The MDM2 and MDM4 oncoproteins are both involved in regulating the tumour suppressor, p53. While the MDM2–p53 interface is structurally and biophysically well characterised, the MDM4-p53 interaction has only recently attracted researchers’ attentions. The goal of this project was to establish structural and chemical ground rules for the disruption of the interactions between the N-terminal domains of MDM2/4 and p53, which is an attractive anticancer strategy. In the current work, successful recombinant production and purification protocols for both the N-terminal domains of MDM2 (i.e. MDM2-N, residues 11-118) and MDM4 (MDM4-N, residues 14-111) have been established, yielding protein in sufficient quantity and quality for analysis using nuclear magnetic resonance spectroscopy (NMR). Two screening strategies were employed to identify small-molecule antagonists of the MDM2-N:p53 interaction. First, a virtual screening exercise identified several compounds that were shown (by NMR) to bind to MDM2-N with μM KDs. Docking studies supported by NMR chemical shift perturbation analysis suggested proposals for binding modes. The results are discussed in relation to the previously reported binding to MDM2-N of well-characterised inhibitors of the MDM2:p53 interaction such as Nutlin-3. Second, a fragment-based library was screened against MDM2-N using TROSY-type NMR spectra to monitor binding. Several hits were identified and the results are discussed with regard to the “druggability” of the MDM2-N p53 interaction. To better understand the p53-binding groove of MDM4-N, multidimensional NMR was used to investigate the structure and backbone dynamics of double-isotopically labelled samples of MDM4-N, both free (i.e. apo-MDM4-N) and in complexes with a p53-derived peptide or Nutlin-3. The apo-MDM4-N is more conformationally dynamic than MDM2, since it contains unstructured regions. These regions appear to become structured upon binding of a ligand. MDM4 appears to bind its ligand through conformational selection and/or an induced fit mechanism involving reorganization of key sub-sites within the binding groove. This study highlighted Abstract differences between Nutlin-3 and peptide binding that suggest the rational design of specific inhibitors of the MDM4:p53 interaction.

Bring Frigo transporterar och distribuerar kylda och frysta livsmedel inom Sverige och övriga Norden genom ett temperaturkontrollerat nätverk av fordon, kyllager, fryslager och terminaler. En av Bring Frigo:s terminaler är belägen i Linköping dit livsmedel som ska distribueras till eller från Östergötland ankommer för att lastas om mellan fjärr- och distributionsbilar. Idag räcker kapaciteten på terminalen i Linköping precis till för att kunna hantera det flöde av livsmedel som passerar genom terminalen. Då Bring Frigo nyligen ingått en affär med en större svensk matgrossist om att distribuera matgrossistens livsmedel inom Östergötland i sitt befintliga transportnätverk behöver terminalens kapacitet utökas för att detta ska vara möjligt. I samband med denna förändring vill Bring Frigo passa på att ta fram riktlinjer för hur omlastningsprocessen kan optimeras. Bring Frigo önskar erhålla riktlinjer för vart livsmedlen temporärt ska placeras inne i terminalen under omlastningsprocessen och hur lastbilar ska tilldelas lastkajer så att transportsträckan inne i terminalen hålls så kort som möjligt. Som ett första steg för att besvara var livsmedlen temporärt bör placeras inne i terminalen utformades en intern layout över den tilltänkta ombyggda terminalen. Därefter utvecklades och implementerades en heuristik som, utifrån den framtagna layouten och historiska data över livsmedelsflödet genom terminalen, tog fram var olika livsmedel temporärt bör placeras inne i terminalen och hur tilldelningen av lastkajer bör ske så att erfordrad transportsträcka hålls så kort som möjligt under omlastningsprocessen. Med hjälp av de resultat som erhölls från heuristiken formulerades specifika riktlinjer för respektive arbetsdag. Riktlinjerna för respektive dag delades vidare in i två olika nivåer beroende på om dagen kategoriserades som en dag med normal eller hög arbetsnivå utifrån totala antalet lastbärare som förväntas passera terminalen den aktuella dagen. Slutsatsen av studien är att de riktlinjer som utformats för omlastningsprocessen på terminalen bör reducera den erfordrade transportsträckan av livsmedel inne på terminalen och på så sätt effektivisera omlastningsprocessen, men att detta inte kan säkerställas i och med att historiska data använts som indata till heuristiken.

International Telemetering Conference Proceedings / October 28-31, 1996 / Town and Country Hotel and Convention Center, San Diego, California / Orbiting satellites can be tracked by following preprogrammed ephemeris data in the ground station controller. This tracking method is advantageous, because of the reduced acquisition cost of non-autotracking receiver and antenna feed components. Further, widely separated frequency bands can readily be tracked, without the complexity of a frequency specific auto-track system. Two types of mobile tracking systems are described. They are composed of elevation-over-azimuth-over-tilt and of an X-Y axis pedestal configuration. The calibration methods for establishing time and geographical references are discussed, as well as the challenges of minimizing the effects of system and environment induced error contributors.

