The control of mitosis in mammalian tissues

The question of which factors are central in determining whether a cell will undertake a new round of mitosis or will decycle has been examined in the isolated thymic lymphocyte model. Such cell populations possess both in vivo and in vitro a subpopulation of quiescent lymphoblasts which may be induced to reinitiate their mitotic programme. In the intact animal the major determinant of proliferative activity is the plasma ionised calcium concentration. However it has been established in culture that a variety of hormones, ions, cyclic nucleotides, plant lectins and ionophores may like calcium elicit a mitogenic response. These agents do not appear however to initiate DNA synthesis in an identical fashion. Rather there are two distinct intracellular mitogenic axes. The first axis includes a number of adenylate cyclase stimulants, cyclic AMP, phosphodiesterase inhibitors and magnesium ions. It was found that all these mitogens required extracellular magnesium ions to exhibit their stimulatory capacity. This dichotomy in mitogenic activity was further emphasised by the observation that these mitogens are all inhibited by testosterone, whilst the magnesium-independent mitogens were insensitive to this androgen. Indeed this second group of stimulatory factors required the presence of calcium ions in the extracellular milieu for activity, and were, in contrast to the magnesium-dependent mitogens inhibited by the presence of oestradiol in the culture. By examining the interrelationships between these various mitogens and inhibitors it has been possible to propose a mechanism to describe the activation process in the thymocyte. Studies of the metabolism of cyclic nucleotides, membrane potential and transmembrane ion fluxes indicate that there may be a complex relationship between membrane fluidity, ion balance and cyclic nucleotide levels which may individually or in concert promote the initiation of DNA synthesis. A number of possible mechanisms are discussed to account for these observations.

Carbon monoxide expedites metabolic exhaustion to inhibit tumor growth

One classical feature of cancer cells is their metabolic acquisition of a highly glycolytic phenotype. Carbon monoxide (CO), one of the products of the cytoprotective molecule heme oxygenase-1 (HO-1) in cancer cells, has been implicated in carcinogenesis and therapeutic resistance. However, the functional contributions of CO and HO-1 to these processes are poorly defined. In human prostate cancers, we found that HO-1 was nuclear localized in malignant cells, with low enzymatic activity in moderately differentiated tumors correlating with relatively worse clinical outcomes. Exposure to CO sensitized prostate cancer cells but not normal cells to chemotherapy, with growth arrest and apoptosis induced in vivo in part throughmitotic catastrophe. CO targeted mitochondria activity in cancer cells as evidenced by higher oxygen consumption, free radical generation, and mitochondrial collapse. Collectively, our findings indicated that CO transiently induces an anti-Warburg effect by rapidly fueling cancer cell bioenergetics, ultimately resulting in metabolic exhaustion. ©2013 AACR.

Branching Populations of Cells Bearing a Continuous Label

2000 Mathematics Subject Classification: 60J80.

Brain-derived neurotrophic factor as an indicator of chemical neurotoxicity:an animal-free CNS cell culture model

Recent changes to the legislation on chemicals and cosmetics testing call for a change in the paradigm regarding the current 'whole animal' approach for identifying chemical hazards, including the assessment of potential neurotoxins. Accordingly, since 2004, we have worked on the development of the integrated co-culture of post-mitotic, human-derived neurons and astrocytes (NT2.N/A), for use as an in vitro functional central nervous system (CNS) model. We have used it successfully to investigate indicators of neurotoxicity. For this purpose, we used NT2.N/A cells to examine the effects of acute exposure to a range of test chemicals on the cellular release of brain-derived neurotrophic factor (BDNF). It was demonstrated that the release of this protective neurotrophin into the culture medium (above that of control levels) occurred consistently in response to sub-cytotoxic levels of known neurotoxic, but not non-neurotoxic, chemicals. These increases in BDNF release were quantifiable, statistically significant, and occurred at concentrations below those at which cell death was measureable, which potentially indicates specific neurotoxicity, as opposed to general cytotoxicity. The fact that the BDNF immunoassay is non-invasive, and that NT2.N/A cells retain their functionality for a period of months, may make this system useful for repeated-dose toxicity testing, which is of particular relevance to cosmetics testing without the use of laboratory animals. In addition, the production of NT2.N/A cells without the use of animal products, such as fetal bovine serum, is being explored, to produce a fully-humanised cellular model.

