performed global RNA sequencing to determine gene expression changes. ONS cells expressed markers of neuroglial differentiation, providing a unique cellular model to explore changes of early AD-associated pathways. Our transcriptomics data from ONS cells revealed differentially expressed genes (DEGs) associated with cognitive processes in AD cells compared to MCI, or matched healthy controls (HC). A-Kinase Anchoring Protein 6 (AKAP6) was the most significantly altered gene in AD compared to both MCI and HC, and has been linked to cognitive function. The greatest change in gene expression of all DEGs occurred between AD and MCI. Gene pathway analysis revealed defects in multiple cellular processes with aging, intellectual deficiency and alternative splicing being the most significantly dysregulated in AD ONS cells. Our results demonstrate that ONS cells can provide a cellular model for AD that recapitulates disease-associated differences. We have revealed potential novel genes, including AKAP6 that may have a role in AD, particularly MCI to AD transition, and should be further examined.</p