Plusieurs études ont découvert et renforcé l'implication de la dynamique mitochondriale dans le cancer. J'ai découvert un rôle inattendu des protéines kinases de la famille PKD dans la fission mitochondriale. La perte de l'activité PKD a conduit à un blocage de la fission et a entraîné une élongation significative des mitochondries par fusion continue. D'un point de vue mécanique, nous avons montré que les protéines PKD régulent la dynamique mitochondriale en activant le facteur de fission mitochondrial (MFF) par phosphorylation de plusieurs sites. MFF agit comme un récepteur principal de la GTPase DRP1, qui resserre les mitochondries, et il est essentiel à une bonne division mitochondriale. Les trois membres de la famille PKD peuvent phosphoryler MFF. La phosphorylation de MFF est médiée par PKD et la fragmentation mitochondriale se produit pendant la mitose. Comme démontré dans études sur les phosphoprotéomes, la phosphorylation du MFF est augmentée dans les cancers très mitotiques. Ainsi, l'axe de signalisation PKD-MFF régulant la dynamique mitochondriale en mitose pourrait devenir une voie thérapeutique attrayante pour le traitement du cancer. / Over the last two decades, multiple studies have uncovered and strengthen the implication of mitochondrial dynamics in cancer. During my thesis, I discovered an unanticipated role for the PKD kinase family in mitochondrial fission. Loss of PKD activity led to blockade of mitochondrial fission and resulted in a significant elongation of mitochondria by unopposed fusion. Mechanistically, we showed that PKDs regulated mitochondrial dynamics by activating the mitochondrial fission factor (MFF) through phosphorylation of multiple sites. MFF acts as a main receptor for the large GTPase DRP1, which constricts mitochondria, and it is critical for proper mitochondrial division. All three PKD family members could phosphorylate MFF. PKD-mediated MFF phosphorylation and mitochondrial fragmentation occurred specifically during mitosis. As MFF phosphorylation was found to be significantly upregulated in highly mitotic cancers, which was evidenced in several global phosphoproteome studies, the discovered PKD-MFF signaling axis regulating mitochondrial dynamics in mitosis could become an attractive therapeutic avenue for cancer treatment.

Mitochondria are important cellular organelles whose functions include generation of ATP, sequestration and release of pro-apoptotic molecules and calcium buffering. Mitochondria function is tightly linked to organelle morphology, which exits in a dynamic spectrum between a highly interconnected/fused mitochondria network to a punctate/fragmented scattering of individual mitochondrion. A family of large GTPase enzymes modulates this spectrum, with fusion catalyzed through the actions of mitofusin 1 and 2 (Mfn1/2) on the outer mitochondria membrane (OMM) and optic atrophy 1 (Opa1) causing fusion of the inner mitochondria membrane (IMM). On the other end of the spectrum, fragmentation is catalyzed through the actions of dynamin-related protein 1 (Drp1). Drp1 is recruited from the cytosol to binding partners at the OMM, organizes into concentric spiral rings, undergoes GTP hydrolysis to constrict the ring and pinches mitochondrion in two. While fragmentation is achieved through the action of only one GTPase enzyme, the mechanisms behind the complex regulation of Drp1 remain relatively obscure. In order to expand upon known Drp1 regulatory mechanisms, an examination of how both Drp1 splicing and Drp1 recruitment to the OMM contributes to protein regulation is necessary. Drp1 contains three alternatively spliced exons, resulting in the potential generation of eight protein isoforms. Each of these isoforms is capable of inducing mitochondrial fragmentation, however one exon arrangement (termed Drp1-x01) can also bind to microtubules within the cell. Characterization of the Drp1-x01 isoform at both the RNA and protein level indicate an important, yet incompletely characterized, role in immune system biology. Drp1 is capable of interacting with several proteins localized at the OMM. Among these, mitochondria fission factor (Mff) has been implicated in the formation of Drp1 spirals and the eventual fragmentation process. Mff contains four alternatively spliced exons as well as several phosphorylation sites identified through nonbiased phosphoproteomic screens. Inclusion of alternative exons to the Mff structure decreases its ability to recruit Drp1 from the cytosol, while phosphomimetic substitutions to conserved serine residues enhances the Drp1::Mff interaction. Taken together, this suggests that regulation of mitochondrial fragmentation occurs at the pretranslational (alternative splicing) and the posttranslational (phosphorylation) level is critical for maintaining the complex, yet essential, balance between mitochondrial fission and fragmentation.