Kiigazítás recesszió nélkül. Esettanulmány a magyar stabilizációról = Adjustment without recession: A Case Study of Hungarian Stabilization

1995. március 12-én a magyar kormány és a központi bank szigorú kiigazítási és stabilizációs programot hirdetett meg. A cikk az első eredmények számbavételére tesz kísérletet. A program meghirdetése előtt Magyarország két egymást követő év- ben hatalmas fizetésimérleg-hiányt mutatott fel, és nemzetközi megítélése romlani kezdett. A program radikális intézkedései nyomán elkerülhetővé vált a mexikói vál- sághoz hasonló pénzügyi katasztrófa. Sok makrogazdasági mutató jól érzékelhető javulást jelez: lényegesen csökkent a kereskedelmi mérleg és a folyó fizetési mérleg hiánya, a költségvetés elsődleges egyenlege pozitív lett. Az ilyesféle stabilizációs programokat rendszerint súlyos visszaesés és a munkanélküliség nagy növekedése kíséri. Magyarország elkerülte ezeket a mellékhatásokat: a GDP drasztikus vissza- esés helyett valamelyest tovább növekedett, és a munkanélküliség változatlan ma- radt. A javulásnak nagy ára volt: az életszínvonal erőteljes csökkenése, az infláció felgyorsulása, bár a magyarországi infláció még mindig a kézben tartott, mérsékelt infláció sávjában maradt. A cikk ismerteti a program heterodox módszereit: 1. nagy leértékelés, az előre meghirdetett csúszó árfolyam rezsimjének bevezetése, valamint ideiglenes import- vámpótlék kivetése; 2. határozott jövedelempolitika, amely 12 százalékos reálbércsök- kenést kényszerített ki; 3. fiskális intézkedések, köztük jóléti jogosultságok csök- kentése (a program meghirdetése előtt ezek a jogosultságok tabuk voltak); 4. a hitel- kínálat átcsoportosítása a vállalati szektor javára, a jövedelmezőség növekedése; 5. feszített (bár nem mértéktelenül feszített) monetáris politika, amely lehetővé tette a sikeres vállalatok expanzióját; 6. a privatizáció felgyorsítása, nagy és sikeres lépé- sek egyes kulcsszektorok (energia, telekommunikáció) privatizációjában. Végezetül a tanulmány óva int a túlzott magabiztosságtól és felhívja a figyelmet a potenciális veszélyekre. A makrogazdasági javulás még törékeny. A magyar fejlődés legbiztatóbb sajátossága a termelékenység erőteljes és folyamatos növekedése. / === / On March 12, 1995 Hungary s government and central bank announced a tough program of adjustment and stabilization. This study is an attempt to asses the first results. Before the announcement of the program Hungary had a huge current account deficit for two consecutive years, and her international reputation started to decline. The program s radical measures made it possible to avoid a Mexico-style financial catastrophe. Many macroeconomic indicators show tangible improvement: the trade deficit and the deficit on the current account have been reduced significantly, the primary budget shifted to surplus. These kinds of adjustment programs are usually associated with deep recession and a large increase of unemployment. Hungary avoided these adverse side-effects: GDP instead of a drastic decline, continued to grow somewhat, and unemployment remained unchanged. There was a high price for the improvement: a sharp decline in the standard of living, and an acceleration of inflation, although Hungary is still in the range of controlled, moderate inflation. The paper describes the heterodox instruments of the program: (1) large devaluation, followed by a new exchange rate regime of pre-announced crawling peg, and a temporary import surcharge, (2) energetic income policy, enforcing a 12% cut in real wages; (3) fiscal measures, including cuts in welfare entitlements. That happened for the first time: before the program entitlements had been regarded as taboo ; (4) reallocation of credit supply in favor of the enterprise sector; increase of profitability; (5) tight (but not excessively tight) monetary policy, allowing the expansion of successful private busi- ness; (6) acceleration of privatisation, including large and successful steps in the privatisation of some key sectors (energy, telecommunication). Finally the paper warns against excessive self- confidence and draws the attention to potential dangers. The macroeconomic improvement is still fragile. The most reassuring feature of Hungary s development is the impressive and persistent improvement of productivity.