The University Medical Center in Tucson, Arizona developed and implemented a procedure-specific Limitation of Medical Care (LMC) form on December 1, 1989 to address medical futility and lack of clarity in do-not-attempt-resuscitation (DNAR) orders. A retrospective review of two years of data, with 300 usable responses, showed an increased amount of participation by patients and their surrogates in the DNAR decision with the LMC form. Use of the form was also associated with an increased number of medical interventions specified to be withheld after a DNAR or LMC order was written. There was no decrease in expenditures or length of survival associated with use of the form, nor was there a decrease in the number of codes called for patients who had an order that resuscitation was not to be attempted. An average $13,347 of charges were accrued in the ICU for patients in the pre-form group, $4,314 on average being after a DNAR order was written. An average $21,957 of charges were accrued in the ICU for patients in the post-form group, $8,733 on average being after a DNAR order was written. An average $20,523 of total charges were accrued for patients in the pre-form group, $7,156 on average being after a DNAR order was written. An average $29,830 of total charges were accrued in the ICU for patients in the post-form group, $12,550 on average being after a DNAR order was written. Recommendations for the UMC Bioethics Committee and future research suggestions are presented.

Background: The End of Life Care Strategy stated that there should be a reduction of expected deaths in the acute setting. In order to achieve this goal, when it has been identified that where the patient's preferred place of care is home, clinicians need to be able to recognise when a patient is dying in order to achieve their preferred place of death. The aims of this study were to identify any factors that help or hinder a clinician when they are determining when irreversible dying begins and to seek consensus on which of these topics would be useful to include in an education programme. Method: A 3 stage mixed methods study was developed. Phase 1was a Systematic Review of current primary research in order to provide an evidence base for the study. Phase 2 involved unstructured interviews with clinicians in the acute setting utilising the Grounded Theory approach to the analysis identify potential factors. Phase 3 was a Delphi study used to identify which of these factors would be useful in an education programme. Conclusions: The Systematic Review identified four themes "Patient Observation", "Knowledge of the Patient", "Communication" and "Attitudes of the Clinician". These were confirmed by the interviews and a further theme "Experience" identified. The over-arching theme emerging from the findings of the interviews was that clinicians have a fear of getting the timing of the recognition of irreversible dying wrong because the decision making process is so complex and this is exacerbated by fear of missing the treatable. Many factors identified in the interviews were acknowledged as factors that could be included in an education package. It was also identified that there is the need for a culture shift in society regarding death and dying and a change in the philosophy of care for health care professionals.

Thesis advisor: James P. Morken / The first highly enantioselective diboration of unfunctionalized terminal alkenes has been developed using a platinum-phosphonite complex. This transformation produces versatile 1,2-bis(boronate)esters that can manipulated chemoselectively to generate a pletheroa of enantioenriched structural motifs. When combined with an appropriate palladium catalyst, the diboration product undergoes an efficient alkyl boron cross-coupling with aryl and vinyl electrophiles producing a wide range of enantioenriched homobenzylic and homoallylic boronates. Alternatively, when the 1,2-bis(boronate)ester diboration product contains an adjacent Z-olefin (derived from diboration of cis-1,3-dienes), allylation to aldehydes can be achieved delivering the syndiastereomer of product exclusively with excellent chirality transfer. Notably, the products obtained from the two described reactions contain an additional boronate moiety, which can be further functionalized through known carbon-boron bond transformations. / Thesis (PhD) — Boston College, 2014. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Introduktion: Majoriteten av dödsfall sker på sjukhus och antal människor som är i behov av palliativ vård förväntas öka. Närstående spelar en viktig roll i den palliativa vården och det är därför viktigt att veta hur de upplever vården. Syfte: Att belysa närståendes upplevelser av palliativ vård på sjukhus. Metod: Litteraturstudie med induktiv ansats enligt Polit och Beck (2017) i nio steg. Artiklar söktes fram i databasen CINAHL, tolv artiklar med både kvalitativ och kvantitativ metod användes till studiens resultat. Huvudresultat: Fem kategorier identifierades till resultatet. Dessa kategorier var: Omvårdnad, Delaktighet, Bemötande, Kommunikation och Stöd. Slutsats: Generellt upplevde närstående att patienten erhöll god palliativ vård på sjukhus. Det framgick att en del närstående hade ett behov av att vara delaktiga i omvårdnaden av patienten och de flesta ville vara delaktiga i beslutsfattandet. Närstående upplevde att vårdpersonalens bemötande och kommunikation varierade. Närståendes behov av stöd och att bli informerade framgick tydligt i studien.