International Telemetering Conference Proceedings / October 27-30, 1997 / Riviera Hotel and Convention Center, Las Vegas, Nevada / Telemetry format descriptions and engineering unit conversion calibrations are generated in an assortment of formats and numbering systems on various media. Usually this information comes to the central telemetry receiving/processing system from multiple sources, fragmented and disjointed. As present day flight tests require more and more telemetry parameters to be instrumented and processed, standardization and automation for handling this ever increasing amount of information becomes more and more critical. In response to this need, the Telemetry Definition and Processing (TDAP) system has been developed by the Air Force Development Test Center (AFDTC) Eglin AFB, Florida. TDAP standardizes the format of information required to convert PCM data and MIL-STD-1553 Bus data into engineering units. This includes both the format of the data files and the software necessary to display, output, and extract subsets of data. These standardized files are electronically available for TDAP users to review/update and are then used to automatically set up telemetry acquisition systems. This paper describes how TDAP is used to standardize the development and operational test community’s telemetry data reduction process, both real-time and post-test.

Syftet med denna studie är att öka förståelsen för fotbollens komplexitet och att närma sig en modell för hur man på ett mer objektivt sätt kan analysera avslut.Vi har använt oss av videoobservationer på 25 av MFF:s matcher i allsvenskan 2006. Med hjälp av tidigare forskning har vi tagit fram ett analysformulär för avsluten och ett för hörnorna. Dessa består av elva respektive tio faktorer som används för att beskriva varje avslut respektive hörna.MFF har 341 avslut och gör 42 mål. Mer än tre fjärdedelar av avsluten kommer efter anfall med tre eller färre passningar. Avslutaren använder sig av ett tillslag i lite mer än hälften av alla avslut och vid 74 % av målen. Anfallen där MFF avslutar startar med en bollerövring i 67 % av fallen och 33 % startar med en fast situation.MFF har 149 hörnor och kommer till avslut 27 gånger varav 4 resulterar i mål. Det har stor betydelse för hörnans resultat om MFF är först på bollen eller inte när hörnan slås in i straffområdet. MFF är endast först på bollen 20 av 149 hörnor. När laget är först på bollen kommer de till avslut på varannan hörna (50 %) jämfört med endast 13 % när laget inte är först på bollen. Vår studie är en statistisk sammanställning av MFF:s avslut och offensiva hörnor i allsvenskan 2006. Den beskriver delar av MFF:s anfallsspel och kan ligga till grund för många intressanta diskussioner kring fotboll och dess anfallsstrategier. Däremot är vi försiktiga med att dra alltför stora slutsatser endast utifrån statistiken.

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In the year of 2020 the member states of the European Union (EU) negotiated two major budgets: the regular Multiannual Financial Framework (MFF) for the years 2021-2027 and the covid-19 Recovery Instrument “Next Generation EU”. The first was a recurring negotiation, deciding the political and financial priorities of the EU for a mid-term period. The latter was a new proposal, an urgent response of recovery support to the covid-19 crisis. What began as diverse national responses to the crisis and an absence of any common EU measures, ended up in a historical rescue package, including the Recovery Instrument and a reinforcement of the MFF. The aim of this study is to investigate whether there are any signs of difference in negotiation approach, i.e. the use of bargaining versus problem-solving, between the two negotiations of the MFF and the Recovery Instrument. This thesis also seeks to find out if any potential dissimilarity can be explained by the factors of politicization, type of policy and crisis context. The study has been conducted by interviewing eight Swedish government officials involved in these negotiations and analyzing the stenographic protocols of the European Affairs Committee of the Swedish parliament. According to the results there were more signs of problem-solving in the Recovery Instrument negotiations than in the MFF negotiations. This is interesting as budget negotiations are known for being characterized by bargaining. Further, the Recovery Instrument differed from the MFF by being more politicized and a constituent issue, which according to prior research speaks in favor of bargaining. Despite this, the result speaks in favor of more problem-solving in the Recovery Instrument compared to the MFF. These findings demonstrate that even in budget negotiations regarding highly politicized issues of a constituent character, crisis-related factors can generate problem-solving in negotiations.

Agenda 2030, corporate social responsibility (CSR), football, globalization, Malmö FF (MFF), sport, sustainable development

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