Analysis of Heterokaryon Formation in Fusarium oxysporum f. sp. cubense.

Fusarium oxysporum forma specialis cubense is a soilborne phytopathogen that infects banana. The true evolutionary identity of this so called species, Fusarium oxysporum, is still unknown. Many techniques have been applied in order to gain insight for the observed genetic diversity of this species. The current classification system is based on vegetative compatibility groups (VCG's). Vegetative compatibility is a self non-self recognition system in which only those belonging to a VCG can form stable heterokaryons, cells containing two distinct nuclei. Heterokaryons in turn, are formed from hypha! anastomosis, the fusion of two hyphae. Furthermore, subsequent to heterokaryon formation potential mechanisms exist which may generate genetic variability. One is through viral transfer upon hyphal anastomosis. The other mechanism is a form of mitotic recombination referred to as the parasexual cycle. Very little research has been performed to directly obser.ve the cellular events; hypha! anastomosis, heterokaryon formation, and the parasexual cycle in Fusarium oxysporum f. sp. cubense. The purpose of this research was to design and use methods which would allow for the detection of hypha! anastomosis and heterokaryon formation, as well as any characteristics surrounding this event, within and between VCG's in Foe. First, some general growth properties were recorded: the number of nuclei per hypha, the size ofthe hyphal tip cell, the size of the cell adjacent to the hypha! tip (pre-tip) cell, and the number of cells to the first branch point. Second, four methods were designed in order to assay hyphal anastomosis and heterokaryon formation: 1) pairings on membrane: phase or brightfield microscopy, 2) pairings on membrane: fluorescence microscopy, 3) spore crosses: fluorescence microscopy, and 4) double picks in fractionated MMA. All of these methods were promtsmg.

On Record: Soundscapes as Metaphor and Physical Manifestation of Memory in Early Holocaust Novels and Contemporary Criticism

This thesis compares two perspectives on the production of Holocaust memory: a novel that leads up to The Holocaust in Britain and one that reflects the hindsight perspective of a liberator in the Soviet Union. The novels are Virginia Woolf’s BETWEEN THE ACTS and Vasily Grossman’s LIFE AND FATE. The analysis offers a locus of analysis for the diasporic literary energy created by the catastrophe in the 20th and 21st centuries. The project offers a theorized standpoint on the role of literature on official historical archives. Proposing a method through which contemporary readers can engage the diasporic event of The Holocaust, the project adopts both the extended metaphor and literal expression of soundscapes. Soundscapes encompass the immaterial processes of memorialization and the literal sonic textures developed in Holocaust novels. The critical perspective incorporates contemporary notions of narratology, archival practices, and cultural manifestations of language into the notion of literary ethnomusicology.

