Experience of 170 cases of ductal carcinoma in ' (DCIS)

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Applications of MCMC methods on function spaces

In the course of this thesis, several different applications of data assimilation will be looked at. In each case, a rigorous mathematical framework will be constructed, in a Bayesian context, to enable the use of various types of data to infer on various infinite dimensional parameters of the system that has been observed. After careful consideration of the forward problem, well-defined posterior distributions on function space are constructed. Using MCMC methods which are defined on these function spaces themselves, we can construct Markov chains whose invariant measures are the posterior of interest. From this point, we can implement these methods on a computer, having finally discretised the problem. The philosophy that we adhere to throughout, is the idea that numerical methods formulated on function space are robust under discretisation, and do not suffer from the curse of dimensionality typically suffered by sampling methods formulated after disretisation. The first few chapters (after the introductory chapter) will focus on various aspects of data assimilation of observations of Stokes ow dynamics. Chapter 2 will focus on Eulerian data where direct observations of the velocity of the fluid at various points in time and space will be made. Chapter 3 will concentrate on data assimilation of indirect observations of the field, in the form of the positions of passive tracers in the flow. In these two chapters we will assume that the forcing of the system is known and that we are merely trying to recover the initial condition of the flow field. In chapter 4 we will consider both Eulerian and Lagrangian data assimilation, with the added complexity of trying to use the data to not only infer on the initial condition but also on the space-time dependant forcing of the system. In chapter 5 we will try to show how these smoothing methods could be adapted into a filtering algorithm, and a simple example will be presented. In the final chapter, 6, this Bayesian framework on function space will be applied to a shape matching problem with applications in the biomedical sciences.EThOS - Electronic Theses Online ServiceEngineering and Physical Sciences Research Council (EPSRC)GBUnited Kingdo

Regulation of HAX-1 anti-apoptotic protein by Omi/HtrA2 protease during cell death

Omi/HtrA2 is a nuclear-encoded mitochondrial serine protease that has a pro-apoptotic function in mammalian cells. Upon induction of apoptosis, Omi translocates to the cytoplasm and participates in caspase-dependent apoptosis by binding and degrading inhibitor of apoptosis proteins. Omi can also initiate caspase-independent apoptosis in a process that relies entirely on its ability to function as an active protease. To investigate the mechanism of Omi-induced apoptosis, we set out to isolate novel substrates that are cleaved by this protease. We identified HS1-associated protein X-1 (HAX-1), a mitochondrial anti-apoptotic protein, as a specific Omi interactor that is cleaved by Omi both in vitro and in vivo. HAX-1 degradation follows Omi activation in cells treated with various apoptotic stimuli. Using a specific inhibitor of Omi, HAX-1 degradation is prevented and cell death is reduced. Cleavage of HAX-1 was not observed in a cell line derived from motor neuron degeneration 2 mice that carry a mutated form of Omi that affects its proteolytic activity. Degradation of HAX-1 is an early event in the apoptotic process and occurs while Omi is still confined in the mitochondria. Our results suggest that Omi has a unique pro-apoptotic function in mitochondria that involves removal of the HAX-1 antiapoptotic protein. This function is distinct from its ability to activate caspase-dependent apoptosis in the cytoplasm by degrading inhibitor of apoptosis proteins

HAX-1 overexpression, splicing and cellular localization in tumors

<p>Abstract</p> <p>Background</p> <p>HAX-1 has been described as a protein potentially involved in carcinogenesis and especially metastasis. Its involvement in regulation of apoptosis and cell migration along with some data indicating its overexpression in cancer cell lines and tumors suggests that HAX-1 may play a role in neoplastic transformation. Here we present the first systematic analysis of HAX-1 expression in several solid tumors.</p> <p>Methods</p> <p>Using quantitative RT-PCR, we have determined the mRNA levels of <it>HAX1 </it>splice variant I in several solid tumors. We have also analyzed by semiquantitative and quantitative RT-PCR the expression of five <it>HAX-1 </it>splice variants in breast cancer samples and in normal tissue from the same individuals. Quantitative PCR was also employed to analyze the effect of estrogen on <it>HAX1 </it>expression in breast cancer cell line. Immunohistochemical analysis of HAX-1 was performed on normal and breast cancer samples.</p> <p>Results</p> <p>The results reveal statistically important <it>HAX1 </it>up-regulation in breast cancer, lung cancer and melanoma, along with some minor variations in the splicing pattern. HAX-1 up-regulation in breast cancer samples was confirmed by immunohistochemical analysis, which also revealed an intriguing HAX-1 localization in the nuclei of the tumor cells, associated with strong ER status.</p> <p>Conclusion</p> <p>HAX-1 elevated levels in cancer tissues point to its involvement in neoplastic transformation, especially in breast cancer. The connection between HAX-1 nuclear location and ER status in breast cancer samples remains to be clarified.</p

Distant homologs of anti-apoptotic factor HAX1 encode parvalbumin-like calcium binding proteins