O presente estudo teve como objetivos conhecer os conflitos éticos relativos a pacientes terminais identificados por enfermeiros das clinicas médica, cirúrgica e pronto socorro adulto de um hospital público e geral; compreender como os enfermeiros tomam as decisões frente a conflitos éticos referentes a esses pacientes e conhecer o que é levado em consideração, pelos enfermeiros, para a tomada de decisão frente a conflitos éticos relacionados a pacientes terminais. Foi feito um estudo exploratório, descritivo e de abordagem qualitativa. Para análise dos dados foi utilizada a análise de conteúdo proposta por Bardin. Foram entrevistados dez enfermeiros de um hospital público e geral do Município de São Paulo. Após a análise, emergiram três categorias e quinze sub-categorias: Categoria 1- A vivência dos enfermeiros em relação ao paciente terminal. Subcategorias: Cuidados como condição essencial para assistência aos pacientes terminais; Postura da família frente ao paciente terminal; Conseqüências da vivência profissional com pacientes terminais; e Postura profissional frente aos pacientes terminais. Categoria 2- Fatores geradores de conflitos éticos em relação ao paciente terminal. Subcategorias: Obstinação terapêutica; Situações administrativas; A quebra do sigilo e desrespeito à privacidade do paciente terminal; Despreparo profissional; e Falta de autonomia do enfermeiro. Categoria 3- Fatores considerados para a tomada de decisão em relação aos conflitos éticos frente ao paciente terminal. Subcategorias: Os aspectos ético-legais; O uso do conhecimento científico; A participação das equipes multiprofissional e de enfermagem; O respeito à autonomia do paciente e da família; A importância do esclarecimento de pacientes e familiares; e A multifatorialidade concorrendo para a tomada de decisão. O estudo evidenciou que os conflitos éticos relativos aos pacientes terminais, vivenciados pelos enfermeiros, emergem de seu cotidiano e são decorrentes de diversos fatores relacionados à assistência, ao gerenciamento e à capacitação dos profissionais. Foi evidenciado, ainda, que os enfermeiros apontam fatores que devem ser levados em consideração no processo de tomada de decisão, mas revelam sua pouca participação nesse processo frente aos conflitos éticos relativos a pacientes terminais. / The present study aims to identify and understand the ethical conflicts related to terminal patients experienced by nurses and are what considered for decision making to cope with these conflicts. The methodology adopted was the qualitative strand, using the content analysis proposed by Bardin. Ten nurses were interviewed in a general hospital in Sao Paulo. After the analysis emerged three categories and fifteen sub-categories: Category 1 - The experience of nurses in relation to the patient terminal. Subcategories: care as an essential condition for assistance to terminally ill patients; Posture family towards the patient terminal; Consequences of professional experience with terminal patients, and professional attitude to patients facing terminal. Category 2 - Factors generators to ethical conflicts in respect to the terminal patient. Subcategory: Therapeutic futility; Situations administrative on generating of conflict; The breaking secrecy and privacy disrespect of the patient terminal; A lack of professional preparation; and lack of autonomy of nurses. Category 3 - Factors considered in the decision-making in relation to the conflicts ethic facing the terminally ill patient. Subcategories: ethical and legal aspects; The use of scientific knowledge; The participation of multidisciplinary teams and nursing staff; The Respect for patient autonomy and family; The importance of clarifying patients and families, and, The multifactorial competing to decision-making. The study showed that ethical conflicts related to the patients, experienced by nurses, emerge from their everyday and are caused by several factors related to assistance, to management and capacitation professional. It was evidenced, also, that the nurses point to factors that must be taken account in decision-making process, but they reveal their little participation in this process front to the ethical conflicts related to terminally ill patients.

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Att vara närstående till en person i livets slutskede kan vara en stor påfrestning. Vid palliativ vård är det därför viktigt att inte enbart se patienten utan även de närstående och deras behov av omsorg och delaktighet. Palliativ vård är en helhetsvård som bygger på att lindra och stödja i livets slutskede. Syftet med denna uppsats är att beskriva vad närstående till patienter i den palliativa vården upplever som betydelsefullt i sjuksköterskans bemötande av de närstående.Uppsatsen är en litteraturstudie med kvalitativ innehållsanalys och omfattar vetenskapliga artiklar som har sökts via databaser Pubmed, Cinahl och Medline.Resultatet visar på att de närståendes bedömning av sjuksköterskan bygger på ett tredelat behov.  Behov av kommunikation – att ha en ständig dialog med sjuksköterskan och övrig vårdpersonal oavsett om det hänt något nytt eller ej. Behov av information – att ha en öppen och ärlig information om tillståndet av den vårdade och vad som kan förväntas hända härnäst. Behov av stöd till delaktighet – att bli sedd, hörd och lyssnad på som närstående i de tankar och funderingar som tynger som mest.Av resultatet framgår att sjuksköterskan bemötande karaktäriseras av att ge närstående korrekt information och stöd för att de närstående ska kunna känna delaktighet i omvårdnaden.Sjuksköterskan behöver skapa en öppen kommunikation med närstående för att kunna förstå vilken situation de närstående befinner sig i. Genom att uppmärksamma närståendes behov kan trygghet skapas hos de närstående. Om närståendes upplever trygghet och säkerhet kommer detta även att kunna smitta av sig till patienten vilket kan innebära att hon eller han kan får en bättre sista tid i livet. / Program: Sjuksköterskeutbildning