Prognostic value of the diagnostic criteria distinguishing endometrial stromal sarcoma, low grade from undifferentiated endometrial sarcoma, 2 entities within the invasive endometrial stromal neoplasia family

The World Health Organization (WHO 2003) recognizes 3 endometrial stromal neoplasms: noninvasive endometrial stromal nodule and the 2 invasive neoplasms, endometrial stromal sarcoma (ESS), low grade and undifferentiated endometrial sarcoma (UES). It is important to note that the WHO 2003 does not define moderate atypia (an important differentiating diagnostic criterion for ESS, low grade and UES), nor does it discuss its significance. Moreover, studies on reproducibility and additional prognostic value of other diagnostic features in large are lacking. Using strict definitions, we analyzed the agreement between routine and expert-review necrosis and nuclear atypia in 91 invasive endometrial stromal neoplasias (IESN). The overall 5-year and 10-year recurrence-free survival rate estimates of the 91 IESN patients were 82% and 75%, respectively. Necrosis was well reproducible, and nuclear atypia was reasonably well reproducible. The 10-year recurrence-free survival rates for necrosis absent/inconspicuous versus prominent were 89% and 45% (P<0.001) and those for review-confirmed none/mild, moderate, severe atypia were 90%, 30%, and <20% (P<0.00001). Therefore, cases with moderate/severe atypia should be grouped together. Nuclear atypia and necrosis had independent prognostic values (Cox regression). Once these features were taken into account, no other feature had an independent additional prognostic value, including mitotic count. Using "none/mild atypia, necrosis absent/inconspicuous" as ESS, low grade versus "moderate/severe atypia present or necrosis present" as UES resulted in 68 ESS, low grade and 23 UES cases with disease-specific overall mortality-free survival of 99% versus 48% (P<0.00001, hazard ratio=45.4). When strictly defined microscopic criteria are used, the WHO 2003 diagnoses of ESS, low grade and UES are well reproducible and prognostically strong. © 2012 International Society of Gynecological Pathologists.

From Polarity to Morphogenesis PAK Behaviors and Mechanism for Bud Sensing in Morphogenesis Checkpoint

Bud formation by Saccharomyces cerevisiae is a fundamental process for yeast proliferation. Bud emergence is initiated by the polarization of the cytoskeleton, leading to local secretory vesicle delivery and gulcan synthase activity. The master regulator of polarity establishment is a small Rho-family GTPase – Cdc42. Cdc42 forms a clustered patch at the incipient budding site in late G1 and mediates downstream events which lead to bud emergence. Cdc42 promotes morphogenesis via its various effectors. PAKs (p21-activated kinases) are important Cdc42 effectors which mediate actin cytoskeleton polarization and septin filament assembly. The PAKs Cla4 and Ste20 share common binding domains for GTP-Cdc42 and they are partially redundant in function. However, we found that Cla4 and Ste20 behaved differently during the polarization and this depended on their different membrane interaction domains. Also, Cla4 and Ste20 compete for a limited number of binding sites at the polarity patch during bud emergence. These results suggest that PAKs may be differentially regulated during polarity establishment.

Morphogenesis of yeast must be coordinated with the nuclear cycle to enable successful proliferation. Many environmental stresses temporarily disrupt bud formation, and in such circumstances, the morphogenesis checkpoint halts nuclear division until bud formation can resume. Bud emergence is essential for degradation of the mitotic inhibitor, Swe1. Swe1 is localized to the septin cytoskeleton at the bud neck by the Swe1-binding protein Hsl7. Neck localization of Swe1 is required for Swe1 degradation. Although septins form a ring at the presumptive bud site prior to bud emergence, Hsl7 is not recruited to the septins until after bud emergence, suggesting that septins and/or Hsl7 respond to a “bud sensor”. Here we show that recruitment of Hsl7 to the septin ring depends on a combination of two septin-binding kinases: Hsl1 and Elm1. We elucidate which domains of these kinases are needed, and show that artificial targeting of those domains suffices to recruit Hsl7 to septin rings even in unbudded cells. Moreover, recruitment of Elm1 is responsive to bud emergence. Our findings suggest that Elm1 plays a key role in sensing bud emergence.

Molecular Mechanisms of Airway Epithelial Progenitor Cell Maintenance and Repair.

