Conceptual Design Tool for Structural Layout Optimization in the Early Design Phase

This thesis develops a conceptual design tool capable of generating optimized structural layout suggestions for building design in the early design phase. The structural layout of a building is the arrangement and design of the load-bearing elements that support the weight of the building and resist external forces. The structural layout in this project solely consists of prefabricated reinforced (RC) elements. The use of prefabricated RC elements is embedded in the Danish construction industry and will likely remain so in the foreseeable future. Therefore, there is great potential for more effective use of concrete in terms of sustainability and decreasing cost. The proposed design tool can help fulfill this potential. Action Research (AR) is used to create the conceptual framework of the design tool. The AR analysis consists of semi-structured interviews and a co-creation workshop where architects, engineers, and contractors contribute to the development of the design tool to ensure that the final tool conforms to real-world practice. The final design tool is based on this framework and developed using four core principles: optimization, interactivity, dissemination, and automation. A novel parametric modeling method is developed in the design tool called Adjacent Polygon (APoly) representation. The APoly method creates a dynamic parametric representation of a given building plan to generate diverse yet feasible structural layout suggestions. The evaluation modules of different structural typologies are constructed using surrogate models in the form of Neural Networks. The surrogate models are combined in a hierarchical structure to create an algorithm capable of predicting the optimized geometry and corresponding cost for a structural element based on the external conditions inputted into the algorithm. The entire network of prediction models is then combined with a meta-heuristic optimization algorithm in the form of a Genetic Algorithm (GA) to create a surrogate-assisted optimization framework. A repair algorithm is incorporated into the GA to increase the number of valid solutions generated during each optimization iteration to decrease the convergence time. The performance and reliability of the design tool are validated through two groups of local and global case studies. The first group consists of parameter sensitivity studies on the local approximation modules for each structural typology. The second group of validation studies examines the design tool’s effectiveness across relevant building plans and scenarios. The corresponding results demonstrate that the tool can effectively adapt to these different settings and produce optimized structural layout suggestions. It is also demonstrated that the design tool can conduct multi-objective optimization and produce a front of Pareto optimal solutions

Enhancing the efficacy of cytotoxic agents for cancer therapy using photochemical internalisation.

Photochemical internalisation (PCI) is a technique for improving cellular delivery of certain bioactive agents which are prone to sequestration within endolysosomes. There is a wide range of agents suitable for PCI-based delivery including toxins, oligonucleotides, genes and immunoconjugates which demonstrates the versatility of this technique. The basic mechanism of PCI involves triggering release of the agent from endolysosomes within the target cells using a photosensitiser which is selectively retained with the endolysosomal membranes. Excitation of the photosensitiser by visible light leads to disruption of the membranes via photooxidative damage thereby releasing the agent into the cytosol. This treatment enables the drugs to reach their intended subcellular target more efficiently and improves their efficacy. In this review we summarise the applications of this technique with the main emphasis placed on cancer chemotherapy

Multi-Modality Therapeutics with Potent Anti-Tumor Effects: Photochemical Internalization Enhances Delivery of the Fusion Toxin scFvMEL/rGel

BACKGROUND: There is a need for drug delivery systems (DDS) that can enhance cytosolic delivery of anti-cancer drugs trapped in the endo-lysosomal compartments. Exposure of cells to specific photosensitizers followed by light exposure (photochemical internalization, PCI) results in transfer of agents from the endocytic compartment into the cytosol. METHODOLOGY AND PRINCIPAL FINDINGS: The recombinant single-chain fusion construct scFvMEL/rGel is composed of an antibody targeting the progenitor marker HMW-MAA/NG2/MGP/gp240 and the highly effective toxin gelonin (rGel). Here we demonstrate enhanced tumor cell selectivity, cytosolic delivery and anti-tumor activity by applying PCI of scFvMEL/rGel. PCI performed by light activation of cells co-incubated with scFvMEL/rGel and the endo-lysosomal targeting photosensitizers AlPcS(2a) or TPPS(2a) resulted in enhanced cytotoxic effects against antigen-positive cell lines, while no differences in cytotoxicity between the scFvMEL/rGel and rGel were observed in antigen-negative cells. Mice bearing well-developed melanoma (A-375) xenografts (50-100 mm(3)) were treated with PCI of scFvMEL/rGel. By 30 days after injection, approximately 100% of mice in the control groups had tumors>800 mm(3). In contrast, by day 40, 50% of mice in the PCI of scFvMEL/rGel combination group had tumors<800 mm(3) with no increase in tumor size up to 110 days. PCI of scFvMEL/rGel resulted in a synergistic effect (p<0.05) and complete regression (CR) in 33% of tumor-bearing mice (n = 12). CONCLUSIONS/SIGNIFICANCE: This is a unique demonstration that a non-invasive multi-modality approach combining a recombinant, targeted therapeutic such as scFvMEL/rGel and PCI act in concert to provide potent in vivo efficacy without sacrificing selectivity or enhancing toxicity. The present DDS warrants further evaluation of its clinical potential