<p>Abstract</p> <p>Background</p> <p>Apoptosis is a highly ordered and orchestrated multiphase process controlled by the numerous cellular and extra-cellular signals, which executes the programmed cell death <it>via </it>release of cytochrome c alterations in calcium signaling, caspase-dependent limited proteolysis and DNA fragmentation. Besides the general modifiers of apoptosis, several tissue-specific regulators of this process were identified including HAX1 (HS-1 associated protein X-1) - an anti-apoptotic factor active in myeloid cells. Although HAX1 was the subject of various experimental studies, the mechanisms of its action and a functional link connected with the regulation of apoptosis still remains highly speculative.</p> <p>Findings</p> <p>Here we provide the data which suggests that HAX1 may act as a regulator or as a sensor of calcium. On the basis of iterative similarity searches, we identified a set of distant homologs of HAX1 in insects. The applied fold recognition protocol gives us strong evidence that the distant insects' homologs of HAX1 are novel parvalbumin-like calcium binding proteins. Although the whole three EF-hands fold is not preserved in vertebrate our analysis suggests that there is an existence of a potential single EF-hand calcium binding site in HAX1. The molecular mechanism of its action remains to be identified, but the risen hypothesis easily translates into previously reported lines of various data on the HAX1 biology as well as, provides us a direct link to the regulation of apoptosis. Moreover, we also report that other family of myeloid specific apoptosis regulators - myeloid leukemia factors (MLF1, MLF2) share the homologous C-terminal domain and taxonomic distribution with HAX1.</p> <p>Conclusions</p> <p>Performed structural and active sites analyses gave new insights into mechanisms of HAX1 and MLF families in apoptosis process and suggested possible role of HAX1 in calcium-binding, still the analyses require further experimental verification.</p

HtrA2/Omi Terminates Cytomegalovirus Infection and Is Controlled by the Viral Mitochondrial Inhibitor of Apoptosis (vMIA)

Viruses encode suppressors of cell death to block intrinsic and extrinsic host-initiated death pathways that reduce viral yield as well as control the termination of infection. Cytomegalovirus (CMV) infection terminates by a caspase-independent cell fragmentation process after an extended period of continuous virus production. The viral mitochondria-localized inhibitor of apoptosis (vMIA; a product of the UL37x1 gene) controls this fragmentation process. UL37x1 mutant virus-infected cells fragment three to four days earlier than cells infected with wt virus. Here, we demonstrate that infected cell death is dependent on serine proteases. We identify mitochondrial serine protease HtrA2/Omi as the initiator of this caspase-independent death pathway. Infected fibroblasts develop susceptibility to death as levels of mitochondria-resident HtrA2/Omi protease increase. Cell death is suppressed by the serine protease inhibitor TLCK as well as by the HtrA2-specific inhibitor UCF-101. Experimental overexpression of HtrA2/Omi, but not a catalytic site mutant of the enzyme, sensitizes infected cells to death that can be blocked by vMIA or protease inhibitors. Uninfected cells are completely resistant to HtrA2/Omi induced death. Thus, in addition to suppression of apoptosis and autophagy, vMIA naturally controls a novel serine protease-dependent CMV-infected cell-specific programmed cell death (cmvPCD) pathway that terminates the CMV replication cycle

New mediterranean biodiversity records (November, 2016)

This Collective Article presents information on 26 taxa belonging to 8 Phyla and extending from the western Mediterranean to the Levantine Sea. The new records were found in 9 countries as follows: Spain: first record for the Mediterranean of the crab Cancer bellianus; Algeria: further records of the alien fish Lagocephalus sceleratus in western Algerian waters; Italy: first report on the presence and establishment of the ctenophore Mnemiopsis leidyi in Lessina and Varano Lagoons (W. Adriatic) and of Penaeus aztecus in Corigliano Gulf (Italian Ionian). Moreover, the extension of the distribution range of the polychaete Branchiomma bairdi to W. Sicily as well as that of the crab Ocypode cursor and the bryozoan Catenicella paradoxa to E. Sicily are cited. Slovenia: the record of the rare saccoglossan gastropod Placida cremoniana from Piran (Gulf of Trieste) is the first for the Adriatic; Greece: the native sea slug Eubranchus farrani is the first from the Eastern Mediterranean; many sightings of the bamboo corals Isididae distributed along all the E. Ionian Sea and the establishment of P. aztecus in all Greek waters are also reported for first time; the westernmost extension of the alien urchin Diadema setosum in Cretan waters is cited and new sightings of the alien species Goniobranchus annulatus and Pterois miles are presented. Turkey: the alien fish Champsodon capensis is reported for first time from the Aegean Sea and the native acari Agauopsis microrhyncha from the Levantine Sea; a new observation of the alien crab Atergatis roseus in Güllük Bay-Aegean is also mentioned; Cyprus: first records of the alien urchin D. setosum and Lobotes surinamensis in Cypriot waters; Lebanon: several sightings of Monachus monachus from Lebanese waters indicate a potential better status for the species in the area; Egypt: first records of the alien crab Dorippe quadridens and the alien gastropods Nerita sanguinolenta and Conomurex persicus from the Mediterranean Egyptian waters; extension of the distribution range of Diodora funiculata and Diodora rueppellii and a second record of the alien Fulvia fragilis in the same area