The lungs are vital organs whose airways are lined with a continuous layer of epithelial cells. Epithelial cells in the distal most part of the lung, the alveolar space, are specialized to facilitate gas exchange. Proximal to the alveoli is the airway epithelium, which provides an essential barrier and is the first line of defense against inhaled toxicants, pollutants, and pathogens. Although the postnatal lung is a quiescent organ, it has an inherent ability to regenerate in response to injury. Proper balance between maintaining quiescence and undergoing repair is crucial, with imbalances in these processes leading to fibrosis or tumor development. Stem and progenitor cells are central to maintaining balance, given that they proliferate and renew both themselves and the various differentiated cells of the lung. However, the precise mechanisms regulating quiescence and repair in the lungs are largely unknown. In this dissertation, ionizing radiation is used as a physiologically relevant injury model to better understand the repair process of the airway epithelium. We use in vitro and in vivo mouse models to study the response of a secretory progenitor, the club cell, to various doses and qualities of ionizing radiation. Exposure to radiation found in space environments and in some types of radiotherapy caused clonal expansion of club cells specifically in the most distal branches of the airway epithelium, indicating that the progenitors residing in the terminal bronchioles are radiosensitive. This clonal expansion is due to an increase in p53-dependent apoptosis, senescence, and mitotic defects. Through the course of this work, we discovered that p53 is not only involved in radiation response, but is also a novel regulator of airway epithelial homeostasis. p53 acts in a gene dose-dependent manner to regulate the composition of airway epithelium by maintaining quiescence and regulating differentiation of club progenitor cells in the steady-state lung. The work presented in this dissertation represents an advance in our understanding of the molecular mechanisms underlying maintenance of airway epithelial progenitor cells as well as their repair following ionizing radiation exposure.

Governmentality and exclusion in post-disaster spaces : conducting the conduct of the survivors of Typhoon Sendong in Cagayan de Oro, Philippines

Lorsque les aléas naturels se déroulent en catastrophes, les réponses des religieux, de l’Etat, et d’autres acteurs puissants dans une société révèlent à la fois les relations complexes entre ces parties et leur pouvoir dans la production des espaces auxquelles les survivants accèdent. La réponse en cas de catastrophe comprend la création d’espaces post-catastrophes, tels que des centres d’évacuation, des logements de transition et des sites de réinstallation permanente, qui ciblent spécifiquement un sous-ensemble particulier de survivants, et visent à les aider à survivre, à faire face, et à se remettre de la catastrophe. Les acteurs puissants dans une société dirigent les processus de secours, de récupération et de reconstruction sont des acteurs puissants qui cherchent à problématiser et à rendre un problème technique dans des termes qu’ils sont idéalement placés pour aborder à travers une variété d'interventions. Ce projet de recherche vise à répondre à la question: où les survivants d'une catastrophe reconstruisent-ils leurs vies et leurs moyens de subsistance? Il enquête sur un cas spécifique de la migration environnementale dans laquelle des dizaines de milliers d'habitants ont été déplacés de façon permanente et temporaire de leurs résidences habituelles après le typhon Sendong à Cagayan de Oro, Philippines en 2011. La recherche est basée sur des entretiens avec les acteurs puissants et les survivants, des vidéos participatives réalisées par des survivants pauvres urbains, et des activités de cartographie. L’étude se fonde sur la théorie féministe, les études de migration, les études dans la gouvernementalité, la recherche sur les changements de l’environnement planétaire, et les études régionales afin de situer les diverses expériences de la migration dans un contexte géographique et historique. Cette thèse propose une topographie critique dans laquelle les processus et les pratiques de production d’espaces post-catastrophe sont exposés. Parce que l’espace est nécessairement malléable, fluide, et relationnelle en raison de l'évolution constante des activités, des conflits, et des expériences qui se déroulent dans le paysage, une analyse de l'espace doit être formulée en termes de relations sociales qui se produisent dans et au-delà de ses frontières poreuses. En conséquence, cette étude explore comment les relations sociales entre les survivants et les acteurs puissants sont liées à l’exclusion, la gouvernementalité, la mobilité, et la production des espaces, des lieux et des territoires. Il constate que, si les trajectoires de migration de la plupart des survivants ont été confinés à l'intérieur des limites de la ville, les expériences de ces survivants et leur utilisation des espaces urbains sont très différentes. Ces différences peuvent être expliquées par des structures politiques, économiques, et sociales, et par les différences religieuses, économiques, et de genre. En outre, il fait valoir que les espaces post-catastrophe doivent être considérés comme des «espaces d’exclusion» où les fiduciaires exercent une rationalité gouvernementale. C’est-à-dire, les espaces post-catastrophe prétendument inclusives servent à marginaliser davantage les populations vulnérables. Ces espaces offrent aussi des occasions pour les acteurs puissants dans la société philippine d'effectuer des interventions gouvernementales dans lesquelles certaines personnes et les paysages sont simplifiées, rendues lisibles, et améliorés.