Immunotoxins and Other Conjugates Containing Saporin-S6 for Cancer Therapy

Ribosome-inactivating proteins (RIPs) are a family of plant toxins that permanently damage ribosomes and possibly other cellular substrates, thus causing cell death. RIPs are mostly divided in two types: Type 1 RIPs that are single-chain enzymatic proteins, and type 2 RIPs that consist of an active A chain (similar to a type 1 RIP) linked to a B chain with lectin properties. RIP-containing conjugates have been used in many experimental strategies against cancer cells, often showing great efficacy in clinical trials. Saporin-S6, a type 1 RIP extracted from Saponaria officinalis L. seeds, has been extensively utilized to construct anti-cancer conjugates because of its high enzymatic activity, stability and resistance to conjugation procedures, resulting in the efficient killing of target cells. This review summarizes saporin-S6-containing conjugates and their application in cancer therapy, considering in-vitro and in-vivo studies both in animal models and in clinical trials. The review is structured on the basis of the targeting of hematological versus solid tumors and on the antigen recognized on the cell surface

Role of ER Stress Response in Photodynamic Therapy: ROS Generated in Different Subcellular Compartments Trigger Diverse Cell Death Pathways

We have analyzed the molecular mechanisms of photoinduced cell death using porphyrins with similar structure differing only in the position of the ethylene glycol (EG) chain on the phenyl ring. Meta- and para-positioned EG chains targeted porphyrins to different subcellular compartments. After photoactivation, both types of derivatives induced death of tumor cells via reactive oxygen species (ROS). Para derivatives pTPP(EG)4 and pTPPF(EG)4 primarily accumulated in lysosomes activated the p38 MAP kinase cascade, which in turn induced the mitochondrial apoptotic pathway. In contrast, meta porphyrin derivative mTPP(EG)4 localized in the endoplasmic reticulum (ER) induced dramatic changes in Ca2+ homeostasis manifested by Ca2+ rise in the cytoplasm, activation of calpains and stress caspase-12 or caspase-4. ER stress developed into unfolded protein response. Immediately after irradiation the PERK pathway was activated through phosphorylation of PERK, eIF2α and induction of transcription factors ATF4 and CHOP, which regulate stress response genes. PERK knockdown and PERK deficiency protected cells against mTPP(EG)4-mediated apoptosis, confirming the causative role of the PERK pathway

"De møter jo sånne saktekster veldig ofte, overalt" : utvalg av sakprosatekster til norskundervisningen

Temaet i denne oppgaven er utvalg av sakprosatekster til norskundervisningen. Temaet belyses med et utvalg av sakprosatekster som Landslaget for norskundervisning (LNU) la frem i mars 2009 med tittelen Sakprosakanon. Lærerplanen i norsk legger ingen klare retningslinjer for hvilke tekster og sjangere elevene skal lese. LNUs utvalg er ment som et forslag til et tekstutvalg for skolen, og inkluderer tekster fra historie og samtid. Formålet med utvalget er å sette fokus på sakprosa i skolen. Jeg undersøker seks av samtidstekstene og de kriteriene som LNU har lagt til grunn. Oppgavens problemstilling er: Hva karakteriserer kriteriene LNU legger til grunn for sitt utvalg av sakprosatekster til norskundervisningen, og hva kjennetegner utvalget av samtidstekster representert ved seks av dem? Oppgavens teoretiske rammeverk består både av teori knyttet til tekstforskning og teori knyttet til leseforskning. En stor del av den tekstteoretiske delen bygger på teori hentet fra Johan Tønnesson, og omfatter blantannet sakprosabegrepet, litterær og funksjonell sakprosa og modelleserbegrepet. Den teoretiske delen om lesing omfatter teori om leseforståelse, presentert av blantannet Ivar Bråten og Astrid Roe. Metoden som er brukt omfatter tekstanalyse og kvalitative intervjuer. Jeg har analysert seks samtidstekster fra LNU og fire tekster fra de frigitte PISA-oppgavene i lesing. Jeg har også undersøkt hvordan sakprosa presenteres i to læreverk for 10. trinn og Vg1, og hvilke sakprosasjangere innenfor samtidstekstene som inkluderes. I tillegg har jeg intervjuet ti elever gruppevis og fire lærere individuelt på 10. trinn og Vg1. I intervjuene har jeg undersøkt lærernes og elevenes oppfatninger av seks samtidstekster fra LNUs utvalg, og deres kriterier for tekstutvalg til norskundervisningen. Hovedfunn i avhandlingen er blant annet at LNUs kriterier for tekstutvalg kan sees som et resultat av at utvalget deres av sakprosatekster er navngitt som en kanon. Flere av samtidstekstene må settes inn i en historisk og samfunnsmessig kontekst for at leseren skal forstå innholdet i dem. Sett i lys av PISA tekstene, inneholder LNUs samtidstekster færre tekster som kan defineres som funksjonelle sakprosatekster. LNUs tekstutvalg inkluderer flere sakprosasjangere enn tekstsamlingene i læreverkene. Lærerne som er intervjuet likte best de tekstene som viser tydelighet i sjanger, mens elevene som er intervjuet engasjerte seg mest i de tekstene som innholdsmessig interesserte dem

