Mutant IDH inhibits HNF-4α to block hepatocyte differentiation and promote biliary cancer

Mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 are among the most common genetic alterations in intrahepatic cholangiocarcinoma (IHCC), a deadly liver cancer1, 2, 3, 4, 5. Mutant IDH proteins in IHCC and other malignancies acquire an abnormal enzymatic activity allowing them to convert α-ketoglutarate (αKG) to 2-hydroxyglutarate (2HG), which inhibits the activity of multiple αKG-dependent dioxygenases, and results in alterations in cell differentiation, survival, and extracellular matrix maturation6, 7, 8, 9, 10. However, the molecular pathways by which IDH mutations lead to tumour formation remain unclear. Here we show that mutant IDH blocks liver progenitor cells from undergoing hepatocyte differentiation through the production of 2HG and suppression of HNF-4α, a master regulator of hepatocyte identity and quiescence. Correspondingly, genetically engineered mouse models expressing mutant IDH in the adult liver show an aberrant response to hepatic injury, characterized by HNF-4α silencing, impaired hepatocyte differentiation, and markedly elevated levels of cell proliferation. Moreover, IDH and Kras mutations, genetic alterations that co-exist in a subset of human IHCCs4, 5, cooperate to drive the expansion of liver progenitor cells, development of premalignant biliary lesions, and progression to metastatic IHCC. These studies provide a functional link between IDH mutations, hepatic cell fate, and IHCC pathogenesis, and present a novel genetically engineered mouse model of IDH-driven malignancy

APPLICATION OF THE TRANSMISSION ELECTRONIC MICROSCOPY FOR INVESTIGATIONS OF S.C. CELTIC GRAPHITE POTTERY

An attempt was undertaken by the authors to apply the transmission electronic microscopy for their studies on „Celtic” pottery. Typical in most findings representing the relics of the Celtic culture is the presence of pottery pieces manufactured from graphite material or soot. The authors subjected to examinations the broken sherds coming from a Celtic settlement at Pleszów. The electronographic and X-ray method allowed to identify in an undisputable way the crystalline phase of graphite. In the case of fragments investigated it has been found beyond the doubt that the pottery mass contained natural graphite and no soot admixtures at all

TECHNOLOGICAL INVESTIGATIONS OF SELECTED TILE FRAGMENTS FROM THE DUBIECKO CASTLE AREA

Fragments of selected 10 Gothic and Renaissance tiles coming from the Dubiecko castle area were subjected to technological investigations aimed at achieving the characteristics of material from which the tiles were manufactured and also establishing the approximate features of their make. To determine the raw material of the pottery mass samples were taken for macroscopic examination and the nicol observations including the planimetrie measurements. The above examinations have shown that clay used for the tile manufacture in most cases w'as fairly homogeneous with considerable content of fin e - grained, primary non-plastic components. This could be handled as an indication that, although the production of tiles covered a relatively wide span of t ime, for their manufacture local resources of raw materials were used. As an artificial non-plastic admixture 20 to 27 per cent of sifted quartz grit (no grains of more than 500 u mesh have been found) together with pottery (chamotte) cullet was used; however, no traces of cullet were found in one sample denoted „B-5”. Further, it has been found that some decorative e le ments were formed using the potter’s wheel which the fact has been clearly reflected through the direction of material’s inner pattern in some samples (in particular of that in sample marked A-3). In order to determine the maximum temperature at which the tiles were baked the samples cut out from greater units were subjected to dilatometric measurements allowing to settle their caking point in accordance with the original maximum temperature of product baking. In addition, a thermic differential analysis was applied by means of the curve tracing, recording the changes occurring in substance as result of heat absorbtion or emission (with possible effects only above the temperature to which the sample has originally been heated). The investigations conducted have shown that the temperatures at which the tiles were baked varied from 850°C to 1020°C