Does the Pareto Distribution of Hurricane Damage Inherit its Fat Tail from a Zipf Distribution of Assets at Hazard?

Tropical Cyclones are a continuing threat to life and property. Willoughby (2012) found that a Pareto (power-law) cumulative distribution fitted to the most damaging 10% of US hurricane seasons fit their impacts well. Here, we find that damage follows a Pareto distribution because the assets at hazard follow a Zipf distribution, which can be thought of as a Pareto distribution with exponent 1. The Z-CAT model is an idealized hurricane catastrophe model that represents a coastline where populated places with Zipf- distributed assets are randomly scattered and damaged by virtual hurricanes with sizes and intensities generated through a Monte-Carlo process. Results produce realistic Pareto exponents. The ability of the Z-CAT model to simulate different climate scenarios allowed testing of sensitivities to Maximum Potential Intensity, landfall rates and building structure vulnerability. The Z-CAT model results demonstrate that a statistical significant difference in damage is found when only changes in the parameters create a doubling of damage.

Arte después de la inundación : Dos casos de procesamiento de la dislocación después de la catástrofe

Se analiza una inundación en Argentina y las respuestas desde colectivos artísticos. Se tomaron dos casos comparativamente, "La marca del agua" y "Volver a habitar", ;para observar las diferencias de las intervenciones poscatástrofe. La hermenéutica de la teoría del discurso permitió ajustar la metodología, indagando sobre las formas de procesamiento de la dislocación desde las prácticas, textos lingüísticos y obras de arte. Las intervenciones de carácter antagónico variaron su significación producto del ;contexto en el que se insertaron, mientras las que se orientaron a la reconstrucción de la catástrofe potenciaron relaciones de solidaridad y amistad

Arte después de la inundación : Dos casos de procesamiento de la dislocación después de la catástrofe

Se analiza una inundación en Argentina y las respuestas desde colectivos artísticos. Se tomaron dos casos comparativamente, "La marca del agua" y "Volver a habitar", ;para observar las diferencias de las intervenciones poscatástrofe. La hermenéutica de la teoría del discurso permitió ajustar la metodología, indagando sobre las formas de procesamiento de la dislocación desde las prácticas, textos lingüísticos y obras de arte. Las intervenciones de carácter antagónico variaron su significación producto del ;contexto en el que se insertaron, mientras las que se orientaron a la reconstrucción de la catástrofe potenciaron relaciones de solidaridad y amistad

Arte después de la inundación : Dos casos de procesamiento de la dislocación después de la catástrofe

Se analiza una inundación en Argentina y las respuestas desde colectivos artísticos. Se tomaron dos casos comparativamente, "La marca del agua" y "Volver a habitar", ;para observar las diferencias de las intervenciones poscatástrofe. La hermenéutica de la teoría del discurso permitió ajustar la metodología, indagando sobre las formas de procesamiento de la dislocación desde las prácticas, textos lingüísticos y obras de arte. Las intervenciones de carácter antagónico variaron su significación producto del ;contexto en el que se insertaron, mientras las que se orientaron a la reconstrucción de la catástrofe potenciaron relaciones de solidaridad y amistad