Photochemical internalization of epidermal growth factor receptor-targeted drugs

Lack of specificity of anticancer drug treatments represents a major limitation for cancer cure. Thus, novel strategies are required to increase the selectivity of cancer therapeutics. Adverse effects can be reduced by drug delivery systems which decrease uptake in normal cells and target the drug to the cancer cells. This can be achieved by linking the drug to a carrier, i.e. an antibody or ligand which specifically recognizes cancer cells. In addition, limited penetration through the plasma membrane is a major obstacle for macromolecular therapy and a modality for cytosolic drug delivery is therefore warranted. The present thesis concerns epidermal growth factor receptor (EGFR) targeting toxins delivered by photochemical internalization (PCI) as a possible modality for selective treatment of cancer. It was found that PCI of EGFR targeting toxins exerts a 3-fold selectivity towards cancer cells: (i) the photosensitizer is preferentially retained in tumour tissues, (ii) the light is directed only to the tumour area and (iii) utilization of an anticancer drug which targets EGFR positive cancer cells. Studies on protein signal transduction revealed, however, possible interactions between the EGFR targeting drugs and photochemical reactions and the method therefore needs to be optimized with respect to the targeting moiety as well as the treatment protocol

«… og hvordan kan vi vite det, da?»: Ungdomsskoleelevers lesestrategier i møte med tekstoppgaver i samfunnsfag som krever en kritisk tilnærming

Evnen til å lese kritisk er framhevet i den siste revisjonen av norske læreplaner. Kritisk lesing kan operasjonaliseres på ulike måter, men innebærer blant annet å forstå argu­mentasjon. I denne studien utforskes ungdomsskoleelevers lesestrategier når de får opp­gaver som krever at de identifiserer tekstlige bevis i samfunnsfaglige tekster. Studien retter seg mot hvilke lesestrategier elever som svarer feil på tekstoppgaver, benytter. Første steg i analysen tar utgangspunkt i elevers svar på to oppgaver fra nasjonale prøver i lesing for 8. trinn, en åpen oppgave (N = 34 569) og en flervalgsoppgave (N = 33 000). Det gjøres en innholdsanalyse av et utvalg skriftlige feilsvar på den åpne oppgaven (N = 500); i tillegg analyseres de ulike svaralternativene i flervalgsoppgaven. I andre steg analyseres intervjudata fra verbal protokoll med elever på 8. trinn (N = 7) som besvarer de samme to oppgavene fra nasjonale prøver. Intervjudataene kommer fra en samtale om elevenes strategibruk der en film (øyeskann) av elevenes lesing brukes som støtte i samtalen og i analyse av de verbale protokollene. Funnene indikerer at en del elever bruker overflatiske søkelesingsstrategier, og de trekker ikke en logisk slutning mellom påstand og bevis. Det ser også ut til at elever har utfordringer med å identifisere et bevis som står i motsetning til det de forventer ut fra forkunnskapene sine. Studien har implikasjoner for praksisfeltet ved å gi innblikk i mulige årsaker til at elever har utfordringer med tekstoppgaver som krever en kritisk tilnærming. Studien belyser også spørsmål knyttet til om og hvordan kritisk lesing kan måles gjennom standardiserte prøver. Ved å kombinere ulike metoder, kan studien i tillegg gi bidrag til videre forsk­ning på elevers strategibruk.The ability to read critically is emphasized in the latest revision of the Norwegian cur­ricula. Critical reading can be operationalized in various ways, but involves under­standing of argumentation in texts. This study draws attention to middle school students’ reading strategies when they are given tasks that require them to identify textual evi­dence in social science texts. The study focuses on students’ incorrect answers. The first step of the analysis is based on students’ written responses to two tasks from the Nor­wegian national tests in reading for grade 8, one constructed response item (N = 34 569) and one multiple choice item (N = 33 000). A content analysis of a sample (N = 500) of incorrect answers to the constructed response item, is conducted. In addition, the alternatives in the multiple-choice item are analyzed. In the second step, interview data from verbal protocols with students in grade 8 (N = 7), who answer the same two tasks, are analyzed. The students are interviewed about their use of strategies, and a film (eye scan) of their reading is used as support in the conversation and in the analysis of the data. The findings indicate that some students use superficial reading strategies and they do not draw a logical conclusion between claim and evidence. Some students have challenges in identifying evidence that is contrary to what they expect based on their prior knowledge. The study has implications for the field of practice by providing an insight into possible reasons why students have challenges with tasks that require a critical approach to the text. The study also highlights questions about whether and how critical reading can be measured by standardized tests. By combining different methods, the study can also contribute to further research on students’ use of strategies