SUR L’HISTOIRE DES LIANTS DANS LES MATÉRIAUX DE CONSTRUCTION

Les liants sont appliqués dans l’architecture, depuis l’époque la plus reculée jusqu’à nos jours, pour lier les éléments de la construction, du revêtement et de l’ornementation et aussi comme matériau d’isolation contre faction de l’eau. En principe, les liants se repartissent en deux groupes: adhésifs qui durcissent à l’aiir et notamment tous ceux dont les principaux composants sont: le plâtre, le carbonate de magnésium, la chaux cuite à teneur en oxyde de calcium au-dessus de 94%; hydrauliques qui durcissent aussi bien dans l’eau qu’à l’air, produits à partir de matières brutes calcaires et de leurs dérivés. Leur teneur en oxyde de calcium est inférieure à 94%. Dépendamment des difficultés technologiques dans le processus de leur production certains de ces matériaux ont pu être appliqués déjà dans l’antiquité, tandis que d’autres — exigeant un traitement plus soigné ou une haute température de production n’ont pu être employés que beaucoup plus tard. L’argile par exemple et le limon, ainsi que le plâtre furent largement employés déjà dans l’ancienne Egypte et dans la Petite Asie ancienne. Les premiers exemples connus d’emploi du limon apparaissent dans l’ancienne Egypte aux environs de l’an 3000 av. J. Chr. Dans l’architecture assyrienne l’on rencontre parfois, quoique très rarement, des exemples de mortier de chaux et chez les Phéniciens — des mortiers hydrauliques. Les anciens Grecs employaient déjà sur une vaste échelle les mortiers de chaux adhésifs et hydrauliques — ces derniers obtenus grâce à une addition de tufs volcaniques broyés. Leurs connaissances dans ce domaine furent ensuite reprises par les Romains dont l’architecture démontre une grande durabilité qui fait naître l’opinion qu’ils possédaient une méthode de production des mortiers particulière, inconnue jusqu’ici. Cependant les analyses démontrent que cette durabilité des anciens liants était due au soin que l’on apportait alors dans le choix des matériaux bruts et dans les processus de production du mortier. Pour fabriquer les mortiers hydrauliques on utilisait fréquemment alors les cendres volcaniques. Les Romains se servaient du plâtre surtout pour le revêtement des murs et pour les décorations en stuc. A l’époque du haut Moyen-Âge la production des liants subit un déclin et ce n’est qu’au Xille siècle qu’elle marque une amélioration sensible dans ce domaine. Ce résultat est du, bien moins à une nouvelle technique employée qu’au renouveau des soins apportés à leur production. On applique dès lors aussi dans une plus large mesure des additions organiques dans leur composé, qui accéléraient le processus de leur durcissement. Une nouvelle époque s’ouvre dans la production des liants au XVIIIe siècle lorsque les recherches scientifiques dans ce domaine sont entreprises à une plus vaste échelle. Le premier quart du XIXe siècle amène la découverte du ciment portlandais. Peu à peu, le béton dans sa forme originale connue déjà par les Romains, s’établit et joue le premier rôle dans l’architecture nouvelle, au début, en tant que béton armé et ensuite sous forme de ses nombreuses et nouvelles variétés

Numerical experiments using an electrostatic, relativistic plasma simulation code

A 1-1/2 dimensional electrostatic, relativistic, plasma simulation model was constructed, implemented on the UBC FPS array processor, and tested by solving three problems in plasma physics. The model will handle a variety of different initial conditions including cold plasmas, cold beams, and drifting maxwellians. Relativistic particle velocities are properly modelled and up to two species of particles may be specified. The numerical experiments run with the model included cold plasma oscillations, cold and warm two-stream instabilities, and Landau damping. Results of the simulations were compared to theory and excellent agreement was obtained in all the cases studied. The model may now be used with confidence to research various (relativistic) electrostatic problems. It could also be modified to make it fully electromagnetic, in which case it would be useful for simulating many additional phenomena, including laser-plasma interactions.Science, Faculty ofPhysics and Astronomy, Department ofGraduat

The otherness of I : narrative, pedagogical being and fulfillment

This thesis proposes that Charles Taylor's notion of the 'dialogical human life'---or what I call 'dialogical being in the world'---can be expanded to include pedagogical and democratical aspects. Furthermore, given the collapse of foundational epistemologies, I propose that teacher fulfillment may be negotiated through 'hermeneutical understanding', which recognizes the participation of the knower ('I') in the known (the 'other'). Such hermeneutical understanding is achieved through acknowledging my 'dialogical, democratical and pedagogical being in the world' (my life) as an unfolding story, which connects present acts of understanding the 'other' (including the otherness of self) with the past and future vision of fulfillment

DATING OF ANCIENT POTTERY WITH THE USE OF THERMOLUMINESCENCE

Thermoluminescence is a phenomenon exhibited to varying degree by many minerals. It consists in the ability of emission of light within and above the range of ordinary red-hot glow when a substance called the luminophore is heated. The light represents here the released energy that has been stored in the form of electrons trapped in the c r y s ta l, lattice of the given mineral and is proportional to the total dose of radiation once received. In most pottery specimens mineral constituents (e.g. quartz) may be found possessing the property of accumulating thermoluminescence and also that of receiving small but significant doses of nuclear radiation coming from radioactive impurities in clay of which the pottery was made. Heating to temperatures above 500°C removes the accumulated thermoluminescence and consequently the firing of clay into pottery brings the luminescence dowTn to zero. However, after that the thermoluminescence grow’s in time. This grow is also dependant on the particular thermoluminescent constituents present in the given pottery fragments as well as upon the radiation dose- rate as explained above. As a result of laboratory measurements the thermoluminescence carried by pottery can be expressed as an equivalent radiation dose that is determined through exposing the pottery piece to radiation of an artificial radioisotope. Dating of ancient pottery with the use of thermoluminescence is at present under ex tensiv e development in many research centres and it is hoped that the improved techniques will greatly contribute to reduction of indistinctness and errors but it hardly seems that a method could ever be worked out giving the results with their accuracy exceeding that of ± 5 per cent. Another aspect of pottery dating is the detection of fakes